KR20230064910A - Use of platelet activating factor as a biomarker for determining persistancy of food allergy - Google Patents
Use of platelet activating factor as a biomarker for determining persistancy of food allergy Download PDFInfo
- Publication number
- KR20230064910A KR20230064910A KR1020210150519A KR20210150519A KR20230064910A KR 20230064910 A KR20230064910 A KR 20230064910A KR 1020210150519 A KR1020210150519 A KR 1020210150519A KR 20210150519 A KR20210150519 A KR 20210150519A KR 20230064910 A KR20230064910 A KR 20230064910A
- Authority
- KR
- South Korea
- Prior art keywords
- food allergy
- activating factor
- platelet activating
- allergy
- paf
- Prior art date
Links
- 206010016946 Food allergy Diseases 0.000 title claims abstract description 231
- 208000004262 Food Hypersensitivity Diseases 0.000 title claims abstract description 228
- 235000020932 food allergy Nutrition 0.000 title claims abstract description 228
- HVAUUPRFYPCOCA-AREMUKBSSA-N 2-O-acetyl-1-O-hexadecyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCOC[C@@H](OC(C)=O)COP([O-])(=O)OCC[N+](C)(C)C HVAUUPRFYPCOCA-AREMUKBSSA-N 0.000 title claims abstract description 109
- 108010003541 Platelet Activating Factor Proteins 0.000 title claims abstract description 108
- 239000000090 biomarker Substances 0.000 title description 6
- 230000002688 persistence Effects 0.000 claims abstract description 31
- 108010024976 Asparaginase Proteins 0.000 claims description 60
- 102100031538 Phosphatidylcholine-sterol acyltransferase Human genes 0.000 claims description 60
- 230000000694 effects Effects 0.000 claims description 29
- 238000000034 method Methods 0.000 claims description 23
- 210000002966 serum Anatomy 0.000 claims description 23
- 108090000623 proteins and genes Proteins 0.000 claims description 18
- 238000002360 preparation method Methods 0.000 claims description 17
- 238000002965 ELISA Methods 0.000 claims description 16
- 239000012530 fluid Substances 0.000 claims description 16
- 208000004739 Egg Hypersensitivity Diseases 0.000 claims description 15
- 239000000203 mixture Substances 0.000 claims description 15
- 201000010860 egg allergy Diseases 0.000 claims description 14
- 206010020751 Hypersensitivity Diseases 0.000 claims description 13
- 208000026935 allergic disease Diseases 0.000 claims description 13
- 239000003795 chemical substances by application Substances 0.000 claims description 12
- 238000004587 chromatography analysis Methods 0.000 claims description 12
- 230000007815 allergy Effects 0.000 claims description 11
- 102000004169 proteins and genes Human genes 0.000 claims description 10
- 238000004949 mass spectrometry Methods 0.000 claims description 7
- 210000004369 blood Anatomy 0.000 claims description 5
- 239000008280 blood Substances 0.000 claims description 5
- 230000002860 competitive effect Effects 0.000 claims description 5
- 238000007398 colorimetric assay Methods 0.000 claims description 4
- 206010003445 Ascites Diseases 0.000 claims description 3
- 206010036790 Productive cough Diseases 0.000 claims description 3
- 210000004381 amniotic fluid Anatomy 0.000 claims description 3
- 210000001175 cerebrospinal fluid Anatomy 0.000 claims description 3
- 238000004737 colorimetric analysis Methods 0.000 claims description 3
- 208000012106 cystic neoplasm Diseases 0.000 claims description 3
- 235000020256 human milk Nutrition 0.000 claims description 3
- 210000004251 human milk Anatomy 0.000 claims description 3
- 238000003119 immunoblot Methods 0.000 claims description 3
- 238000011532 immunohistochemical staining Methods 0.000 claims description 3
- 210000004880 lymph fluid Anatomy 0.000 claims description 3
- 210000003097 mucus Anatomy 0.000 claims description 3
- 210000002445 nipple Anatomy 0.000 claims description 3
- 210000002381 plasma Anatomy 0.000 claims description 3
- 210000004910 pleural fluid Anatomy 0.000 claims description 3
- 210000003296 saliva Anatomy 0.000 claims description 3
- 210000000582 semen Anatomy 0.000 claims description 3
- 210000004911 serous fluid Anatomy 0.000 claims description 3
- 210000003802 sputum Anatomy 0.000 claims description 3
- 208000024794 sputum Diseases 0.000 claims description 3
- 210000001138 tear Anatomy 0.000 claims description 3
- 210000002700 urine Anatomy 0.000 claims description 3
- 238000001114 immunoprecipitation Methods 0.000 claims 1
- 210000004324 lymphatic system Anatomy 0.000 claims 1
- 238000003745 diagnosis Methods 0.000 abstract description 23
- 239000003550 marker Substances 0.000 abstract description 7
- 230000002503 metabolic effect Effects 0.000 abstract description 3
- 230000008901 benefit Effects 0.000 abstract description 2
- 239000002207 metabolite Substances 0.000 description 40
- 239000000523 sample Substances 0.000 description 18
- RYCNUMLMNKHWPZ-SNVBAGLBSA-N 1-acetyl-sn-glycero-3-phosphocholine Chemical compound CC(=O)OC[C@@H](O)COP([O-])(=O)OCC[N+](C)(C)C RYCNUMLMNKHWPZ-SNVBAGLBSA-N 0.000 description 16
- 235000013601 eggs Nutrition 0.000 description 16
- WRGQSWVCFNIUNZ-GDCKJWNLSA-N 1-oleoyl-sn-glycerol 3-phosphate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](O)COP(O)(O)=O WRGQSWVCFNIUNZ-GDCKJWNLSA-N 0.000 description 14
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 description 14
- PGLIUCLTXOYQMV-UHFFFAOYSA-N Cetirizine hydrochloride Chemical compound Cl.Cl.C1CN(CCOCC(=O)O)CCN1C(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 PGLIUCLTXOYQMV-UHFFFAOYSA-N 0.000 description 13
- MEFKEPWMEQBLKI-AIRLBKTGSA-O S-adenosyl-L-methionine Chemical compound O[C@@H]1[C@H](O)[C@@H](C[S+](CC[C@H]([NH3+])C([O-])=O)C)O[C@H]1N1C2=NC=NC(N)=C2N=C1 MEFKEPWMEQBLKI-AIRLBKTGSA-O 0.000 description 13
- 101001064282 Homo sapiens Platelet-activating factor acetylhydrolase IB subunit beta Proteins 0.000 description 12
- 102100030655 Platelet-activating factor acetylhydrolase IB subunit beta Human genes 0.000 description 12
- 238000004458 analytical method Methods 0.000 description 10
- 238000002705 metabolomic analysis Methods 0.000 description 10
- 208000024891 symptom Diseases 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 230000001431 metabolomic effect Effects 0.000 description 9
- 235000013336 milk Nutrition 0.000 description 9
- 239000008267 milk Substances 0.000 description 9
- 210000004080 milk Anatomy 0.000 description 9
- 230000002085 persistent effect Effects 0.000 description 9
- LMKIIOSMODSXGM-UHFFFAOYSA-N 2-hydroxydocosa-2,4,6,8,10,12-hexaenoic acid Chemical compound CCCCCCCCCC=CC=CC=CC=CC=CC=C(O)C(O)=O LMKIIOSMODSXGM-UHFFFAOYSA-N 0.000 description 8
- 108700028369 Alleles Proteins 0.000 description 8
- JZNWSCPGTDBMEW-UHFFFAOYSA-N Glycerophosphorylethanolamin Natural products NCCOP(O)(=O)OCC(O)CO JZNWSCPGTDBMEW-UHFFFAOYSA-N 0.000 description 8
- CWRILEGKIAOYKP-SSDOTTSWSA-M [(2r)-3-acetyloxy-2-hydroxypropyl] 2-aminoethyl phosphate Chemical compound CC(=O)OC[C@@H](O)COP([O-])(=O)OCCN CWRILEGKIAOYKP-SSDOTTSWSA-M 0.000 description 8
- 239000012634 fragment Substances 0.000 description 8
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 8
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 6
- 206010012438 Dermatitis atopic Diseases 0.000 description 6
- 241000282414 Homo sapiens Species 0.000 description 6
- 201000008937 atopic dermatitis Diseases 0.000 description 6
- 235000013305 food Nutrition 0.000 description 6
- 150000002305 glucosylceramides Chemical class 0.000 description 6
- 239000013615 primer Substances 0.000 description 6
- 239000002987 primer (paints) Substances 0.000 description 6
- 238000003757 reverse transcription PCR Methods 0.000 description 6
- 238000000018 DNA microarray Methods 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 238000009396 hybridization Methods 0.000 description 5
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 5
- 238000003908 quality control method Methods 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- ZPDQFUYPBVXUKS-YADHBBJMSA-N 1-stearoyl-sn-glycero-3-phosphoserine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@@H](O)COP(O)(=O)OC[C@H](N)C(O)=O ZPDQFUYPBVXUKS-YADHBBJMSA-N 0.000 description 4
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 4
- 244000105624 Arachis hypogaea Species 0.000 description 4
- 238000008157 ELISA kit Methods 0.000 description 4
- 102000004190 Enzymes Human genes 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
- 108060003951 Immunoglobulin Proteins 0.000 description 4
- 239000000427 antigen Substances 0.000 description 4
- 108091007433 antigens Proteins 0.000 description 4
- 102000036639 antigens Human genes 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 235000019253 formic acid Nutrition 0.000 description 4
- PFJKOHUKELZMLE-VEUXDRLPSA-N ganglioside GM3 Chemical compound O[C@@H]1[C@@H](O)[C@H](OC[C@@H]([C@H](O)/C=C/CCCCCCCCCCCCC)NC(=O)CCCCCCCCCCCCC\C=C/CCCCCCCC)O[C@H](CO)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@]2(O[C@H]([C@H](NC(C)=O)[C@@H](O)C2)[C@H](O)[C@H](O)CO)C(O)=O)[C@@H](O)[C@@H](CO)O1 PFJKOHUKELZMLE-VEUXDRLPSA-N 0.000 description 4
- 102000018358 immunoglobulin Human genes 0.000 description 4
- 239000002773 nucleotide Substances 0.000 description 4
- 125000003729 nucleotide group Chemical group 0.000 description 4
- 235000020660 omega-3 fatty acid Nutrition 0.000 description 4
- 235000020232 peanut Nutrition 0.000 description 4
- YBYRMVIVWMBXKQ-UHFFFAOYSA-N phenylmethanesulfonyl fluoride Chemical compound FS(=O)(=O)CC1=CC=CC=C1 YBYRMVIVWMBXKQ-UHFFFAOYSA-N 0.000 description 4
- 238000011002 quantification Methods 0.000 description 4
- 238000007637 random forest analysis Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 206010002198 Anaphylactic reaction Diseases 0.000 description 3
- 108091023037 Aptamer Proteins 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 241000880493 Leptailurus serval Species 0.000 description 3
- 238000000585 Mann–Whitney U test Methods 0.000 description 3
- 108091034117 Oligonucleotide Proteins 0.000 description 3
- 238000009004 PCR Kit Methods 0.000 description 3
- YQHZVYJAGWMHES-ZLUOBGJFSA-N Ser-Ala-Ser Chemical compound OC[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(O)=O YQHZVYJAGWMHES-ZLUOBGJFSA-N 0.000 description 3
- 238000000692 Student's t-test Methods 0.000 description 3
- 241000209140 Triticum Species 0.000 description 3
- 235000021307 Triticum Nutrition 0.000 description 3
- 238000001790 Welch's t-test Methods 0.000 description 3
- 239000013566 allergen Substances 0.000 description 3
- 230000000172 allergic effect Effects 0.000 description 3
- 150000001413 amino acids Chemical group 0.000 description 3
- 230000036783 anaphylactic response Effects 0.000 description 3
- 208000003455 anaphylaxis Diseases 0.000 description 3
- 208000010668 atopic eczema Diseases 0.000 description 3
- 229960000074 biopharmaceutical Drugs 0.000 description 3
- 229960002685 biotin Drugs 0.000 description 3
- 235000020958 biotin Nutrition 0.000 description 3
- 239000011616 biotin Substances 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 238000000546 chi-square test Methods 0.000 description 3
- 230000002596 correlated effect Effects 0.000 description 3
- 238000009826 distribution Methods 0.000 description 3
- 238000004817 gas chromatography Methods 0.000 description 3
- 238000003205 genotyping method Methods 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 238000000506 liquid--solid chromatography Methods 0.000 description 3
- 238000010239 partial least squares discriminant analysis Methods 0.000 description 3
- 108091033319 polynucleotide Proteins 0.000 description 3
- 239000002157 polynucleotide Substances 0.000 description 3
- 102000040430 polynucleotide Human genes 0.000 description 3
- 230000000770 proinflammatory effect Effects 0.000 description 3
- YIBNHAJFJUQSRA-YNNPMVKQSA-N prostaglandin H2 Chemical compound C1[C@@H]2OO[C@H]1[C@H](/C=C/[C@@H](O)CCCCC)[C@H]2C\C=C/CCCC(O)=O YIBNHAJFJUQSRA-YNNPMVKQSA-N 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- OTKJDMGTUTTYMP-ZWKOTPCHSA-N sphinganine Chemical compound CCCCCCCCCCCCCCC[C@@H](O)[C@@H](N)CO OTKJDMGTUTTYMP-ZWKOTPCHSA-N 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- 230000009885 systemic effect Effects 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 238000004809 thin layer chromatography Methods 0.000 description 3
- 108010061238 threonyl-glycine Proteins 0.000 description 3
- XNRNNGPBEPRNAR-JQBLCGNGSA-N thromboxane B2 Chemical compound CCCCC[C@H](O)\C=C\[C@H]1OC(O)C[C@H](O)[C@@H]1C\C=C/CCCC(O)=O XNRNNGPBEPRNAR-JQBLCGNGSA-N 0.000 description 3
- WWUZIQQURGPMPG-UHFFFAOYSA-N (-)-D-erythro-Sphingosine Natural products CCCCCCCCCCCCCC=CC(O)C(N)CO WWUZIQQURGPMPG-UHFFFAOYSA-N 0.000 description 2
- 108020005065 3' Flanking Region Proteins 0.000 description 2
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 description 2
- 108010013043 Acetylesterase Proteins 0.000 description 2
- DONWIPDSZZJHHK-HJGDQZAQSA-N Asp-Lys-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC(=O)O)N)O DONWIPDSZZJHHK-HJGDQZAQSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 102000016911 Deoxyribonucleases Human genes 0.000 description 2
- 108010053770 Deoxyribonucleases Proteins 0.000 description 2
- PJBVXVBTTFZPHJ-GUBZILKMSA-N Glu-Leu-Asp Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)O)NC(=O)[C@H](CCC(=O)O)N PJBVXVBTTFZPHJ-GUBZILKMSA-N 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 102100034343 Integrase Human genes 0.000 description 2
- 108010044467 Isoenzymes Proteins 0.000 description 2
- PMGDADKJMCOXHX-UHFFFAOYSA-N L-Arginyl-L-glutamin-acetat Natural products NC(=N)NCCCC(N)C(=O)NC(CCC(N)=O)C(O)=O PMGDADKJMCOXHX-UHFFFAOYSA-N 0.000 description 2
- LZDNBBYBDGBADK-UHFFFAOYSA-N L-valyl-L-tryptophan Natural products C1=CC=C2C(CC(NC(=O)C(N)C(C)C)C(O)=O)=CNC2=C1 LZDNBBYBDGBADK-UHFFFAOYSA-N 0.000 description 2
- BQSLGJHIAGOZCD-CIUDSAMLSA-N Leu-Ala-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(O)=O BQSLGJHIAGOZCD-CIUDSAMLSA-N 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- -1 MgCl 2 Chemical compound 0.000 description 2
- YBAFDPFAUTYYRW-UHFFFAOYSA-N N-L-alpha-glutamyl-L-leucine Natural products CC(C)CC(C(O)=O)NC(=O)C(N)CCC(O)=O YBAFDPFAUTYYRW-UHFFFAOYSA-N 0.000 description 2
- FXGIMYRVJJEIIM-UWVGGRQHSA-N Pro-Leu-Gly Chemical compound OC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@@H]1CCCN1 FXGIMYRVJJEIIM-UWVGGRQHSA-N 0.000 description 2
- 208000009144 Pure autonomic failure Diseases 0.000 description 2
- 108010092799 RNA-directed DNA polymerase Proteins 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 108010006785 Taq Polymerase Proteins 0.000 description 2
- 102000004142 Trypsin Human genes 0.000 description 2
- 108090000631 Trypsin Proteins 0.000 description 2
- 208000024780 Urticaria Diseases 0.000 description 2
- KISFXYYRKKNLOP-IHRRRGAJSA-N Val-Phe-Ser Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(=O)O)N KISFXYYRKKNLOP-IHRRRGAJSA-N 0.000 description 2
- 108010041407 alanylaspartic acid Proteins 0.000 description 2
- KOSRFJWDECSPRO-UHFFFAOYSA-N alpha-L-glutamyl-L-glutamic acid Natural products OC(=O)CCC(N)C(=O)NC(CCC(O)=O)C(O)=O KOSRFJWDECSPRO-UHFFFAOYSA-N 0.000 description 2
- YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 description 2
- 108010008355 arginyl-glutamine Proteins 0.000 description 2
- 238000012098 association analyses Methods 0.000 description 2
- WPIHMWBQRSAMDE-YCZTVTEBSA-N beta-D-galactosyl-(1->4)-beta-D-galactosyl-N-(pentacosanoyl)sphingosine Chemical compound CCCCCCCCCCCCCCCCCCCCCCCCC(=O)N[C@@H](CO[C@@H]1O[C@H](CO)[C@H](O[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)[C@H](O)[C@H]1O)[C@H](O)\C=C\CCCCCCCCCCCCC WPIHMWBQRSAMDE-YCZTVTEBSA-N 0.000 description 2
- 210000001124 body fluid Anatomy 0.000 description 2
- 239000010839 body fluid Substances 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 238000010219 correlation analysis Methods 0.000 description 2
- 238000002790 cross-validation Methods 0.000 description 2
- 238000007405 data analysis Methods 0.000 description 2
- 235000005911 diet Nutrition 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000013568 food allergen Substances 0.000 description 2
- 235000021588 free fatty acids Nutrition 0.000 description 2
- 238000000574 gas--solid chromatography Methods 0.000 description 2
- 238000001641 gel filtration chromatography Methods 0.000 description 2
- 238000005227 gel permeation chromatography Methods 0.000 description 2
- 108010055341 glutamyl-glutamic acid Proteins 0.000 description 2
- 108010050848 glycylleucine Proteins 0.000 description 2
- 238000003364 immunohistochemistry Methods 0.000 description 2
- 238000004255 ion exchange chromatography Methods 0.000 description 2
- 238000004460 liquid liquid chromatography Methods 0.000 description 2
- 230000001926 lymphatic effect Effects 0.000 description 2
- 108010009298 lysylglutamic acid Proteins 0.000 description 2
- 108010054155 lysyllysine Proteins 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 238000001840 matrix-assisted laser desorption--ionisation time-of-flight mass spectrometry Methods 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 238000002552 multiple reaction monitoring Methods 0.000 description 2
- 238000004816 paper chromatography Methods 0.000 description 2
- 150000003904 phospholipids Chemical class 0.000 description 2
- 239000013312 porous aromatic framework Substances 0.000 description 2
- 230000002797 proteolythic effect Effects 0.000 description 2
- 239000011535 reaction buffer Substances 0.000 description 2
- 239000003161 ribonuclease inhibitor Substances 0.000 description 2
- 238000004062 sedimentation Methods 0.000 description 2
- 150000003408 sphingolipids Chemical class 0.000 description 2
- WWUZIQQURGPMPG-KRWOKUGFSA-N sphingosine Chemical compound CCCCCCCCCCCCC\C=C\[C@@H](O)[C@@H](N)CO WWUZIQQURGPMPG-KRWOKUGFSA-N 0.000 description 2
- 239000008223 sterile water Substances 0.000 description 2
- 238000012353 t test Methods 0.000 description 2
- 239000012588 trypsin Substances 0.000 description 2
- SWTYBBUBEPPYCX-VIIQGJSXSA-N (4Z,7Z,10Z,13Z,15E,19Z)-17-hydroxydocosahexaenoic acid Chemical compound CC\C=C/CC(O)\C=C\C=C/C\C=C/C\C=C/C\C=C/CCC(O)=O SWTYBBUBEPPYCX-VIIQGJSXSA-N 0.000 description 1
- SEVOKGDVLLIUMT-SKSHMZPZSA-N (4Z,7Z,10Z,14E,16Z,19Z)-13-hydroxydocosahexaenoic acid Chemical compound CC\C=C/C\C=C/C=C/C(O)C\C=C/C\C=C/C\C=C/CCC(O)=O SEVOKGDVLLIUMT-SKSHMZPZSA-N 0.000 description 1
- OZXAIGIRPOOJTI-XJAVJPOHSA-N (4Z,8E,10Z,13Z,16Z,19Z)-7-hydroxydocosahexaenoic acid Chemical compound CC\C=C/C\C=C/C\C=C/C\C=C/C=C/C(O)C\C=C/CCC(O)=O OZXAIGIRPOOJTI-XJAVJPOHSA-N 0.000 description 1
- KFINXCASWPGHEW-UHFFFAOYSA-N (9S*,10R*,11R*,12Z,15Z)-9,10,11-trihydroxyoctadeca-12,15-dienoic acid Natural products CCC=CCC=CC(O)C(O)C(O)CCCCCCCC(O)=O KFINXCASWPGHEW-UHFFFAOYSA-N 0.000 description 1
- RBXXJOPBVLMRSZ-RTWAWAEBSA-N 1-heptadecanoyl-sn-glycero-3-phosphoserine Chemical compound CCCCCCCCCCCCCCCCC(=O)OC[C@@H](O)COP(O)(=O)OC[C@H](N)C(O)=O RBXXJOPBVLMRSZ-RTWAWAEBSA-N 0.000 description 1
- HEQMDGOBDIGJOC-XMMPIXPASA-N 1-icosanoyl-sn-glycero-3-phosphoethanolamine Chemical compound CCCCCCCCCCCCCCCCCCCC(=O)OC[C@@H](O)COP(O)(=O)OCCN HEQMDGOBDIGJOC-XMMPIXPASA-N 0.000 description 1
- VXUOFDJKYGDUJI-OAQYLSRUSA-N 1-myristoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCC(=O)OC[C@@H](O)COP([O-])(=O)OCC[N+](C)(C)C VXUOFDJKYGDUJI-OAQYLSRUSA-N 0.000 description 1
- DDCYKEYDTGCKAS-SKSHMZPZSA-N 10-HDoHE Chemical compound CC\C=C/C\C=C/C\C=C/C=C/C(O)C\C=C/C\C=C/CCC(O)=O DDCYKEYDTGCKAS-SKSHMZPZSA-N 0.000 description 1
- ZNHVWPKMFKADKW-UHFFFAOYSA-N 12-HETE Chemical compound CCCCCC=CCC(O)C=CC=CCC=CCCCC(O)=O ZNHVWPKMFKADKW-UHFFFAOYSA-N 0.000 description 1
- ZNHVWPKMFKADKW-ZYBDYUKJSA-N 12-HETE Natural products CCCCC\C=C/C[C@@H](O)\C=C\C=C/C\C=C/CCCC(O)=O ZNHVWPKMFKADKW-ZYBDYUKJSA-N 0.000 description 1
- JQTSFVHRPKVILF-UHFFFAOYSA-N 2,3-dihydroxyicosa-2,4,6,8-tetraenoic acid Chemical compound CCCCCCCCCCCC=CC=CC=CC(O)=C(O)C(O)=O JQTSFVHRPKVILF-UHFFFAOYSA-N 0.000 description 1
- ZMHRXVSSWJALGN-GOGKNFEWSA-N 2-(4Z,7Z,10Z,13Z,16Z-docosapentaenoyl)-sn-glycero-3-phosphoethanolamine Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CCC(=O)O[C@H](CO)COP(O)(=O)OCCN ZMHRXVSSWJALGN-GOGKNFEWSA-N 0.000 description 1
- FJDVENKXPUIXRG-WMTBOZPISA-N 2-[(5Z,8Z,11Z)-icosatrienoyl]-sn-glycero-3-phosphoethanolamine Chemical compound CCCCCCCC\C=C/C\C=C/C\C=C/CCCC(=O)O[C@H](CO)COP(O)(=O)OCCN FJDVENKXPUIXRG-WMTBOZPISA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- NNDIXBJHNLFJJP-UHFFFAOYSA-N 20-Hydroxyeicosatetraenoic acid Chemical compound OCCCCCC=CCC=CCC=CCC=CCCCC(O)=O NNDIXBJHNLFJJP-UHFFFAOYSA-N 0.000 description 1
- UAIUNKRWKOVEES-UHFFFAOYSA-N 3,3',5,5'-tetramethylbenzidine Chemical compound CC1=C(N)C(C)=CC(C=2C=C(C)C(N)=C(C)C=2)=C1 UAIUNKRWKOVEES-UHFFFAOYSA-N 0.000 description 1
- UXGXCGPWGSUMNI-BVHTXILBSA-N 5(S),15(S)-DiHETE Chemical compound CCCCC[C@H](O)\C=C\C=C/C\C=C/C=C/[C@@H](O)CCCC(O)=O UXGXCGPWGSUMNI-BVHTXILBSA-N 0.000 description 1
- 208000004998 Abdominal Pain Diseases 0.000 description 1
- MBWYUTNBYSSUIQ-HERUPUMHSA-N Ala-Asn-Trp Chemical compound C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)O)N MBWYUTNBYSSUIQ-HERUPUMHSA-N 0.000 description 1
- GGNHBHYDMUDXQB-KBIXCLLPSA-N Ala-Glu-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)N GGNHBHYDMUDXQB-KBIXCLLPSA-N 0.000 description 1
- GRPHQEMIFDPKOE-HGNGGELXSA-N Ala-His-Glu Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CCC(O)=O)C(O)=O GRPHQEMIFDPKOE-HGNGGELXSA-N 0.000 description 1
- XCZXVTHYGSMQGH-NAKRPEOUSA-N Ala-Ile-Met Chemical compound C[C@H]([NH3+])C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCSC)C([O-])=O XCZXVTHYGSMQGH-NAKRPEOUSA-N 0.000 description 1
- SOBIAADAMRHGKH-CIUDSAMLSA-N Ala-Leu-Ser Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O SOBIAADAMRHGKH-CIUDSAMLSA-N 0.000 description 1
- IORKCNUBHNIMKY-CIUDSAMLSA-N Ala-Pro-Glu Chemical compound C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(O)=O IORKCNUBHNIMKY-CIUDSAMLSA-N 0.000 description 1
- AUFACLFHBAGZEN-ZLUOBGJFSA-N Ala-Ser-Cys Chemical compound N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CS)C(=O)O AUFACLFHBAGZEN-ZLUOBGJFSA-N 0.000 description 1
- PEEYDECOOVQKRZ-DLOVCJGASA-N Ala-Ser-Phe Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O PEEYDECOOVQKRZ-DLOVCJGASA-N 0.000 description 1
- CREYEAPXISDKSB-FQPOAREZSA-N Ala-Thr-Tyr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O CREYEAPXISDKSB-FQPOAREZSA-N 0.000 description 1
- 208000028185 Angioedema Diseases 0.000 description 1
- PEFFAAKJGBZBKL-NAKRPEOUSA-N Arg-Ala-Ile Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O PEFFAAKJGBZBKL-NAKRPEOUSA-N 0.000 description 1
- VBFJESQBIWCWRL-DCAQKATOSA-N Arg-Ala-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCCNC(N)=N VBFJESQBIWCWRL-DCAQKATOSA-N 0.000 description 1
- RVDVDRUZWZIBJQ-CIUDSAMLSA-N Arg-Asn-Glu Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O RVDVDRUZWZIBJQ-CIUDSAMLSA-N 0.000 description 1
- XVLLUZMFSAYKJV-GUBZILKMSA-N Arg-Asp-Arg Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O XVLLUZMFSAYKJV-GUBZILKMSA-N 0.000 description 1
- SQKPKIJVWHAWNF-DCAQKATOSA-N Arg-Asp-Lys Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(O)=O SQKPKIJVWHAWNF-DCAQKATOSA-N 0.000 description 1
- QAXCZGMLVICQKS-SRVKXCTJSA-N Arg-Glu-His Chemical compound C1=C(NC=N1)C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CCCN=C(N)N)N QAXCZGMLVICQKS-SRVKXCTJSA-N 0.000 description 1
- JQFJNGVSGOUQDH-XIRDDKMYSA-N Arg-Glu-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCN=C(N)N)N)C(O)=O)=CNC2=C1 JQFJNGVSGOUQDH-XIRDDKMYSA-N 0.000 description 1
- PNIGSVZJNVUVJA-BQBZGAKWSA-N Arg-Gly-Asn Chemical compound NC(N)=NCCC[C@H](N)C(=O)NCC(=O)N[C@@H](CC(N)=O)C(O)=O PNIGSVZJNVUVJA-BQBZGAKWSA-N 0.000 description 1
- PZBSKYJGKNNYNK-ULQDDVLXSA-N Arg-Leu-Tyr Chemical compound CC(C)C[C@H](NC(=O)[C@@H](N)CCCN=C(N)N)C(=O)N[C@@H](Cc1ccc(O)cc1)C(O)=O PZBSKYJGKNNYNK-ULQDDVLXSA-N 0.000 description 1
- HNJNAMGZQZPSRE-GUBZILKMSA-N Arg-Pro-Asn Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(N)=O)C(O)=O HNJNAMGZQZPSRE-GUBZILKMSA-N 0.000 description 1
- YCYXHLZRUSJITQ-SRVKXCTJSA-N Arg-Pro-Pro Chemical compound NC(=N)NCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(O)=O)CCC1 YCYXHLZRUSJITQ-SRVKXCTJSA-N 0.000 description 1
- AMIQZQAAYGYKOP-FXQIFTODSA-N Arg-Ser-Asn Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(O)=O AMIQZQAAYGYKOP-FXQIFTODSA-N 0.000 description 1
- RYQSYXFGFOTJDJ-RHYQMDGZSA-N Arg-Thr-Leu Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O RYQSYXFGFOTJDJ-RHYQMDGZSA-N 0.000 description 1
- JKRPBTQDPJSQIT-RCWTZXSCSA-N Arg-Thr-Met Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCSC)C(=O)O)NC(=O)[C@H](CCCN=C(N)N)N)O JKRPBTQDPJSQIT-RCWTZXSCSA-N 0.000 description 1
- FMYQECOAIFGQGU-CYDGBPFRSA-N Arg-Val-Ile Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O FMYQECOAIFGQGU-CYDGBPFRSA-N 0.000 description 1
- UTSMXMABBPFVJP-SZMVWBNQSA-N Arg-Val-Trp Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)O)NC(=O)[C@H](CCCN=C(N)N)N UTSMXMABBPFVJP-SZMVWBNQSA-N 0.000 description 1
- XYOVHPDDWCEUDY-CIUDSAMLSA-N Asn-Ala-Leu Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(O)=O XYOVHPDDWCEUDY-CIUDSAMLSA-N 0.000 description 1
- SJPZTWAYTJPPBI-GUBZILKMSA-N Asn-Gln-His Chemical compound C1=C(NC=N1)C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CC(=O)N)N SJPZTWAYTJPPBI-GUBZILKMSA-N 0.000 description 1
- SNAKIVFVLVUCKB-UHFFFAOYSA-N Asn-Glu-Ala-Lys Natural products NCCCCC(C(O)=O)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(N)CC(N)=O SNAKIVFVLVUCKB-UHFFFAOYSA-N 0.000 description 1
- YYSYDIYQTUPNQQ-SXTJYALSSA-N Asn-Ile-Ile Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O YYSYDIYQTUPNQQ-SXTJYALSSA-N 0.000 description 1
- GQRDIVQPSMPQME-ZPFDUUQYSA-N Asn-Ile-Leu Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(O)=O GQRDIVQPSMPQME-ZPFDUUQYSA-N 0.000 description 1
- RCFGLXMZDYNRSC-CIUDSAMLSA-N Asn-Lys-Ala Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(O)=O RCFGLXMZDYNRSC-CIUDSAMLSA-N 0.000 description 1
- ALHMNHZJBYBYHS-DCAQKATOSA-N Asn-Lys-Arg Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O ALHMNHZJBYBYHS-DCAQKATOSA-N 0.000 description 1
- FBODFHMLALOPHP-GUBZILKMSA-N Asn-Lys-Glu Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(O)=O FBODFHMLALOPHP-GUBZILKMSA-N 0.000 description 1
- CDGHMJJJHYKMPA-DLOVCJGASA-N Asn-Phe-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)NC(=O)[C@H](CC(=O)N)N CDGHMJJJHYKMPA-DLOVCJGASA-N 0.000 description 1
- VHQSGALUSWIYOD-QXEWZRGKSA-N Asn-Pro-Val Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C(C)C)C(O)=O VHQSGALUSWIYOD-QXEWZRGKSA-N 0.000 description 1
- HPNDKUOLNRVRAY-BIIVOSGPSA-N Asn-Ser-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CO)NC(=O)[C@H](CC(=O)N)N)C(=O)O HPNDKUOLNRVRAY-BIIVOSGPSA-N 0.000 description 1
- SNYCNNPOFYBCEK-ZLUOBGJFSA-N Asn-Ser-Ser Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O SNYCNNPOFYBCEK-ZLUOBGJFSA-N 0.000 description 1
- UXHYOWXTJLBEPG-GSSVUCPTSA-N Asn-Thr-Thr Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O UXHYOWXTJLBEPG-GSSVUCPTSA-N 0.000 description 1
- CBWCQCANJSGUOH-ZKWXMUAHSA-N Asn-Val-Ala Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C)C(O)=O CBWCQCANJSGUOH-ZKWXMUAHSA-N 0.000 description 1
- KVMPVNGOKHTUHZ-GCJQMDKQSA-N Asp-Ala-Thr Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O KVMPVNGOKHTUHZ-GCJQMDKQSA-N 0.000 description 1
- WSOKZUVWBXVJHX-CIUDSAMLSA-N Asp-Arg-Glu Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(O)=O WSOKZUVWBXVJHX-CIUDSAMLSA-N 0.000 description 1
- IXIWEFWRKIUMQX-DCAQKATOSA-N Asp-Arg-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@@H](N)CC(O)=O IXIWEFWRKIUMQX-DCAQKATOSA-N 0.000 description 1
- KIJLEFNHWSXHRU-NUMRIWBASA-N Asp-Gln-Thr Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O KIJLEFNHWSXHRU-NUMRIWBASA-N 0.000 description 1
- TVIZQBFURPLQDV-DJFWLOJKSA-N Asp-His-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CC1=CN=CN1)NC(=O)[C@H](CC(=O)O)N TVIZQBFURPLQDV-DJFWLOJKSA-N 0.000 description 1
- CJUKAWUWBZCTDQ-SRVKXCTJSA-N Asp-Leu-Lys Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(O)=O CJUKAWUWBZCTDQ-SRVKXCTJSA-N 0.000 description 1
- LKVKODXGSAFOFY-VEVYYDQMSA-N Asp-Met-Thr Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCSC)C(=O)N[C@@H]([C@@H](C)O)C(O)=O LKVKODXGSAFOFY-VEVYYDQMSA-N 0.000 description 1
- APXVSPGLYXFFSD-AJNGGQMLSA-N Asp-Phe-Asp-Gln Chemical compound NC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)N)CC1=CC=CC=C1 APXVSPGLYXFFSD-AJNGGQMLSA-N 0.000 description 1
- GWIJZUVQVDJHDI-AVGNSLFASA-N Asp-Phe-Glu Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CCC(O)=O)C(O)=O GWIJZUVQVDJHDI-AVGNSLFASA-N 0.000 description 1
- USNJAPJZSGTTPX-XVSYOHENSA-N Asp-Phe-Thr Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(O)=O USNJAPJZSGTTPX-XVSYOHENSA-N 0.000 description 1
- UAXIKORUDGGIGA-DCAQKATOSA-N Asp-Pro-Lys Chemical compound C1C[C@H](N(C1)C(=O)[C@H](CC(=O)O)N)C(=O)N[C@@H](CCCCN)C(=O)O UAXIKORUDGGIGA-DCAQKATOSA-N 0.000 description 1
- DRCOAZZDQRCGGP-GHCJXIJMSA-N Asp-Ser-Ile Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O DRCOAZZDQRCGGP-GHCJXIJMSA-N 0.000 description 1
- JSHWXQIZOCVWIA-ZKWXMUAHSA-N Asp-Ser-Val Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O JSHWXQIZOCVWIA-ZKWXMUAHSA-N 0.000 description 1
- JSNWZMFSLIWAHS-HJGDQZAQSA-N Asp-Thr-Leu Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)O)NC(=O)[C@H](CC(=O)O)N)O JSNWZMFSLIWAHS-HJGDQZAQSA-N 0.000 description 1
- NWAHPBGBDIFUFD-KKUMJFAQSA-N Asp-Tyr-Leu Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC(C)C)C(O)=O NWAHPBGBDIFUFD-KKUMJFAQSA-N 0.000 description 1
- BJDHEININLSZOT-KKUMJFAQSA-N Asp-Tyr-Lys Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCCCN)C(O)=O BJDHEININLSZOT-KKUMJFAQSA-N 0.000 description 1
- QOJJMJKTMKNFEF-ZKWXMUAHSA-N Asp-Val-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)CC(O)=O QOJJMJKTMKNFEF-ZKWXMUAHSA-N 0.000 description 1
- MZQXAWAWDWCIKG-SPSBLGDNSA-N Avenoleic acid Chemical compound CCC[C@@H](O)C\C=C/C\C=C/CCCCCCCC(O)=O MZQXAWAWDWCIKG-SPSBLGDNSA-N 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 101100279438 Caenorhabditis elegans egg-3 gene Proteins 0.000 description 1
- 101100279442 Caenorhabditis elegans egg-6 gene Proteins 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- 208000002881 Colic Diseases 0.000 description 1
- QFMCHXSGIZPBKG-ZLUOBGJFSA-N Cys-Ala-Asp Chemical compound C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)O)NC(=O)[C@H](CS)N QFMCHXSGIZPBKG-ZLUOBGJFSA-N 0.000 description 1
- URDUGPGPLNXXES-WHFBIAKZSA-N Cys-Gly-Cys Chemical compound SC[C@H](N)C(=O)NCC(=O)N[C@@H](CS)C(O)=O URDUGPGPLNXXES-WHFBIAKZSA-N 0.000 description 1
- VTBGVPWSWJBERH-DCAQKATOSA-N Cys-Leu-Met Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCSC)C(=O)O)NC(=O)[C@H](CS)N VTBGVPWSWJBERH-DCAQKATOSA-N 0.000 description 1
- ORYFTECKJZTNQP-DCAQKATOSA-N Cys-Met-Lys Chemical compound CSCC[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CS)N ORYFTECKJZTNQP-DCAQKATOSA-N 0.000 description 1
- CMYVIUWVYHOLRD-ZLUOBGJFSA-N Cys-Ser-Ala Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(O)=O CMYVIUWVYHOLRD-ZLUOBGJFSA-N 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- 208000031940 Disease Attributes Diseases 0.000 description 1
- 208000000059 Dyspnea Diseases 0.000 description 1
- 206010013975 Dyspnoeas Diseases 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 208000018522 Gastrointestinal disease Diseases 0.000 description 1
- KVYVOGYEMPEXBT-GUBZILKMSA-N Gln-Ala-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCC(N)=O KVYVOGYEMPEXBT-GUBZILKMSA-N 0.000 description 1
- YNNXQZDEOCYJJL-CIUDSAMLSA-N Gln-Arg-Asp Chemical compound C(C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)O)NC(=O)[C@H](CCC(=O)N)N)CN=C(N)N YNNXQZDEOCYJJL-CIUDSAMLSA-N 0.000 description 1
- QYTKAVBFRUGYAU-ACZMJKKPSA-N Gln-Asp-Asn Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O QYTKAVBFRUGYAU-ACZMJKKPSA-N 0.000 description 1
- WQWMZOIPXWSZNE-WDSKDSINSA-N Gln-Asp-Gly Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)NCC(O)=O WQWMZOIPXWSZNE-WDSKDSINSA-N 0.000 description 1
- CRRFJBGUGNNOCS-PEFMBERDSA-N Gln-Asp-Ile Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O CRRFJBGUGNNOCS-PEFMBERDSA-N 0.000 description 1
- VGTDBGYFVWOQTI-RYUDHWBXSA-N Gln-Gly-Phe Chemical compound NC(=O)CC[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 VGTDBGYFVWOQTI-RYUDHWBXSA-N 0.000 description 1
- IULKWYSYZSURJK-AVGNSLFASA-N Gln-Leu-Lys Chemical compound NC(=O)CC[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(O)=O IULKWYSYZSURJK-AVGNSLFASA-N 0.000 description 1
- GURIQZQSTBBHRV-SRVKXCTJSA-N Gln-Lys-Arg Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O GURIQZQSTBBHRV-SRVKXCTJSA-N 0.000 description 1
- KUBFPYIMAGXGBT-ACZMJKKPSA-N Gln-Ser-Ala Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(O)=O KUBFPYIMAGXGBT-ACZMJKKPSA-N 0.000 description 1
- AKDOUBMVLRCHBD-SIUGBPQLSA-N Gln-Tyr-Ile Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O AKDOUBMVLRCHBD-SIUGBPQLSA-N 0.000 description 1
- OACPJRQRAHMQEQ-NHCYSSNCSA-N Gln-Val-Arg Chemical compound NC(=O)CC[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O OACPJRQRAHMQEQ-NHCYSSNCSA-N 0.000 description 1
- FYBSCGZLICNOBA-XQXXSGGOSA-N Glu-Ala-Thr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O FYBSCGZLICNOBA-XQXXSGGOSA-N 0.000 description 1
- KBKGRMNVKPSQIF-XDTLVQLUSA-N Glu-Ala-Tyr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O KBKGRMNVKPSQIF-XDTLVQLUSA-N 0.000 description 1
- OJGLIOXAKGFFDW-SRVKXCTJSA-N Glu-Arg-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CCC(=O)O)N OJGLIOXAKGFFDW-SRVKXCTJSA-N 0.000 description 1
- ZOXBSICWUDAOHX-GUBZILKMSA-N Glu-Asn-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](N)CCC(O)=O ZOXBSICWUDAOHX-GUBZILKMSA-N 0.000 description 1
- VAIWPXWHWAPYDF-FXQIFTODSA-N Glu-Asp-Gln Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O VAIWPXWHWAPYDF-FXQIFTODSA-N 0.000 description 1
- XKPOCESCRTVRPL-KBIXCLLPSA-N Glu-Cys-Ile Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CS)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O XKPOCESCRTVRPL-KBIXCLLPSA-N 0.000 description 1
- KVBPDJIFRQUQFY-ACZMJKKPSA-N Glu-Cys-Ser Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CS)C(=O)N[C@@H](CO)C(O)=O KVBPDJIFRQUQFY-ACZMJKKPSA-N 0.000 description 1
- BUZMZDDKFCSKOT-CIUDSAMLSA-N Glu-Glu-Glu Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O BUZMZDDKFCSKOT-CIUDSAMLSA-N 0.000 description 1
- YLJHCWNDBKKOEB-IHRRRGAJSA-N Glu-Glu-Phe Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O YLJHCWNDBKKOEB-IHRRRGAJSA-N 0.000 description 1
- ZPASCJBSSCRWMC-GVXVVHGQSA-N Glu-His-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CC1=CN=CN1)NC(=O)[C@H](CCC(=O)O)N ZPASCJBSSCRWMC-GVXVVHGQSA-N 0.000 description 1
- VMKCPNBBPGGQBJ-GUBZILKMSA-N Glu-Leu-Asn Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CCC(=O)O)N VMKCPNBBPGGQBJ-GUBZILKMSA-N 0.000 description 1
- HRBYTAIBKPNZKQ-AVGNSLFASA-N Glu-Lys-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CCC(O)=O HRBYTAIBKPNZKQ-AVGNSLFASA-N 0.000 description 1
- AQNYKMCFCCZEEL-JYJNAYRXSA-N Glu-Lys-Tyr Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 AQNYKMCFCCZEEL-JYJNAYRXSA-N 0.000 description 1
- GPSHCSTUYOQPAI-JHEQGTHGSA-N Glu-Thr-Gly Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(O)=O GPSHCSTUYOQPAI-JHEQGTHGSA-N 0.000 description 1
- JVZLZVJTIXVIHK-SXNHZJKMSA-N Glu-Trp-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)NC(=O)[C@H](CCC(=O)O)N JVZLZVJTIXVIHK-SXNHZJKMSA-N 0.000 description 1
- QRWPTXLWHHTOCO-DZKIICNBSA-N Glu-Val-Tyr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O QRWPTXLWHHTOCO-DZKIICNBSA-N 0.000 description 1
- MZZSCEANQDPJER-ONGXEEELSA-N Gly-Ala-Phe Chemical compound NCC(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 MZZSCEANQDPJER-ONGXEEELSA-N 0.000 description 1
- QSDKBRMVXSWAQE-BFHQHQDPSA-N Gly-Ala-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)CN QSDKBRMVXSWAQE-BFHQHQDPSA-N 0.000 description 1
- FUTAPPOITCCWTH-WHFBIAKZSA-N Gly-Asp-Asp Chemical compound [H]NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O FUTAPPOITCCWTH-WHFBIAKZSA-N 0.000 description 1
- MHHUEAIBJZWDBH-YUMQZZPRSA-N Gly-Asp-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)CN MHHUEAIBJZWDBH-YUMQZZPRSA-N 0.000 description 1
- NPSWCZIRBAYNSB-JHEQGTHGSA-N Gly-Gln-Thr Chemical compound [H]NCC(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O NPSWCZIRBAYNSB-JHEQGTHGSA-N 0.000 description 1
- ZQIMMEYPEXIYBB-IUCAKERBSA-N Gly-Glu-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)CN ZQIMMEYPEXIYBB-IUCAKERBSA-N 0.000 description 1
- QITBQGJOXQYMOA-ZETCQYMHSA-N Gly-Gly-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)CNC(=O)CN QITBQGJOXQYMOA-ZETCQYMHSA-N 0.000 description 1
- TVDHVLGFJSHPAX-UWVGGRQHSA-N Gly-His-Arg Chemical compound NC(N)=NCCC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)CN)CC1=CN=CN1 TVDHVLGFJSHPAX-UWVGGRQHSA-N 0.000 description 1
- QSVMIMFAAZPCAQ-PMVVWTBXSA-N Gly-His-Thr Chemical compound [H]NCC(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H]([C@@H](C)O)C(O)=O QSVMIMFAAZPCAQ-PMVVWTBXSA-N 0.000 description 1
- SWQALSGKVLYKDT-ZKWXMUAHSA-N Gly-Ile-Ala Chemical compound NCC(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(O)=O SWQALSGKVLYKDT-ZKWXMUAHSA-N 0.000 description 1
- SWQALSGKVLYKDT-UHFFFAOYSA-N Gly-Ile-Ala Natural products NCC(=O)NC(C(C)CC)C(=O)NC(C)C(O)=O SWQALSGKVLYKDT-UHFFFAOYSA-N 0.000 description 1
- UTYGDAHJBBDPBA-BYULHYEWSA-N Gly-Ile-Asp Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)O)NC(=O)CN UTYGDAHJBBDPBA-BYULHYEWSA-N 0.000 description 1
- HKSNHPVETYYJBK-LAEOZQHASA-N Gly-Ile-Glu Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)O)NC(=O)CN HKSNHPVETYYJBK-LAEOZQHASA-N 0.000 description 1
- LIXWIUAORXJNBH-QWRGUYRKSA-N Gly-Leu-His Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)CN LIXWIUAORXJNBH-QWRGUYRKSA-N 0.000 description 1
- UHPAZODVFFYEEL-QWRGUYRKSA-N Gly-Leu-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)CN UHPAZODVFFYEEL-QWRGUYRKSA-N 0.000 description 1
- NNCSJUBVFBDDLC-YUMQZZPRSA-N Gly-Leu-Ser Chemical compound NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O NNCSJUBVFBDDLC-YUMQZZPRSA-N 0.000 description 1
- PTIIBFKSLCYQBO-NHCYSSNCSA-N Gly-Lys-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CCCCN)NC(=O)CN PTIIBFKSLCYQBO-NHCYSSNCSA-N 0.000 description 1
- WDEHMRNSGHVNOH-VHSXEESVSA-N Gly-Lys-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCCCN)NC(=O)CN)C(=O)O WDEHMRNSGHVNOH-VHSXEESVSA-N 0.000 description 1
- IXHQLZIWBCQBLQ-STQMWFEESA-N Gly-Pro-Phe Chemical compound NCC(=O)N1CCC[C@H]1C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 IXHQLZIWBCQBLQ-STQMWFEESA-N 0.000 description 1
- JNGHLWWFPGIJER-STQMWFEESA-N Gly-Pro-Tyr Chemical compound NCC(=O)N1CCC[C@H]1C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 JNGHLWWFPGIJER-STQMWFEESA-N 0.000 description 1
- YOBGUCWZPXJHTN-BQBZGAKWSA-N Gly-Ser-Arg Chemical compound NCC(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CCCN=C(N)N YOBGUCWZPXJHTN-BQBZGAKWSA-N 0.000 description 1
- FGPLUIQCSKGLTI-WDSKDSINSA-N Gly-Ser-Glu Chemical compound NCC(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CCC(O)=O FGPLUIQCSKGLTI-WDSKDSINSA-N 0.000 description 1
- UVTSZKIATYSKIR-RYUDHWBXSA-N Gly-Tyr-Glu Chemical compound [H]NCC(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCC(O)=O)C(O)=O UVTSZKIATYSKIR-RYUDHWBXSA-N 0.000 description 1
- BAYQNCWLXIDLHX-ONGXEEELSA-N Gly-Val-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)CN BAYQNCWLXIDLHX-ONGXEEELSA-N 0.000 description 1
- RVKIPWVMZANZLI-UHFFFAOYSA-N H-Lys-Trp-OH Natural products C1=CC=C2C(CC(NC(=O)C(N)CCCCN)C(O)=O)=CNC2=C1 RVKIPWVMZANZLI-UHFFFAOYSA-N 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- MDBYBTWRMOAJAY-NHCYSSNCSA-N His-Asn-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CC1=CN=CN1)N MDBYBTWRMOAJAY-NHCYSSNCSA-N 0.000 description 1
- WZOGEMJIZBNFBK-CIUDSAMLSA-N His-Asp-Asn Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O WZOGEMJIZBNFBK-CIUDSAMLSA-N 0.000 description 1
- VTMLJMNQHKBPON-QWRGUYRKSA-N His-Gly-His Chemical compound C([C@H](N)C(=O)NCC(=O)N[C@@H](CC=1NC=NC=1)C(O)=O)C1=CN=CN1 VTMLJMNQHKBPON-QWRGUYRKSA-N 0.000 description 1
- RGPWUJOMKFYFSR-QWRGUYRKSA-N His-Gly-Leu Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)NCC(=O)N[C@@H](CC(C)C)C(O)=O RGPWUJOMKFYFSR-QWRGUYRKSA-N 0.000 description 1
- NQKRILCJYCASDV-QWRGUYRKSA-N His-Gly-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)CC1=CN=CN1 NQKRILCJYCASDV-QWRGUYRKSA-N 0.000 description 1
- RAVLQPXCMRCLKT-KBPBESRZSA-N His-Gly-Phe Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)NCC(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O RAVLQPXCMRCLKT-KBPBESRZSA-N 0.000 description 1
- VDHOMPFVSABJKU-ULQDDVLXSA-N His-Phe-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)NC(=O)[C@H](CC2=CN=CN2)N VDHOMPFVSABJKU-ULQDDVLXSA-N 0.000 description 1
- FBVHRDXSCYELMI-PBCZWWQYSA-N His-Thr-Asn Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CC1=CN=CN1)N)O FBVHRDXSCYELMI-PBCZWWQYSA-N 0.000 description 1
- FFYYUUWROYYKFY-IHRRRGAJSA-N His-Val-Leu Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O FFYYUUWROYYKFY-IHRRRGAJSA-N 0.000 description 1
- QLRMMMQNCWBNPQ-QXEWZRGKSA-N Ile-Arg-Gly Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)NCC(=O)O)N QLRMMMQNCWBNPQ-QXEWZRGKSA-N 0.000 description 1
- HDODQNPMSHDXJT-GHCJXIJMSA-N Ile-Asn-Ser Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(O)=O HDODQNPMSHDXJT-GHCJXIJMSA-N 0.000 description 1
- RGSOCXHDOPQREB-ZPFDUUQYSA-N Ile-Asp-Leu Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CC(C)C)C(=O)O)N RGSOCXHDOPQREB-ZPFDUUQYSA-N 0.000 description 1
- DCQMJRSOGCYKTR-GHCJXIJMSA-N Ile-Asp-Ser Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(O)=O DCQMJRSOGCYKTR-GHCJXIJMSA-N 0.000 description 1
- DVRDRICMWUSCBN-UKJIMTQDSA-N Ile-Gln-Val Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](C(C)C)C(=O)O)N DVRDRICMWUSCBN-UKJIMTQDSA-N 0.000 description 1
- KIAOPHMUNPPGEN-PEXQALLHSA-N Ile-Gly-His Chemical compound CC[C@H](C)[C@@H](C(=O)NCC(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N KIAOPHMUNPPGEN-PEXQALLHSA-N 0.000 description 1
- GVKKVHNRTUFCCE-BJDJZHNGSA-N Ile-Leu-Ser Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)O)N GVKKVHNRTUFCCE-BJDJZHNGSA-N 0.000 description 1
- YSGBJIQXTIVBHZ-AJNGGQMLSA-N Ile-Lys-Leu Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(O)=O YSGBJIQXTIVBHZ-AJNGGQMLSA-N 0.000 description 1
- UDBPXJNOEWDBDF-XUXIUFHCSA-N Ile-Lys-Val Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)O)N UDBPXJNOEWDBDF-XUXIUFHCSA-N 0.000 description 1
- WSSGUVAKYCQSCT-XUXIUFHCSA-N Ile-Met-Leu Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(C)C)C(=O)O)N WSSGUVAKYCQSCT-XUXIUFHCSA-N 0.000 description 1
- KCTIFOCXAIUQQK-QXEWZRGKSA-N Ile-Pro-Gly Chemical compound CC[C@H](C)[C@H](N)C(=O)N1CCC[C@H]1C(=O)NCC(O)=O KCTIFOCXAIUQQK-QXEWZRGKSA-N 0.000 description 1
- JDCQDJVYUXNCGF-SPOWBLRKSA-N Ile-Ser-Trp Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)O)N JDCQDJVYUXNCGF-SPOWBLRKSA-N 0.000 description 1
- YJRSIJZUIUANHO-NAKRPEOUSA-N Ile-Val-Ala Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C)C(=O)O)N YJRSIJZUIUANHO-NAKRPEOUSA-N 0.000 description 1
- 108010065920 Insulin Lispro Proteins 0.000 description 1
- 102100037850 Interferon gamma Human genes 0.000 description 1
- 108010074328 Interferon-gamma Proteins 0.000 description 1
- IBMVEYRWAWIOTN-UHFFFAOYSA-N L-Leucyl-L-Arginyl-L-Proline Natural products CC(C)CC(N)C(=O)NC(CCCN=C(N)N)C(=O)N1CCCC1C(O)=O IBMVEYRWAWIOTN-UHFFFAOYSA-N 0.000 description 1
- FADYJNXDPBKVCA-UHFFFAOYSA-N L-Phenylalanyl-L-lysin Natural products NCCCCC(C(O)=O)NC(=O)C(N)CC1=CC=CC=C1 FADYJNXDPBKVCA-UHFFFAOYSA-N 0.000 description 1
- LHSGPCFBGJHPCY-UHFFFAOYSA-N L-leucine-L-tyrosine Natural products CC(C)CC(N)C(=O)NC(C(O)=O)CC1=CC=C(O)C=C1 LHSGPCFBGJHPCY-UHFFFAOYSA-N 0.000 description 1
- IBMVEYRWAWIOTN-RWMBFGLXSA-N Leu-Arg-Pro Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N1CCC[C@@H]1C(O)=O IBMVEYRWAWIOTN-RWMBFGLXSA-N 0.000 description 1
- STAVRDQLZOTNKJ-RHYQMDGZSA-N Leu-Arg-Thr Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(O)=O STAVRDQLZOTNKJ-RHYQMDGZSA-N 0.000 description 1
- BPANDPNDMJHFEV-CIUDSAMLSA-N Leu-Asp-Ala Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C)C(O)=O BPANDPNDMJHFEV-CIUDSAMLSA-N 0.000 description 1
- KTFHTMHHKXUYPW-ZPFDUUQYSA-N Leu-Asp-Ile Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O KTFHTMHHKXUYPW-ZPFDUUQYSA-N 0.000 description 1
- FQZPTCNSNPWHLJ-AVGNSLFASA-N Leu-Gln-Lys Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(O)=O FQZPTCNSNPWHLJ-AVGNSLFASA-N 0.000 description 1
- WQWSMEOYXJTFRU-GUBZILKMSA-N Leu-Glu-Ser Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(O)=O WQWSMEOYXJTFRU-GUBZILKMSA-N 0.000 description 1
- HGFGEMSVBMCFKK-MNXVOIDGSA-N Leu-Ile-Glu Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(O)=O)C(O)=O HGFGEMSVBMCFKK-MNXVOIDGSA-N 0.000 description 1
- RXGLHDWAZQECBI-SRVKXCTJSA-N Leu-Leu-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O RXGLHDWAZQECBI-SRVKXCTJSA-N 0.000 description 1
- ZGUMORRUBUCXEH-AVGNSLFASA-N Leu-Lys-Gln Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(N)=O)C(O)=O ZGUMORRUBUCXEH-AVGNSLFASA-N 0.000 description 1
- BGZCJDGBBUUBHA-KKUMJFAQSA-N Leu-Lys-Leu Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(O)=O BGZCJDGBBUUBHA-KKUMJFAQSA-N 0.000 description 1
- CPONGMJGVIAWEH-DCAQKATOSA-N Leu-Met-Ala Chemical compound CSCC[C@H](NC(=O)[C@@H](N)CC(C)C)C(=O)N[C@@H](C)C(O)=O CPONGMJGVIAWEH-DCAQKATOSA-N 0.000 description 1
- FLNPJLDPGMLWAU-UWVGGRQHSA-N Leu-Met-Gly Chemical compound OC(=O)CNC(=O)[C@H](CCSC)NC(=O)[C@@H](N)CC(C)C FLNPJLDPGMLWAU-UWVGGRQHSA-N 0.000 description 1
- INCJJHQRZGQLFC-KBPBESRZSA-N Leu-Phe-Gly Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)NCC(O)=O INCJJHQRZGQLFC-KBPBESRZSA-N 0.000 description 1
- MJWVXZABPOKJJF-ACRUOGEOSA-N Leu-Phe-Phe Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O MJWVXZABPOKJJF-ACRUOGEOSA-N 0.000 description 1
- PNPYKQFJGRFYJE-GUBZILKMSA-N Lys-Ala-Glu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(O)=O PNPYKQFJGRFYJE-GUBZILKMSA-N 0.000 description 1
- DZQYZKPINJLLEN-KKUMJFAQSA-N Lys-Cys-Tyr Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)O)NC(=O)[C@H](CS)NC(=O)[C@H](CCCCN)N)O DZQYZKPINJLLEN-KKUMJFAQSA-N 0.000 description 1
- GJJQCBVRWDGLMQ-GUBZILKMSA-N Lys-Glu-Ala Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(O)=O GJJQCBVRWDGLMQ-GUBZILKMSA-N 0.000 description 1
- CRNNMTHBMRFQNG-GUBZILKMSA-N Lys-Glu-Cys Chemical compound C(CCN)C[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CS)C(=O)O)N CRNNMTHBMRFQNG-GUBZILKMSA-N 0.000 description 1
- GPJGFSFYBJGYRX-YUMQZZPRSA-N Lys-Gly-Asp Chemical compound NCCCC[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CC(O)=O GPJGFSFYBJGYRX-YUMQZZPRSA-N 0.000 description 1
- CANPXOLVTMKURR-WEDXCCLWSA-N Lys-Gly-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN CANPXOLVTMKURR-WEDXCCLWSA-N 0.000 description 1
- OWRUUFUVXFREBD-KKUMJFAQSA-N Lys-His-Leu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CC(C)C)C(O)=O OWRUUFUVXFREBD-KKUMJFAQSA-N 0.000 description 1
- SLQJJFAVWSZLBL-BJDJZHNGSA-N Lys-Ile-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@@H](N)CCCCN SLQJJFAVWSZLBL-BJDJZHNGSA-N 0.000 description 1
- IZJGPPIGYTVXLB-FQUUOJAGSA-N Lys-Ile-Pro Chemical compound CC[C@H](C)[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CCCCN)N IZJGPPIGYTVXLB-FQUUOJAGSA-N 0.000 description 1
- NJNRBRKHOWSGMN-SRVKXCTJSA-N Lys-Leu-Asn Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O NJNRBRKHOWSGMN-SRVKXCTJSA-N 0.000 description 1
- BXPHMHQHYHILBB-BZSNNMDCSA-N Lys-Lys-Tyr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O BXPHMHQHYHILBB-BZSNNMDCSA-N 0.000 description 1
- MTBLFIQZECOEBY-IHRRRGAJSA-N Lys-Met-Lys Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCCN)C(O)=O MTBLFIQZECOEBY-IHRRRGAJSA-N 0.000 description 1
- ZZHPLPSLBVBWOA-WDSOQIARSA-N Lys-Met-Trp Chemical compound CSCC[C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)O)NC(=O)[C@H](CCCCN)N ZZHPLPSLBVBWOA-WDSOQIARSA-N 0.000 description 1
- LNMKRJJLEFASGA-BZSNNMDCSA-N Lys-Phe-Leu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC(C)C)C(O)=O LNMKRJJLEFASGA-BZSNNMDCSA-N 0.000 description 1
- YCJCEMKOZOYBEF-OEAJRASXSA-N Lys-Thr-Phe Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O YCJCEMKOZOYBEF-OEAJRASXSA-N 0.000 description 1
- PELXPRPDQRFBGQ-KKUMJFAQSA-N Lys-Tyr-Asn Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CCCCN)N)O PELXPRPDQRFBGQ-KKUMJFAQSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- HWROAFGWPQUPTE-OSUNSFLBSA-N Met-Ile-Thr Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H]([C@@H](C)O)C(=O)O)NC(=O)[C@H](CCSC)N HWROAFGWPQUPTE-OSUNSFLBSA-N 0.000 description 1
- CGUYGMFQZCYJSG-DCAQKATOSA-N Met-Lys-Ser Chemical compound [H]N[C@@H](CCSC)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(O)=O CGUYGMFQZCYJSG-DCAQKATOSA-N 0.000 description 1
- IILAGWCGKJSBGB-IHRRRGAJSA-N Met-Phe-Asp Chemical compound CSCC[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC(=O)O)C(=O)O)N IILAGWCGKJSBGB-IHRRRGAJSA-N 0.000 description 1
- JZXKNNOWPBVZEV-XIRDDKMYSA-N Met-Trp-Glu Chemical compound CSCC[C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)N[C@@H](CCC(=O)O)C(=O)O)N JZXKNNOWPBVZEV-XIRDDKMYSA-N 0.000 description 1
- QAVZUKIPOMBLMC-AVGNSLFASA-N Met-Val-Leu Chemical compound CSCC[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CC(C)C QAVZUKIPOMBLMC-AVGNSLFASA-N 0.000 description 1
- VYDLZDRMOFYOGV-TUAOUCFPSA-N Met-Val-Pro Chemical compound CC(C)[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CCSC)N VYDLZDRMOFYOGV-TUAOUCFPSA-N 0.000 description 1
- 206010028164 Multiple allergies Diseases 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- WUGMRIBZSVSJNP-UHFFFAOYSA-N N-L-alanyl-L-tryptophan Natural products C1=CC=C2C(CC(NC(=O)C(N)C)C(O)=O)=CNC2=C1 WUGMRIBZSVSJNP-UHFFFAOYSA-N 0.000 description 1
- SITLTJHOQZFJGG-UHFFFAOYSA-N N-L-alpha-glutamyl-L-valine Natural products CC(C)C(C(O)=O)NC(=O)C(N)CCC(O)=O SITLTJHOQZFJGG-UHFFFAOYSA-N 0.000 description 1
- 108010066427 N-valyltryptophan Proteins 0.000 description 1
- 101100342977 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) leu-1 gene Proteins 0.000 description 1
- 108091028043 Nucleic acid sequence Proteins 0.000 description 1
- DSOWUEHXZJUNID-WHXUGTBJSA-N PE(16:1(9Z)/0:0) Chemical compound CCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](O)COP(O)(=O)OCCN DSOWUEHXZJUNID-WHXUGTBJSA-N 0.000 description 1
- ALJXGNMOATZBMV-XTYNSLPVSA-N PG(20:2(11Z,14Z)/0:0) Chemical compound CCCCC\C=C/C\C=C/CCCCCCCCCC(=O)OC[C@@H](O)COP(O)(=O)OC[C@@H](O)CO ALJXGNMOATZBMV-XTYNSLPVSA-N 0.000 description 1
- GTUVDMUYRYBFAU-INRKLGSDSA-N PG(22:4(7Z,10Z,13Z,16Z)/0:0) Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCCCC(=O)OC[C@@H](O)COP(O)(=O)OC[C@@H](O)CO GTUVDMUYRYBFAU-INRKLGSDSA-N 0.000 description 1
- HRFWJAJQKOFYDE-FTJBHMTQSA-N PS(22:0/0:0) Chemical compound CCCCCCCCCCCCCCCCCCCCCC(=O)OC[C@@H](O)COP(O)(=O)OC[C@H](N)C(O)=O HRFWJAJQKOFYDE-FTJBHMTQSA-N 0.000 description 1
- 208000008267 Peanut Hypersensitivity Diseases 0.000 description 1
- 238000010220 Pearson correlation analysis Methods 0.000 description 1
- BKWJQWJPZMUWEG-LFSVMHDDSA-N Phe-Ala-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC1=CC=CC=C1 BKWJQWJPZMUWEG-LFSVMHDDSA-N 0.000 description 1
- YMORXCKTSSGYIG-IHRRRGAJSA-N Phe-Arg-Cys Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CS)C(=O)O)N YMORXCKTSSGYIG-IHRRRGAJSA-N 0.000 description 1
- IQXOZIDWLZYYAW-IHRRRGAJSA-N Phe-Asp-Met Chemical compound CSCC[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)N IQXOZIDWLZYYAW-IHRRRGAJSA-N 0.000 description 1
- QPQDWBAJWOGAMJ-IHPCNDPISA-N Phe-Asp-Trp Chemical compound C([C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(O)=O)C1=CC=CC=C1 QPQDWBAJWOGAMJ-IHPCNDPISA-N 0.000 description 1
- LXUJDHOKVUYHRC-KKUMJFAQSA-N Phe-Cys-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CS)NC(=O)[C@H](CC1=CC=CC=C1)N LXUJDHOKVUYHRC-KKUMJFAQSA-N 0.000 description 1
- YZJKNDCEPDDIDA-BZSNNMDCSA-N Phe-His-Lys Chemical compound C([C@@H](C(=O)N[C@@H](CCCCN)C(O)=O)NC(=O)[C@@H](N)CC=1C=CC=CC=1)C1=CN=CN1 YZJKNDCEPDDIDA-BZSNNMDCSA-N 0.000 description 1
- BEEVXUYVEHXWRQ-YESZJQIVSA-N Phe-His-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC2=CN=CN2)NC(=O)[C@H](CC3=CC=CC=C3)N)C(=O)O BEEVXUYVEHXWRQ-YESZJQIVSA-N 0.000 description 1
- MYQCCQSMKNCNKY-KKUMJFAQSA-N Phe-His-Ser Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CC2=CN=CN2)C(=O)N[C@@H](CO)C(=O)O)N MYQCCQSMKNCNKY-KKUMJFAQSA-N 0.000 description 1
- RSPUIENXSJYZQO-JYJNAYRXSA-N Phe-Leu-Gln Chemical compound NC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CC1=CC=CC=C1 RSPUIENXSJYZQO-JYJNAYRXSA-N 0.000 description 1
- XROLYVMNVIKVEM-BQBZGAKWSA-N Pro-Asn-Gly Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CC(N)=O)C(=O)NCC(O)=O XROLYVMNVIKVEM-BQBZGAKWSA-N 0.000 description 1
- XKHCJJPNXFBADI-DCAQKATOSA-N Pro-Asp-Lys Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CCCCN)C(=O)O XKHCJJPNXFBADI-DCAQKATOSA-N 0.000 description 1
- SKICPQLTOXGWGO-GARJFASQSA-N Pro-Gln-Pro Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CCC(=O)N)C(=O)N2CCC[C@@H]2C(=O)O SKICPQLTOXGWGO-GARJFASQSA-N 0.000 description 1
- SUENWIFTSTWUKD-AVGNSLFASA-N Pro-Leu-Val Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(O)=O SUENWIFTSTWUKD-AVGNSLFASA-N 0.000 description 1
- RMODQFBNDDENCP-IHRRRGAJSA-N Pro-Lys-Leu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(O)=O RMODQFBNDDENCP-IHRRRGAJSA-N 0.000 description 1
- IIRBTQHFVNGPMQ-AVGNSLFASA-N Pro-Val-Lys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@@H]1CCCN1 IIRBTQHFVNGPMQ-AVGNSLFASA-N 0.000 description 1
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 1
- 108010029485 Protein Isoforms Proteins 0.000 description 1
- 102000001708 Protein Isoforms Human genes 0.000 description 1
- 208000003251 Pruritus Diseases 0.000 description 1
- WTWGOQRNRFHFQD-JBDRJPRFSA-N Ser-Ala-Ile Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O WTWGOQRNRFHFQD-JBDRJPRFSA-N 0.000 description 1
- IDCKUIWEIZYVSO-WFBYXXMGSA-N Ser-Ala-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@@H](NC(=O)[C@@H](N)CO)C)C(O)=O)=CNC2=C1 IDCKUIWEIZYVSO-WFBYXXMGSA-N 0.000 description 1
- KYKKKSWGEPFUMR-NAKRPEOUSA-N Ser-Arg-Ile Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O KYKKKSWGEPFUMR-NAKRPEOUSA-N 0.000 description 1
- UBRXAVQWXOWRSJ-ZLUOBGJFSA-N Ser-Asn-Asp Chemical compound C([C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)O)NC(=O)[C@H](CO)N)C(=O)N UBRXAVQWXOWRSJ-ZLUOBGJFSA-N 0.000 description 1
- RNMRYWZYFHHOEV-CIUDSAMLSA-N Ser-Gln-Arg Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O RNMRYWZYFHHOEV-CIUDSAMLSA-N 0.000 description 1
- YMTLKLXDFCSCNX-BYPYZUCNSA-N Ser-Gly-Gly Chemical compound OC[C@H](N)C(=O)NCC(=O)NCC(O)=O YMTLKLXDFCSCNX-BYPYZUCNSA-N 0.000 description 1
- WSTIOCFMWXNOCX-YUMQZZPRSA-N Ser-Gly-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)CNC(=O)[C@H](CO)N WSTIOCFMWXNOCX-YUMQZZPRSA-N 0.000 description 1
- UIPXCLNLUUAMJU-JBDRJPRFSA-N Ser-Ile-Ser Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(O)=O UIPXCLNLUUAMJU-JBDRJPRFSA-N 0.000 description 1
- FUMGHWDRRFCKEP-CIUDSAMLSA-N Ser-Leu-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(O)=O FUMGHWDRRFCKEP-CIUDSAMLSA-N 0.000 description 1
- NLOAIFSWUUFQFR-CIUDSAMLSA-N Ser-Leu-Asp Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O NLOAIFSWUUFQFR-CIUDSAMLSA-N 0.000 description 1
- HEUVHBXOVZONPU-BJDJZHNGSA-N Ser-Leu-Ile Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O HEUVHBXOVZONPU-BJDJZHNGSA-N 0.000 description 1
- UGTZYIPOBYXWRW-SRVKXCTJSA-N Ser-Phe-Asp Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC(O)=O)C(O)=O UGTZYIPOBYXWRW-SRVKXCTJSA-N 0.000 description 1
- XKFJENWJGHMDLI-QWRGUYRKSA-N Ser-Phe-Gly Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)NCC(O)=O XKFJENWJGHMDLI-QWRGUYRKSA-N 0.000 description 1
- CKDXFSPMIDSMGV-GUBZILKMSA-N Ser-Pro-Val Chemical compound [H]N[C@@H](CO)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C(C)C)C(O)=O CKDXFSPMIDSMGV-GUBZILKMSA-N 0.000 description 1
- VGQVAVQWKJLIRM-FXQIFTODSA-N Ser-Ser-Val Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O VGQVAVQWKJLIRM-FXQIFTODSA-N 0.000 description 1
- FVFUOQIYDPAIJR-XIRDDKMYSA-N Ser-Trp-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)NC(=O)[C@H](CO)N FVFUOQIYDPAIJR-XIRDDKMYSA-N 0.000 description 1
- VVKVHAOOUGNDPJ-SRVKXCTJSA-N Ser-Tyr-Ser Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CO)C(O)=O VVKVHAOOUGNDPJ-SRVKXCTJSA-N 0.000 description 1
- SYCFMSYTIFXWAJ-DCAQKATOSA-N Ser-Val-His Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](CO)N SYCFMSYTIFXWAJ-DCAQKATOSA-N 0.000 description 1
- HNDMFDBQXYZSRM-IHRRRGAJSA-N Ser-Val-Phe Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O HNDMFDBQXYZSRM-IHRRRGAJSA-N 0.000 description 1
- 238000011869 Shapiro-Wilk test Methods 0.000 description 1
- 238000002105 Southern blotting Methods 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- LVHHEVGYAZGXDE-KDXUFGMBSA-N Thr-Ala-Pro Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](C)C(=O)N1CCC[C@@H]1C(=O)O)N)O LVHHEVGYAZGXDE-KDXUFGMBSA-N 0.000 description 1
- CTONFVDJYCAMQM-IUKAMOBKSA-N Thr-Asn-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H]([C@@H](C)O)N CTONFVDJYCAMQM-IUKAMOBKSA-N 0.000 description 1
- NLSNVZAREYQMGR-HJGDQZAQSA-N Thr-Asp-Leu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(O)=O NLSNVZAREYQMGR-HJGDQZAQSA-N 0.000 description 1
- YZUWGFXVVZQJEI-PMVVWTBXSA-N Thr-Gly-His Chemical compound C[C@H]([C@@H](C(=O)NCC(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N)O YZUWGFXVVZQJEI-PMVVWTBXSA-N 0.000 description 1
- UBDDORVPVLEECX-FJXKBIBVSA-N Thr-Gly-Met Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CCSC)C(O)=O UBDDORVPVLEECX-FJXKBIBVSA-N 0.000 description 1
- DJDSEDOKJTZBAR-ZDLURKLDSA-N Thr-Gly-Ser Chemical compound C[C@@H](O)[C@H](N)C(=O)NCC(=O)N[C@@H](CO)C(O)=O DJDSEDOKJTZBAR-ZDLURKLDSA-N 0.000 description 1
- WBCCCPZIJIJTSD-TUBUOCAGSA-N Thr-His-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CC1=CN=CN1)NC(=O)[C@H]([C@@H](C)O)N WBCCCPZIJIJTSD-TUBUOCAGSA-N 0.000 description 1
- NCGUQWSJUKYCIT-SZZJOZGLSA-N Thr-His-Trp Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O NCGUQWSJUKYCIT-SZZJOZGLSA-N 0.000 description 1
- AHOLTQCAVBSUDP-PPCPHDFISA-N Thr-Ile-Lys Chemical compound CC[C@H](C)[C@H](NC(=O)[C@@H](N)[C@@H](C)O)C(=O)N[C@@H](CCCCN)C(O)=O AHOLTQCAVBSUDP-PPCPHDFISA-N 0.000 description 1
- IMDMLDSVUSMAEJ-HJGDQZAQSA-N Thr-Leu-Asn Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O IMDMLDSVUSMAEJ-HJGDQZAQSA-N 0.000 description 1
- FLPZMPOZGYPBEN-PPCPHDFISA-N Thr-Leu-Ile Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O FLPZMPOZGYPBEN-PPCPHDFISA-N 0.000 description 1
- MECLEFZMPPOEAC-VOAKCMCISA-N Thr-Leu-Lys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)O)N)O MECLEFZMPPOEAC-VOAKCMCISA-N 0.000 description 1
- YOOAQCZYZHGUAZ-KATARQTJSA-N Thr-Leu-Ser Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O YOOAQCZYZHGUAZ-KATARQTJSA-N 0.000 description 1
- KZSYAEWQMJEGRZ-RHYQMDGZSA-N Thr-Leu-Val Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(O)=O KZSYAEWQMJEGRZ-RHYQMDGZSA-N 0.000 description 1
- MGJLBZFUXUGMML-VOAKCMCISA-N Thr-Lys-Lys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)O)N)O MGJLBZFUXUGMML-VOAKCMCISA-N 0.000 description 1
- ZESGVALRVJIVLZ-VFCFLDTKSA-N Thr-Thr-Pro Chemical compound C[C@H]([C@@H](C(=O)N[C@@H]([C@@H](C)O)C(=O)N1CCC[C@@H]1C(=O)O)N)O ZESGVALRVJIVLZ-VFCFLDTKSA-N 0.000 description 1
- XGFYGMKZKFRGAI-RCWTZXSCSA-N Thr-Val-Arg Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CCCN=C(N)N XGFYGMKZKFRGAI-RCWTZXSCSA-N 0.000 description 1
- XNRNNGPBEPRNAR-UHFFFAOYSA-N Thromboxane B2 Natural products CCCCCC(O)C=CC1OC(O)CC(O)C1CC=CCCCC(O)=O XNRNNGPBEPRNAR-UHFFFAOYSA-N 0.000 description 1
- NBHGNEJMBNQQKZ-UBHSHLNASA-N Trp-Asp-Cys Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CS)C(=O)O)N NBHGNEJMBNQQKZ-UBHSHLNASA-N 0.000 description 1
- ZCPCXVJOMUPIDD-IHPCNDPISA-N Trp-Asp-Phe Chemical compound C([C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)N)C(O)=O)C1=CC=CC=C1 ZCPCXVJOMUPIDD-IHPCNDPISA-N 0.000 description 1
- OFCKFBGRYHOKFP-IHPCNDPISA-N Trp-Asp-Tyr Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CC3=CC=C(C=C3)O)C(=O)O)N OFCKFBGRYHOKFP-IHPCNDPISA-N 0.000 description 1
- JWGRSJCYCXEIKH-QEJZJMRPSA-N Trp-Glu-Cys Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CS)C(=O)O)N JWGRSJCYCXEIKH-QEJZJMRPSA-N 0.000 description 1
- RRXPAFGTFQIEMD-IVJVFBROSA-N Trp-Ile-Pro Chemical compound CC[C@H](C)[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CC2=CNC3=CC=CC=C32)N RRXPAFGTFQIEMD-IVJVFBROSA-N 0.000 description 1
- DDJHCLVUUBEIIA-BVSLBCMMSA-N Trp-Met-Phe Chemical compound C([C@H](NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C2=CC=CC=C2NC=1)CCSC)C(O)=O)C1=CC=CC=C1 DDJHCLVUUBEIIA-BVSLBCMMSA-N 0.000 description 1
- VMXLNDRJXVAJFT-JYBASQMISA-N Trp-Thr-Ser Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)N)O VMXLNDRJXVAJFT-JYBASQMISA-N 0.000 description 1
- MBLJBGZWLHTJBH-SZMVWBNQSA-N Trp-Val-Arg Chemical compound C1=CC=C2C(C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O)=CNC2=C1 MBLJBGZWLHTJBH-SZMVWBNQSA-N 0.000 description 1
- QOEZFICGUZTRFX-IHRRRGAJSA-N Tyr-Cys-Val Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CS)C(=O)N[C@@H](C(C)C)C(O)=O QOEZFICGUZTRFX-IHRRRGAJSA-N 0.000 description 1
- FDKDGFGTHGJKNV-FHWLQOOXSA-N Tyr-Phe-Gln Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](CC2=CC=C(C=C2)O)N FDKDGFGTHGJKNV-FHWLQOOXSA-N 0.000 description 1
- PSALWJCUIAQKFW-ACRUOGEOSA-N Tyr-Phe-Lys Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CC2=CC=C(C=C2)O)N PSALWJCUIAQKFW-ACRUOGEOSA-N 0.000 description 1
- PLXQRTXVLZUNMU-RNXOBYDBSA-N Tyr-Phe-Trp Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CC2=CNC3=CC=CC=C32)C(=O)O)NC(=O)[C@H](CC4=CC=C(C=C4)O)N PLXQRTXVLZUNMU-RNXOBYDBSA-N 0.000 description 1
- CDBXVDXSLPLFMD-BPNCWPANSA-N Tyr-Pro-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CC1=CC=C(O)C=C1 CDBXVDXSLPLFMD-BPNCWPANSA-N 0.000 description 1
- YYLHVUCSTXXKBS-IHRRRGAJSA-N Tyr-Pro-Ser Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O YYLHVUCSTXXKBS-IHRRRGAJSA-N 0.000 description 1
- DJIJBQYBDKGDIS-JYJNAYRXSA-N Tyr-Val-Val Chemical compound CC(C)[C@H](NC(=O)[C@@H](NC(=O)[C@@H](N)Cc1ccc(O)cc1)C(C)C)C(O)=O DJIJBQYBDKGDIS-JYJNAYRXSA-N 0.000 description 1
- SLLKXDSRVAOREO-KZVJFYERSA-N Val-Ala-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](C)NC(=O)[C@H](C(C)C)N)O SLLKXDSRVAOREO-KZVJFYERSA-N 0.000 description 1
- COYSIHFOCOMGCF-UHFFFAOYSA-N Val-Arg-Gly Natural products CC(C)C(N)C(=O)NC(C(=O)NCC(O)=O)CCCN=C(N)N COYSIHFOCOMGCF-UHFFFAOYSA-N 0.000 description 1
- XPYNXORPPVTVQK-SRVKXCTJSA-N Val-Arg-Met Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCSC)C(=O)O)N XPYNXORPPVTVQK-SRVKXCTJSA-N 0.000 description 1
- ZMDCGGKHRKNWKD-LAEOZQHASA-N Val-Asn-Glu Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CCC(=O)O)C(=O)O)N ZMDCGGKHRKNWKD-LAEOZQHASA-N 0.000 description 1
- OGNMURQZFMHFFD-NHCYSSNCSA-N Val-Asn-Lys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CCCCN)C(=O)O)N OGNMURQZFMHFFD-NHCYSSNCSA-N 0.000 description 1
- NYTKXWLZSNRILS-IFFSRLJSSA-N Val-Gln-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](C(C)C)N)O NYTKXWLZSNRILS-IFFSRLJSSA-N 0.000 description 1
- AHHJARQXFFGOKF-NRPADANISA-N Val-Glu-Cys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CS)C(=O)O)N AHHJARQXFFGOKF-NRPADANISA-N 0.000 description 1
- YDPFWRVQHFWBKI-GVXVVHGQSA-N Val-Glu-His Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N YDPFWRVQHFWBKI-GVXVVHGQSA-N 0.000 description 1
- OXGVAUFVTOPFFA-XPUUQOCRSA-N Val-Gly-Cys Chemical compound CC(C)[C@@H](C(=O)NCC(=O)N[C@@H](CS)C(=O)O)N OXGVAUFVTOPFFA-XPUUQOCRSA-N 0.000 description 1
- KDKLLPMFFGYQJD-CYDGBPFRSA-N Val-Ile-Arg Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)NC(=O)[C@H](C(C)C)N KDKLLPMFFGYQJD-CYDGBPFRSA-N 0.000 description 1
- WNZSAUMKZQXHNC-UKJIMTQDSA-N Val-Ile-Gln Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](C(C)C)N WNZSAUMKZQXHNC-UKJIMTQDSA-N 0.000 description 1
- UKEVLVBHRKWECS-LSJOCFKGSA-N Val-Ile-Gly Chemical compound CC[C@H](C)[C@@H](C(=O)NCC(=O)O)NC(=O)[C@H](C(C)C)N UKEVLVBHRKWECS-LSJOCFKGSA-N 0.000 description 1
- VPGCVZRRBYOGCD-AVGNSLFASA-N Val-Lys-Val Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(O)=O VPGCVZRRBYOGCD-AVGNSLFASA-N 0.000 description 1
- VENKIVFKIPGEJN-NHCYSSNCSA-N Val-Met-Glu Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(=O)O)C(=O)O)N VENKIVFKIPGEJN-NHCYSSNCSA-N 0.000 description 1
- MJFSRZZJQWZHFQ-SRVKXCTJSA-N Val-Met-Val Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCSC)C(=O)N[C@@H](C(C)C)C(=O)O)N MJFSRZZJQWZHFQ-SRVKXCTJSA-N 0.000 description 1
- KJFBXCFOPAKPTM-BZSNNMDCSA-N Val-Trp-Val Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@@H](N)C(C)C)C(=O)N[C@@H](C(C)C)C(O)=O)=CNC2=C1 KJFBXCFOPAKPTM-BZSNNMDCSA-N 0.000 description 1
- 238000001772 Wald test Methods 0.000 description 1
- 238000001793 Wilcoxon signed-rank test Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 108010045023 alanyl-prolyl-tyrosine Proteins 0.000 description 1
- 108010005233 alanylglutamic acid Proteins 0.000 description 1
- 108010070944 alanylhistidine Proteins 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 238000000540 analysis of variance Methods 0.000 description 1
- 125000000129 anionic group Chemical class 0.000 description 1
- 230000000890 antigenic effect Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229940114079 arachidonic acid Drugs 0.000 description 1
- 235000021342 arachidonic acid Nutrition 0.000 description 1
- 108010069926 arginyl-glycyl-serine Proteins 0.000 description 1
- 108010029539 arginyl-prolyl-proline Proteins 0.000 description 1
- 108010069205 aspartyl-phenylalanine Proteins 0.000 description 1
- 108010038633 aspartylglutamate Proteins 0.000 description 1
- 108010092854 aspartyllysine Proteins 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 201000009090 atopic dermatitis 4 Diseases 0.000 description 1
- MKOKWBRPIBQYJJ-WZBOJYASSA-N beta-D-galactosyl-(1->4)-beta-D-glucosyl-(1<->1)-N-[(15Z)-tetracosenoyl]sphingosine Chemical compound O[C@@H]1[C@@H](O)[C@H](OC[C@@H]([C@H](O)/C=C/CCCCCCCCCCCCC)NC(=O)CCCCCCCCCCCCC\C=C/CCCCCCCC)O[C@H](CO)[C@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 MKOKWBRPIBQYJJ-WZBOJYASSA-N 0.000 description 1
- HLIJNIKSBCIDGO-QKLMXXKVSA-N beta-D-galactosyl-(1->4)-beta-D-glucosyl-(1<->1)-N-hexadecanoylsphingosine Chemical compound O[C@@H]1[C@@H](O)[C@H](OC[C@H](NC(=O)CCCCCCCCCCCCCCC)[C@H](O)\C=C\CCCCCCCCCCCCC)O[C@H](CO)[C@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HLIJNIKSBCIDGO-QKLMXXKVSA-N 0.000 description 1
- 239000012472 biological sample Substances 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 238000004422 calculation algorithm Methods 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 125000002091 cationic group Chemical class 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003593 chromogenic compound Substances 0.000 description 1
- 210000000349 chromosome Anatomy 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 230000006957 competitive inhibition Effects 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 230000010485 coping Effects 0.000 description 1
- 230000000875 corresponding effect Effects 0.000 description 1
- 108010016616 cysteinylglycine Proteins 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000000593 degrading effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000005546 dideoxynucleotide Substances 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 230000000378 dietary effect Effects 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- OTKJDMGTUTTYMP-UHFFFAOYSA-N dihydrosphingosine Natural products CCCCCCCCCCCCCCCC(O)C(N)CO OTKJDMGTUTTYMP-UHFFFAOYSA-N 0.000 description 1
- 239000012636 effector Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 150000004665 fatty acids Chemical group 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 150000002270 gangliosides Chemical class 0.000 description 1
- 238000001030 gas--liquid chromatography Methods 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 108010019832 glycyl-asparaginyl-glycine Proteins 0.000 description 1
- 108010051307 glycyl-glycyl-proline Proteins 0.000 description 1
- 108010023364 glycyl-histidyl-arginine Proteins 0.000 description 1
- 108010020688 glycylhistidine Proteins 0.000 description 1
- 230000009610 hypersensitivity Effects 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 230000002163 immunogen Effects 0.000 description 1
- 229960003444 immunosuppressant agent Drugs 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 230000003960 inflammatory cascade Effects 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 230000007803 itching Effects 0.000 description 1
- 108010076756 leucyl-alanyl-phenylalanine Proteins 0.000 description 1
- 108010083708 leucyl-aspartyl-valine Proteins 0.000 description 1
- 108010034529 leucyl-lysine Proteins 0.000 description 1
- 108010091871 leucylmethionine Proteins 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 244000144972 livestock Species 0.000 description 1
- 238000007477 logistic regression Methods 0.000 description 1
- 239000012139 lysis buffer Substances 0.000 description 1
- 108010003700 lysyl aspartic acid Proteins 0.000 description 1
- 108010076718 lysyl-glutamyl-tryptophan Proteins 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 206010025482 malaise Diseases 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 238000010197 meta-analysis Methods 0.000 description 1
- 230000037353 metabolic pathway Effects 0.000 description 1
- 238000007884 metabolite profiling Methods 0.000 description 1
- 108010056582 methionylglutamic acid Proteins 0.000 description 1
- 238000002493 microarray Methods 0.000 description 1
- 244000309715 mini pig Species 0.000 description 1
- 210000001616 monocyte Anatomy 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 235000014571 nuts Nutrition 0.000 description 1
- 210000004789 organ system Anatomy 0.000 description 1
- 238000007427 paired t-test Methods 0.000 description 1
- 238000005192 partition Methods 0.000 description 1
- 201000010853 peanut allergy Diseases 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 108010070409 phenylalanyl-glycyl-glycine Proteins 0.000 description 1
- 108010018625 phenylalanylarginine Proteins 0.000 description 1
- 108010012581 phenylalanylglutamate Proteins 0.000 description 1
- 108010073101 phenylalanylleucine Proteins 0.000 description 1
- 235000015277 pork Nutrition 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 108010014614 prolyl-glycyl-proline Proteins 0.000 description 1
- 108700042769 prolyl-leucyl-glycine Proteins 0.000 description 1
- 108010004914 prolylarginine Proteins 0.000 description 1
- 108010090894 prolylleucine Proteins 0.000 description 1
- 108010053725 prolylvaline Proteins 0.000 description 1
- 230000017854 proteolysis Effects 0.000 description 1
- 238000012175 pyrosequencing Methods 0.000 description 1
- 238000004445 quantitative analysis Methods 0.000 description 1
- 238000007634 remodeling Methods 0.000 description 1
- 108091008146 restriction endonucleases Proteins 0.000 description 1
- 238000007894 restriction fragment length polymorphism technique Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 238000005096 rolling process Methods 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 238000003118 sandwich ELISA Methods 0.000 description 1
- 238000005204 segregation Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000012163 sequencing technique Methods 0.000 description 1
- 108010048818 seryl-histidine Proteins 0.000 description 1
- 108010048397 seryl-lysyl-leucine Proteins 0.000 description 1
- 108010071207 serylmethionine Proteins 0.000 description 1
- 208000013220 shortness of breath Diseases 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 108010031491 threonyl-lysyl-glutamic acid Proteins 0.000 description 1
- 108010080629 tryptophan-leucine Proteins 0.000 description 1
- 108010077037 tyrosyl-tyrosyl-phenylalanine Proteins 0.000 description 1
- 108010015385 valyl-prolyl-proline Proteins 0.000 description 1
- 108010072695 valyl-valyl-tyrosyl-proline Proteins 0.000 description 1
- 108010073969 valyllysine Proteins 0.000 description 1
- 108010027345 wheylin-1 peptide Proteins 0.000 description 1
Images
Classifications
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/564—Immunoassay; Biospecific binding assay; Materials therefor for pre-existing immune complex or autoimmune disease, i.e. systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, rheumatoid factors or complement components C1-C9
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/34—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving hydrolase
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/62—Detectors specially adapted therefor
- G01N30/72—Mass spectrometers
- G01N30/7233—Mass spectrometers interfaced to liquid or supercritical fluid chromatograph
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
- G01N33/6803—General methods of protein analysis not limited to specific proteins or families of proteins
- G01N33/6848—Methods of protein analysis involving mass spectrometry
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/24—Immunology or allergic disorders
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Chemical & Material Sciences (AREA)
- Immunology (AREA)
- Molecular Biology (AREA)
- Physics & Mathematics (AREA)
- Hematology (AREA)
- General Health & Medical Sciences (AREA)
- Analytical Chemistry (AREA)
- Biomedical Technology (AREA)
- Biochemistry (AREA)
- Urology & Nephrology (AREA)
- Biotechnology (AREA)
- General Physics & Mathematics (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Microbiology (AREA)
- Organic Chemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Pathology (AREA)
- Zoology (AREA)
- Biophysics (AREA)
- Cell Biology (AREA)
- Wood Science & Technology (AREA)
- Food Science & Technology (AREA)
- Medicinal Chemistry (AREA)
- Bioinformatics & Computational Biology (AREA)
- Rehabilitation Therapy (AREA)
- Rheumatology (AREA)
- General Engineering & Computer Science (AREA)
- Genetics & Genomics (AREA)
- Spectroscopy & Molecular Physics (AREA)
- Investigating Or Analysing Biological Materials (AREA)
Abstract
Description
본 발명은 식품 알레르기 지속성 판단 마커로서의 혈소판 활성화 인자의 용도에 관한 것으로, 더 상세하게는 진단 당시 수준을 정량하여 향후 식품 알레르기의 지속성 여부를 판단할 수 있는 마커로서의 혈소판 활성화 인자의 용도에 관한 것이다.The present invention relates to the use of platelet activating factor as a marker for determining the persistence of food allergy, and more particularly, to the use of platelet activating factor as a marker capable of determining the persistence of future food allergy by quantifying the level at the time of diagnosis.
소아에서부터 발병하는 식품 알레르기(FA)의 지속성 여부는 환자마다 상당히 다르다. 일부 소아는 어린 나이에 증상을 극복하는 반면 일부 소아는 평생 식품 알레르기가 지속된다. 식품 알레르기에 대한 광범위한 연구가 수행되었지만, 식품 알레르기에 대처하기 위한 방법으로는 여전히 엄격한 식이 회피가 주류를 이루고 있어, 지속적인 증상이 있는 사람들에게 상당한 부담을 안겨준다. 식품 알레르기를 치료하기 위한 정확한 메커니즘이 아직까지 완전히 밝혀지지는 않았으며, 따라서 식품 알레르기를 정확히 예측하고, 이를 치료할 수 있는 방법은 아직까지 제한적이다. 원인 알레르겐의 유형과 수, 증상의 심각성을 포함하여 다양한 요인이 식품 알레르기 치료에 영향을 미친다. 식품 알레르기의 수와 알레르겐 특이적 IgE 수준을 통하여 식품 알레르기 치료를 예측하고자 하는 여러 시도가 있었으나 (Foong RX et al., Pediatr Allergy Immunol 2021; 32:223-33), 이에 대한 정확성에는 논란이 있다. 따라서, 식품 알레르기의 기본이 되는 메커니즘에 대한 연구는 해당 질병을 이해하고 더 잘 예측하는데 필수적이라 할 수 있다. The persistence of childhood-onset food allergy (FA) varies considerably from patient to patient. Some children overcome symptoms at an early age, while others persist with food allergy for life. Although extensive research has been conducted on food allergy, strict dietary avoidance is still the dominant method for coping with food allergy, placing a significant burden on people with persistent symptoms. The exact mechanism for treating food allergy has not yet been fully elucidated, and therefore, methods for accurately predicting and treating food allergy are still limited. A number of factors affect food allergy treatment, including the type and number of causative allergens and the severity of symptoms. Several attempts have been made to predict food allergy treatment through the number of food allergies and allergen-specific IgE levels (Foong RX et al., Pediatr Allergy Immunol 2021; 32:223-33), but their accuracy is controversial. Therefore, research on the mechanisms underlying food allergy is essential for understanding and better predicting the disease.
최근 각광받는 오믹스 (omics) 연구는 게놈과 인간 질병 사이의 상관관계를 밝히는데 큰 잠재력을 보여주었다. 특히 대사체학은 질병에 기여하는 유전적 기초와 환경적 변화를 모두 반영하기 때문에 커다란 통찰력을 제공한다. 식품 알레르기에 대한 여러 대사체 접근법을 통하여 질병 상태 및 중증도와 관련하여 다양한 생체 샘플에서 대사체를 확인할 수 있다. 예를 들어, 이전 연구에서는 땅콩 알레르기가 있는 환자와 땅콩 알레르기가 없는 환자 간에 기준선 대사 산물 수준의 차이가 있다고 확인한 바 있다. 또 다른 연구에서는 건강한 대조군보다 음식 알레르기를 가지는 소아에서 스핑고지질과 리소인지질 수치가 더 낮다고 보고하였다. 그러나, 아직까지 식품 알레르기 치료를 위한 지침을 제공하는 대사체 연구는 없었다.Recently, omics research, which has been in the limelight, has shown great potential in revealing the correlation between genomes and human diseases. In particular, metabolomics provides great insight because it reflects both the genetic basis and environmental changes that contribute to disease. Several metabolomic approaches to food allergy allow the identification of metabolites in a variety of biological samples in relation to disease state and severity. For example, previous studies have identified differences in baseline metabolite levels between patients with and without peanut allergy. Another study reported lower sphingolipid and lysophospholipid levels in children with food allergy than in healthy controls. However, no metabolomic studies have yet provided guidance for the treatment of food allergy.
본 발명자들은 식품 알레르기를 가지는 아동과 건강한 대조군 아동의 혈청 샘플에서 대사체 프로파일링을 진행하여 식품 알레르기의 발병 및 치료와 관련된 대사체를 확인하고자 하였으며, 해당 대사 경로에서 이펙터 분자를 정량화하여 대사체 수준 차이로부터 아동의 식품 알레르기 지속성 여부를 평가할 수 있음을 확인함으로써 본 발명을 완성하였다. The present inventors carried out metabolomic profiling in serum samples of children with food allergy and healthy control children to identify metabolites related to the onset and treatment of food allergy, and quantified effector molecules in the metabolic pathway to determine the level of metabolites. The present invention was completed by confirming that the persistence of food allergy in children can be evaluated from the difference.
본 발명은 식품 알레르기 지속성 여부를 판할 수 있는 신규한 마커로서의 혈소판 활성화 인자의 용도를 제공하는데 있다. The present invention provides the use of a platelet activating factor as a novel marker capable of determining the persistence of food allergy.
상기 목적을 달성하기 위하여, 본 발명은 혈소판 활성화 인자 (platelet activating factor, PAF)의 수준을 측정하는 제제를 포함하는, 식품 알레르기 지속성 판단용 조성물을 제공한다.In order to achieve the above object, the present invention provides a composition for determining the persistence of food allergy, including an agent for measuring the level of platelet activating factor (PAF).
본 발명에 있어서, 상기 제제는 경쟁적 효소 결합 면역 흡착 분석용 (competitive enzyme-linked immuno-sorbent assay) 제제인 것을 특징으로 할 수 있다.In the present invention, the preparation may be characterized in that it is a preparation for competitive enzyme-linked immuno-sorbent assay.
본 발명에 있어서, 상기 제제는 상기 PAF의 수준을 측정하는 크로마토그래피 및/또는 질량분석용 제제인 것을 특징으로 할 수 있다.In the present invention, the preparation may be characterized in that it is a preparation for chromatography and/or mass spectrometry for measuring the level of the PAF.
본 발명은 또한, 혈소판 활성화 인자 아세틸 가수분해 효소 (platelet activating factor acetylhydrolase, PAFAH)의 활성을 측정하는 제제를 포함하는, 식품 알레르기 지속성 판단용 조성물을 제공한다.The present invention also provides a composition for determining the persistence of food allergy, including an agent for measuring the activity of platelet activating factor acetylhydrolase (PAFAH).
본 발명에 있어서, 상기 제제는 비색 분석용 제제인 것을 특징으로 할 수 있다.In the present invention, the preparation may be characterized in that it is a preparation for colorimetric analysis.
본 발명은 또한, 상기 조성물을 포함하는, 식품 알레르기 지속성 판단용 키트를 제공한다.The present invention also provides a kit for determining the persistence of food allergy, including the composition.
본 발명은 또한, 식품 알레르기를 가지는 대상체에서 분리된 샘플에서 The present invention also relates to a sample isolated from a subject with food allergy.
(i) 혈소판 활성화 인자 (platelet activating factor, PAF)의 수준을 측정; 및/또는(i) measuring the level of platelet activating factor (PAF); and/or
(ii) 혈소판 활성화 인자 아세틸 가수분해 효소 (platelet activating factor acetylhydrolase, PAFAH)의 활성을 측정; 하는 단계를 포함하는, 식품 알레르기 지속성 여부 예측을 위한 정보 제공 방법을 제공한다.(ii) measuring the activity of platelet activating factor acetylhydrolase (PAFAH); It provides an information providing method for predicting whether food allergy persists, including the step of doing.
본 발명에 있어서, 상기 (i) 혈소판 활성화 인자 (platelet activating factor, PAF)의 수준은 면역블로팅, 효소 결합 면역흡착 분석법(Enzyme-Linked Immunosorbent Assay: ELISA), 면역 조직 화학 염색, 단백질 칩, 면역침강, 질량분석, 크로마토그래피 또는 이들의 조합으로 수행되는 것을 특징으로 할 수 있다.In the present invention, the level of (i) platelet activating factor (PAF) is determined by immunoblotting, enzyme-linked immunosorbent assay (ELISA), immunohistochemical staining, protein chip, immunohistochemistry It may be characterized by sedimentation, mass spectrometry, chromatography, or a combination thereof.
본 발명에 있어서, 상기 (ii) 혈소판 활성화 인자 아세틸 가수분해 효소 (platelet activating factor acetylhydrolase, PAFAH)의 활성은 비색 분석법으로 측정하는 것을 특징으로 할 수 있다.In the present invention, (ii) the activity of platelet activating factor acetylhydrolase (PAFAH) may be measured by a colorimetric assay.
본 발명에 있어서, 상기 샘플은 혈액, 혈장, 혈청, 소변, 점액, 타액, 눈물, 객담, 척수액, 흉수, 유두 흡인물, 림프액, 기도액, 장액, 비뇨생식관액, 모유, 림프계 체액, 정액, 뇌척수액, 기관계내 체액, 복수, 낭성 종양 체액, 양수액 또는 이들의 조합인 것을 특징으로 할 수 있다.In the present invention, the sample is blood, plasma, serum, urine, mucus, saliva, tears, sputum, spinal fluid, pleural fluid, nipple aspirate, lymph fluid, airway fluid, serous fluid, genitourinary tract fluid, breast milk, lymphatic body fluid, semen, It may be characterized as cerebrospinal fluid, intraorgan system fluid, ascites, cystic tumor fluid, amniotic fluid, or a combination thereof.
본 발명에 있어서, 상기 (i) 혈소판 활성화 인자 (platelet activating factor, PAF)의 수준이 126 pg/mL 이상인 경우, 상기 대상체는 알레르기가 지속될 것으로 예측하는 것을 특징으로 할 수 있다.In the present invention, if the level of (i) platelet activating factor (PAF) is 126 pg/mL or higher, the subject may be characterized as predicting that the allergy will persist.
본 발명에 있어서, 상기 (ii) 혈소판 활성화 인자 아세틸 가수분해 효소 (platelet activating factor acetylhydrolase, PAFAH)의 활성이 0.008 μmol/min/mL 이하인 경우, 상기 대상체는 알레르기가 지속될 것으로 예측하는 것을 특징으로 할 수 있다.In the present invention, when the activity of (ii) platelet activating factor acetylhydrolase (PAFAH) is 0.008 μmol/min/mL or less, the subject is predicted to have an allergy there is.
본 발명에 있어서, 상기 식품 알레르기는 달걀 알레르기이고, 혈소판 활성화 인자의 수준이 130 pg/mL 이상인 경우, 상기 대상체는 달걀 알레르기가 지속될 것으로 예측하는 것을 특징으로 할 수 있다. In the present invention, if the food allergy is egg allergy, and the level of platelet activating factor is 130 pg/mL or higher, the subject may be characterized as predicting that the egg allergy will continue.
본 발명에 따르면, 진단시 혈소판 활성화 인자의 대사량 차이로부터 식품 알레르기 지속성 여부를 평가할 수 있어, 식품 알레르기로 고통받는 환자들에게 식품 알레르기가 지속될지 여부에 대한 정확하고 객관적인 정보를 제공할 수 있고, 이와 같은 정보를 근거로 적절한 임상 치료 계획을 수립할 수 있는 장점이 있다. According to the present invention, it is possible to evaluate the persistence of food allergy from the difference in the metabolism of platelet activating factors at the time of diagnosis, thereby providing accurate and objective information on whether or not the food allergy persists to patients suffering from food allergy. It has the advantage of being able to establish an appropriate clinical treatment plan based on the same information.
도 1은 식품 알레르기 및 식품 알레르기 해소에 기반한 식별 코호트 대상체의 sPLS-DA를 나타낸다. 도 1a는 건강한 대조군 (적색) 및 식품 알레르기를 가지는 대상체 (녹색)에 대한 sPLS-DA 모델의 점수 플롯을 나타내고, 도 1b는 식품 알레르기가 지속된 대상체 (적색) 및 식품 알레르기가 해소된 대상체 (녹색)에 대한 sPLS-DA 모델의 점수 플롯을 나타내며, 도 1c는 건강한 대조군 (청색), 식품 알레르기가 지속된 대상체 (녹색) 및 식품 알레르기가 해소된 대상체 (적색)에 대한 sPLS-DA 모델의 점수 플롯을 나타낸다. MetaboAnalyst 5.0을 사용하여 중심 축척으로 플롯이 그려졌으며, sPLS-DA는 희소 부분 최소 제곱 판별 분석, FA는 식품 알레르기를 의미한다.
도 2는 식별 코호트에서 확인된 식품 알레르기 및 식품 알레르기 해소와 관련된 대사체를 나타낸다. 도 2a는 식품 알레르기를 가지는 대상체 및 대조군 사이에 통계적으로 유의한 차이가 있는 대사체의 수준을 나타낸다. 도 2b는 식품 알레르기가 해소된 대상체 및 식품 알레르기가 지속된 대상체 사이에 통계적으로 유의한 차이가 있는 대사체의 수준을 나타낸다. 대사체는 생화학적 클래스에 따라 그룹화 하였으며, 클래스 당 표현형과 유의하게 연관된 2개 이상의 대사체를 포함하는 생화학적 클래스 또는 이전에 알레르기 질환과 관련된 것들만 표시하였다. FA, 음식 알레르기; AC, 아실카르니틴; LPA, 리소포스파티딘산; HDoHE, 히드록시도코사헥사엔산; PAF, 혈소판 활성화 인자; LPE, 리소포스파티딜에탄올아민; LPC, 리소포스파티딜콜린.
도 3은 식품 알레르기 및 식품 알레르기 해소에 대한 Random Forest 모델의 ROC 곡선을 나타낸다. Random Forest 모델은 (a) 식품 알레르기 (16개 특성) 및 (b) 식품 알레르기 해소 (13개 특성)와 크게 관련된 대사체로 구축되었다. CI, 신뢰 구간.
도 4는 정량 코호트의 대상체에서 혈소판 활성화 인자 (PAF) 및 혈소판 활성화 인자 아세틸 가수분해 효소 (PAFAH) 활성 수준를 나타낸다. 식품 알레르기가 지속된 대상체 및 식품 알레르기가 해소된 대상체 사이에서의 PAF 수준 및 PAFAH 활성에서 통계적으로 유의한 차이가 관찰되었다. *ANOVA p-값 < 0.05; FA, 음식 알레르기
도 5는 정량 코호트에서 총 혈청 IgE와 혈소판 활성화 인자 (PAF) 대사체 수준 간의 상관 관계를 보여준다. 산점도 (Scatter plot)는 PAF 수준 및 PAFAH 활성의 자연 로그 변환 값으로 그려졌다. R 값과 p 값은 Spearman의 상관 분석을 사용하여 계산되었다. 음영 영역은 95% 신뢰 구간을 나타낸다. IgE, 면역글로불린 E
도 6은 달걀 알레르기 환자에서 진단 당시 혈소판 활성화 인자 (PAF)의 수준에 따라 향후 달걀 알레르기 지속 또는 달걀 알레르기 해소 여부를 판별할 수 있음을 보여준다. 1 shows the sPLS-DA of subjects in an identification cohort based on food allergy and resolution of food allergy. Figure 1a shows a score plot of the sPLS-DA model for a healthy control group (red) and a subject with food allergy (green), and Figure 1b shows a subject with continued food allergy (red) and a subject with resolved food allergy (green). ), Figure 1c shows a score plot of the sPLS-DA model for healthy controls (blue), subjects with continued food allergy (green), and subjects with resolved food allergy (red) indicates Plots were drawn with central scale using MetaboAnalyst 5.0, sPLS-DA for sparse partial least squares discriminant analysis and FA for food allergy.
Figure 2 shows metabolomes associated with food allergy and resolution of food allergy identified in the identification cohort. Figure 2a shows the levels of metabolites with statistically significant differences between subjects with food allergy and controls. Figure 2b shows the levels of metabolites with statistically significant differences between subjects whose food allergy was resolved and subjects whose food allergy persisted. Metabolites were grouped according to biochemical class, and only biochemical classes containing two or more metabolites significantly associated with phenotypes per class or those previously associated with allergic disease were indicated. FA, food allergy; AC, acylcarnitine; LPA, lysophosphatidic acid; HDoHE, hydroxydocosahexaenoic acid; PAF, platelet activating factor; LPE, lysophosphatidylethanolamine; LPC, lysophosphatidylcholine.
Figure 3 shows the ROC curve of the random forest model for food allergy and food allergy resolution. A random forest model was built with metabolomes highly associated with (a) food allergy (16 traits) and (b) food allergy resolution (13 traits). CI, confidence interval.
Figure 4 shows platelet activating factor (PAF) and platelet activating factor acetylase (PAFAH) activity levels in subjects in a quantitative cohort. Statistically significant differences were observed in PAF levels and PAFAH activity between subjects whose food allergy persisted and those whose food allergy resolved. *ANOVA p-value <0.05; FA, food allergy
Figure 5 shows the correlation between total serum IgE and platelet activating factor (PAF) metabolite levels in the quantification cohort. Scatter plots were drawn as natural log transformed values of PAF levels and PAFAH activity. R values and p values were calculated using Spearman's correlation analysis. The shaded area represents the 95% confidence interval. IgE, immunoglobulin E
6 shows that it is possible to determine whether egg allergy persists or resolves in the future according to the level of platelet activating factor (PAF) at the time of diagnosis in an egg allergy patient.
다른 식으로 정의되지 않는 한, 본 명세서에서 사용된 모든 기술적 및 과학적 용어들은 본 발명이 속하는 기술분야에서 숙련된 전문가에 의해서 통상적으로 이해되는 것과 동일한 의미를 갖는다. 일반적으로 본 명세서에서 사용된 명명법은 본 기술 분야에서 잘 알려져 있고 통상적으로 사용되는 것이다.Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In general, the nomenclature used herein is one well known and commonly used in the art.
본 발명에서는 식품 알레르기를 진단받은 소아에서 진단 당시 정량적 차이를 보이는 대사체를 확인하고, 이들 소아를 추적 관찰함으로써 이들 대사체가 식품 알레르기 해소 또는 지속 여부와 유의한 상관관계를 나타내는지 확인하고자 하였다. 그 결과, 소아 식품 알레르기가 해소된 피험자와 소아 식품 알레르기가 지속된 피험자 사이, 진단 당시 혈청 대사체 분석에서 혈소판 활성화 인자의 수준에 유의한 차이가 있음을 확인하였다. 구체적으로 소아 식품 알레르기가 해소된 피험자에서는 낮은 수준의 혈청 혈소판 활성화 인자 (PAF)와 함께 높은 수준의 혈소판 활성화 인자 아세틸 가수분해 효소 (PAFAH) 활성이 확인되었으며, 이러한 대사체 간의 균형이 식품 알레르기 해소에 기여하고 식품 알레르기 지속성 여부를 판별할 수 있는 바이오마커로 작용할 수 있음을 알 수 있었다. In the present invention, metabolites showing quantitative differences at the time of diagnosis in children diagnosed with food allergy were identified, and these children were followed up to confirm whether these metabolites showed a significant correlation with the resolution or persistence of food allergy. As a result, it was confirmed that there was a significant difference in the level of platelet activating factor in the serum metabolomic analysis at the time of diagnosis between the subjects whose childhood food allergy was resolved and the subjects whose childhood food allergy persisted. Specifically, a high level of platelet activating factor acetylase (PAFAH) activity was confirmed along with a low level of serum platelet activating factor (PAF) in subjects whose childhood food allergy was resolved, and the balance between these metabolites was found to be responsible for the resolution of food allergy. It was found that it could contribute and act as a biomarker that can determine the persistence of food allergy.
따라서, 본 발명은 일 관점에서, 혈소판 활성화 인자 (platelet activating factor, PAF)의 수준을 측정하는 제제를 포함하는, 식품 알레르기 지속성 판단용 조성물에 관한 것이다.Accordingly, in one aspect, the present invention relates to a composition for determining the persistence of food allergy, including an agent for measuring the level of platelet activating factor (PAF).
본 발명에서, 혈소판 활성화 인자는 PAF (16:1)일 수 있으며, 하기 화학식 (1)로 표시될 수 있으나, 이에 한정되지는 않는다. 상기 혈소판 활성화 인자는, 인지질의 일종으로, PAF (16:1)에서 (16:1)은 16 개의 탄소 원자에 1 개의 이중결합을 포함하는 탄소 사슬을 포함하는 것을 특징으로 할 수 있다. In the present invention, the platelet activating factor is It may be PAF (16: 1), and may be represented by the following formula (1), but is not limited thereto. The platelet activating factor is a type of phospholipid, and PAF (16:1) to (16:1) may be characterized in that it includes a carbon chain including 16 carbon atoms and 1 double bond.
화학식 (1)Formula (1)
본 발명에 있어서, 상기 제제는 경쟁적 효소 결합 면역 흡착 분석용 (competitive enzyme-linked immuno-sorbent assay) 제제인 것을 특징으로 할 수 있으나, 이에 한정되지는 않는다.In the present invention, the preparation may be characterized in that it is a competitive enzyme-linked immuno-sorbent assay preparation, but is not limited thereto.
본 발명에 있어서, 상기 제제는 웰 플레이트 상에 항체를 코팅하고 비오틴(biotin) 표지된 PAF와 비오틴-비표지된 PAF와의 경쟁적 억제반응에 의해 테스트 샘플 내 PAF를 정량화하는 것일 수 있다. In the present invention, the agent may be coated with an antibody on a well plate and quantified PAF in a test sample by a competitive inhibition reaction between biotin-labeled PAF and non-biotin-labeled PAF.
본 발명에 있어서, 상기 항체를 대체하여 항원 결합 단편 또는 압타머를 사용할 수도 있다. In the present invention, an antigen-binding fragment or aptamer may be used instead of the antibody.
다른 양태로서, 상기 제제는 PAF에 특이적으로 결합하는 항체 또는 이의 항원 결합 단편, 또는 압타머인 것을 특징으로 할 수 있으나, 이에 한정되지는 않는다.In another aspect, the agent may be an antibody or antigen-binding fragment thereof that specifically binds to PAF, or an aptamer, but is not limited thereto.
본 발명에 있어서, 상기 제제는 상기 PAF의 수준을 측정하는 크로마토그래피 및/또는 질량분석용 제제인 것을 특징으로 할 수 있으나, 이에 한정되지는 않는다.In the present invention, the preparation may be characterized in that it is a preparation for chromatography and / or mass spectrometry for measuring the level of the PAF, but is not limited thereto.
PAF는 막 인지질, 주로 LPC의 리모델링에 의해 생성된다. LPC는 아라키돈산을 방출하고 IFN 감마 생산을 감소시켜 인간 유래 단핵구의 염증 촉진 활성화를 유도하는 것으로 알려져 있다. PAF는 또한 급성 염증성 캐스케이드를 증폭함으로써 염증성 질환에서 유사한 역할을 하며 알레르기 질환, 특히 식품 유발 중증 아나필락시스와 관련이 있는 것으로 알려져 있다. 혈소판 활성화 인자 아세틸 가수분해 효소 (platelet activating factor acetylhydrolase, PAFAH)는 혈소판 활성화 인자를 촉매하여 염증 유발 효과를 종결시키는데 필수적인 동종효소이다. 아나필락시스의 중증도는 기준선 순환 PAF 수준과 직접적으로 상관관계가 있고 PAFAH 활성과 역으로 상관관계가 있다. PAFs are produced by remodeling of membrane phospholipids, mainly LPCs. It is known that LPC induces pro-inflammatory activation of human monocytes by releasing arachidonic acid and reducing IFN-gamma production. PAFs also play a similar role in inflammatory diseases by amplifying the acute inflammatory cascade and are known to be associated with allergic diseases, particularly food-induced severe anaphylaxis. Platelet activating factor acetylhydrolase (PAFAH) is an essential isoenzyme that catalyzes platelet activating factor to terminate its pro-inflammatory effect. Severity of anaphylaxis directly correlated with baseline circulating PAF levels and inversely correlated with PAFAH activity.
따라서, 본 발명은 다른 관점에서, 혈소판 활성화 인자 아세틸 가수분해 효소 (platelet activating factor acetylhydrolase, PAFAH)의 활성을 측정하는 제제를 포함하는, 식품 알레르기 지속성 판단용 조성물에 관한 것이다.Therefore, from another aspect, the present invention relates to a composition for determining the persistence of food allergy, including an agent for measuring the activity of platelet activating factor acetylhydrolase (PAFAH).
본 발명에서, PAFAH는 파프아세틸하이드로레이스로 표시될 수 있으며, 인간에서 Gene ID: 5048과 7941의 뉴클레오티드 서열을 포함하는 암호화된 단백질일 수 있다. 상기 PAFAH 단백질은 Gene ID: 5048과 7941으로, 예를 들어, NM_000430.4, XM_017024701.1, XM_011523901.2, XM_017024702.2, XM_017024703.1, XM_011523902.3, XM_011523903.2, NP_000421.1, XP_011522203.1, XP_011522204.1, XP_011522205.1, XP_016880190.1, XP_016880191.1, XP_016880192.1, NM_001168357.2, NM_005084.4, NG_016204.1, XR_002956305.1, XR_001743639.2, XM_005249408.4등의 GenBank Accession No. 또는 Q13093, Q15102, P68402, P43034, Q99487등의 Uniprot Accession No.에 따른 뉴클레오티드에 의해 암호화되거나 아미노산 서열을 포함한 단백질일 수 있다. 상기 PAFAH 단백질은 동형 단백질 (isoform) 또는 이의 전구체를 포함하나, 본 발명에서는 이를 대표하여 서열번호 1과 서열번호 2로 표시되는 아미노산 서열을 기재하였다. In the present invention, PAFAH may be expressed as papacetylhydrolase, and may be an encoded protein comprising the nucleotide sequences of Gene IDs: 5048 and 7941 in humans. The PAFAH protein has Gene IDs: 5048 and 7941, for example, NM_000430.4, XM_017024701.1, XM_011523901.2, XM_017024702.2, XM_017024703.1, XM_011523902.3, XM_011523 903.2, NP_000421.1, XP_011522203. 1; GenBank Accession No such as 5.1, XR_001743639.2, XM_005249408.4 . Alternatively, it may be a protein encoded by nucleotides or containing an amino acid sequence according to Uniprot Accession No. such as Q13093, Q15102, P68402, P43034, Q99487. The PAFAH protein includes an isoform or a precursor thereof, but in the present invention, amino acid sequences represented by SEQ ID NO: 1 and SEQ ID NO: 2 are described.
서열번호 1: SEQ ID NO: 1:
MVLSQRQRDELNRAIADYLRSNGYEEAYSVFKKEAELDVNEELDKKYAGLLEKKWTSVIRLQKKVMELESKLNEAKEEFTSGGPLGQKRDPKEWIPRPPEKYALSGHRSPVTRVIFHPVFSVMVSASEDATIKVWDYETGDFERTLKGHTDSVQDISFDHSGKLLASCSADMTIKLWDFQGFECIRTMHGHDHNVSSVAIMPNGDHIVSASRDKTIKMWEVQTGYCVKTFTGHREWVRMVRPNQDGTLIASCSNDQTVRVWVVATKECKAELREHEHVVECISWAPESSYSSISEATGSETKKSGKPGPFLLSGSRDKTIKMWDVSTGMCLMTLVGHDNWVRGVLFHSGGKFILSCADDKTLRVWDYKNKRCMKTLNAHEHFVTSLDFHKTAPYVVTGSVDQTVKVWECR MVLSQRQRDELNRAIADYLRSNGYEEAYSVFKKEAELDVNEELDKKYAGLLEKKWTSVIRLQKKVMELESKLNEAKEEFTSGGPLGQKRDPKEWIPRPPEKYALSGHRSPVTRVIFHPVFSVMVSASEDATIKVWDYETGDFERTLKGHTDSVQDISFDHSGKLLASCSADMTIKLWDFQGFECIRTMHGHDHNVSSVAIMPNG DHIVSASRDKTIKMWEVQTGYCVKTFTGHREWVRMVRPNQDGTLIASCSNDQTVRVWVVATKECKAELREHEHVVECISWAPESSYSSISEATGSETKKSGKPGPFLLSGSRDKTIKMWDVSTGMCLMTLVGHDNWVRGVLFHSGGKFILSCADDKTLRVWDYKNKRCMKTLNAHEHFVTSLDFHKTAPYVVTGSV DQTVKVWECR
서열번호 2: SEQ ID NO: 2:
MVPPKLHVLFCLCGCLAVVYPFDWQYINPVAHMKSSAWVNKIQVLMAAASFGQTKIPRGNGPYSVGCTDLMFDHTNKGTFLRLYYPSQDNDRLDTLWIPNKEYFWGLSKFLGTHWLMGNILRLLFGSMTTPANWNSPLRPGEKYPLVVFSHGLGAFRTLYSAIGIDLASHGFIVAAVEHRDRSASATYYFKDQSAAEIGDKSWLYLRTLKQEEETHIRNEQVRQRAKECSQALSLILDIDHGKPVKNALDLKFDMEQLKDSIDREKIAVIGHSFGGATVIQTLSEDQRFRCGIALDAWMFPLGDEVYSRIPQPLFFINSEYFQYPANIIKMKKCYSPDKERKMITIRGSVHQNFADFTFATGKIIGHMLKLKGDIDSNVAIDLSNKASLAFLQKHLGLHKDFDQWDCLIEGDDENLIPGTNINTTNQHIMLQNSSGIEKYNMVPPKLHVLFCLCGCLAVVYPFDWQYINPVAHMKSSAWVNKIQVLMAAASFGQTKIPRGNGPYSVGCTDLMFDHTNKGTFLRLYYPSQDNDRLDTLWIPNKEYFWGLSKFLGTHWLMGNILRLLFGSMTTPANWNSPLRPGEKYPLVVFSHGLGAFRTLYSAIGIDLASHGFIVAAVEHRDRSASATYYFKDQSAAEIGDKS WLYLRTLKQEEETHIRNEQVRQRAKECSQALSLILDIDHGKPVKNALDLKFDMEQLKDSIDREKIAVIGHSFGGATVIQTLSEDQRFRCGIALDAWMFPLGDEVYSRIPQPLFFINNSEYFQYPANIIKMKKCYSPDKERKMITIRGSVHQNFADFTFATGKIIGHMLKLKGDIDSNVAIDLSNKASLAFLQKHLGLHKDFDQWDCLIEGDD ENLIPGTNINTTNQHIMLQNSSGIEKYN
본 발명에 있어서, 상기 PAFAH의 활성을 측정하는 제제는 비색 분석용 제제인 것을 특징으로 할 수 있으나, 이에 한정되지는 않는다. 분광 검정법이나 방사 측정법을 사용하여 PAFAH의 활성을 측정할 수 있다.In the present invention, the agent for measuring the activity of PAFAH may be characterized in that it is an agent for colorimetric analysis, but is not limited thereto. The activity of PAFAH can be measured using spectrophotometric or radiometric methods.
한편, 본 발명에서는 PAFAH의 서브유닛인 PAFAH1B1의 3' 측면 영역에 위치한 SNP인 rs2290925가 PAF (16:1)와 유의한 상관관계를 나타내는 것을 확인하였다. 즉, 상기 SNP rs2290925에서 이형접합체 (즉, GA)를 가진 피험자는 주요 대립유전자 A의 동형접합체 (즉, AA)를 갖는 대상체에 비해 PAF(16:1) 수준이 더 높게 나타나, PAFAH1B1의 SNP인 rs2290925가 식품 알레르기 지속성 예측에 있어서 높은 통계적 유의성을 갖는 것을 확인하였는 바 (Bonferroni 수정된 p-값 = 0.0384)(표 7), 상기 SNP를 이용하면 효율적으로 식품 알레르기 지속 여부를 진단할 수 있다.Meanwhile, in the present invention, it was confirmed that rs2290925, a SNP located in the 3' flanking region of PAFAH1B1, a subunit of PAFAH, showed a significant correlation with PAF (16:1). That is, subjects with heterozygosity (i.e., GA) at the SNP rs2290925 showed a higher level of PAF (16: 1) than subjects with homozygosity (i.e., AA) of the main allele A, which is the SNP of PAFAH1B1 As it was confirmed that rs2290925 has high statistical significance in predicting the persistence of food allergy (Bonferroni corrected p-value = 0.0384) (Table 7), the SNP can be used to efficiently diagnose the persistence of food allergy.
따라서, 본 발명은 또 다른 관점에서, 혈소판 활성화 인자 아세틸 가수분해 효소 (platelet activating factor acetylhydrolase, PAFAH)의 서브유닛인 PAFAH1B1의 SNP(rs2290925)를 판별하는 제제를 포함하는, 식품 알레르기 지속성 판단용 조성물에 관한 것이다.Therefore, from another aspect, the present invention provides a composition for determining the persistence of food allergy, including an agent for determining the SNP (rs2290925) of PAFAH1B1, a subunit of platelet activating factor acetylhydrolase (PAFAH) it's about
본 발명에 있어서, 상기 PAFAH의 서브유닛인 PAFAH1B1 단백질을 암호화하는 유전자의 Gene ID는 5048으로, 예를 들어, NM_000430.4, XM_017024701.1, XM_011523901.2, XM_017024702.2, XM_017024703.1, XM_011523902.3, XM_011523903.2, NP_000421.1, XP_011522203.1, XP_011522204.1, XP_011522205.1, XP_016880190.1, XP_016880191.1, XP_016880192.1 등의 GeneBank Accession No. 또는 Uniprot Accession No.에 따른 뉴클레오티드 또는 아미노산 서열에 의해 식별 가능한 단백질일 수 있다. In the present invention, the Gene ID of the gene encoding the PAFAH1B1 protein, which is the subunit of PAFAH, is 5048, for example, NM_000430.4, XM_017024701.1, XM_011523901.2, XM_017024702.2, XM_017024703.1, XM_0115239 02. 3; Alternatively, it may be a protein identifiable by a nucleotide or amino acid sequence according to Uniprot Accession No.
본 발명의 일 실시예에 따르면, 상기 rs2290925의 염기의 대립형질이 G이거나 그의 상보적인 염기의 대립형질이 C인 경우, 식품 알레르기를 가지는 것으로 진단되었더라도 향후 지속될 가능성이 높은 것으로 예측할 수 있다. According to one embodiment of the present invention, when the allele of the base of rs2290925 is G or the allele of its complementary base is C, it can be predicted that the food allergy is likely to continue in the future even if it is diagnosed.
본 발명에 있어서, 상기 SNP를 판별하는 제제는 SNP를 검출 및/또는 증폭시킬수 있는 프라이머 및/또는 프로브인 것을 특징으로 할 수 있다. In the present invention, the agent for determining the SNP may be a primer and/or a probe capable of detecting and/or amplifying the SNP.
본 발명에 있어서, 상기 SNP(rs2290925)의 유전자형이 AA인 경우, 유전자형이 GG 또는 GA인 경우에 비해 식품 알레르기 해소 가능성이 높은 것으로 판단하는 것을 특징으로 할 수 있다.In the present invention, when the genotype of the SNP (rs2290925) is AA, it may be characterized in that the possibility of resolving food allergy is higher than when the genotype is GG or GA.
본 명세서에서 용어 "마커"는 식품 알레르기의 지속성 여부를 구분할 수 있는 물질로, 식품 알레르기 환자에서 진단시 양적 차이에 따라 향후 식품 알레르기 지속 또는 식품 알레르기 해소 여부에서 차이를 보이기 때문에 향후 식품 알레르기가 지속 또는 해소 여부를 판별할 수 있어, 그 정량적 수준을 평가함으로써 식품 알레르기 지속성 여부를 판단하거나 평가할 수 있는 물질을 의미한다. In this specification, the term "marker" is a substance that can distinguish whether or not food allergy persists, and since it shows a difference in whether food allergy persists or resolves food allergy in the future depending on the quantitative difference at the time of diagnosis in food allergy patients, food allergy continues or disappears in the future. It refers to a substance that can determine whether or not it resolves, and can judge or evaluate the persistence of food allergy by evaluating its quantitative level.
본 발명에서 예측이란, 식품 알레르기가 지속될 것인지 또는 해소될 것인지의 여부를 미리 판단하거나 평가하는 것을 의미하며, 예후를 판단하거나 치료 효과를 진단한다는 의미를 모두 포함한다. In the present invention, prediction means to judge or evaluate in advance whether a food allergy will persist or be resolved, and includes both the meaning of determining a prognosis or diagnosing a treatment effect.
바람직하게는, 본 발명은 본 발명에 따른 바이오마커를 이용한 소아 식품 알레르기 환자의 진단을 통해 소아의 식품 알레르기 지속성 여부를 미리 예측할 수 있다. Preferably, the present invention can predict in advance whether or not the child's food allergy persists through the diagnosis of the pediatric food allergy patient using the biomarker according to the present invention.
본 발명에서 소아는 3 개월 이상 만 18세 미만을 의미할 수 있고, 바람직하게는 6개월 이상 만 12세 미만을 의미할 수 있으나, 이에 한정되지는 않는다. 따라서, 본 발명은 3 개월 이상 만 18세 미만의 식품 알레르기를 가지는 소아를 진단하여 식품 알레르기 지속성 여부를 예측하는 것을 특징으로 할 수 있으나, 이는 식품 알레르기가 소아 시기에 주로 발병하기 때문인 것으로, 성인에서도 식품 알레르기의 지속성 여부를 판단하기 위하여 본 발명이 적용될 수 있을 것이다. In the present invention, children may mean 3 months or more and less than 18 years of age, preferably 6 months or more and less than 12 years of age, but are not limited thereto. Therefore, the present invention may be characterized by diagnosing children with food allergies aged 3 months or more and younger than 18 years of age to predict whether food allergy persists, but this is because food allergies mainly occur in childhood, and also in adults The present invention may be applied to determine whether or not food allergy persists.
본 발명에 있어서, 상기 마커는 진단 시점으로부터 1년 이상 경과시 식품 알레르기 지속 가능성을 예측하는 것을 특징으로 할 수 있으나, 이에 한정되지는 않으며, 상기 바이오마커는 진단으로부터 1년 내지 10년 경과시, 바람직하게는 1년 내지 5년 경과시, 식품 알레르기 지속 가능성을 예측하는 것을 특징으로 할 수 있고, 일부 양태로서 상기 바이오마커는 진단으로부터 12개월, 13개월, 14개월, 15개월, 16개월, 17개월, 18개월, 19개월, 20개월, 21개월, 22개월, 23개월, 24개월, 25개월, 26개월, 27개월, 28개월, 29개월, 30개월, 31개월, 32개월, 33개월, 34개월, 35개월 또는 36개월 경과시 식품 알레르기 지속 가능성을 예측하는 것을 특징으로 할 수 있다. In the present invention, the marker may be characterized in predicting the sustainability of food allergy when 1 year or more elapses from the time of diagnosis, but is not limited thereto, and the biomarker is 1 year to 10 years after diagnosis, It can be characterized in predicting the sustainability of food allergy, preferably at 1 year to 5 years, and in some embodiments, the biomarker is 12 months, 13 months, 14 months, 15 months, 16 months, 17 months from diagnosis. months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, It can be characterized by predicting the likelihood of food allergy persistence at 34, 35, or 36 months.
본 발명에서, 상기 PAF는 면역원성 단편에 결합된 것일 수 있다. 즉, 상기 PAF는 항체에 의해 인식될 수 있도록 하는 하나 이상의 에피토프(epitope)를 가지고 있는 단편에 결합된 것일 수 있다.In the present invention, the PAF may be bound to an immunogenic fragment. That is, the PAF may be bound to a fragment having at least one epitope that can be recognized by an antibody.
본 명세서에서 용어 "항체"는 당해 분야에서 공지된 용어로서 항원성 부위에 대해서 지시되는 특이적인 단백질 분자를 의미할 수 있다. 일 양상에 따른 항체의 형태는 특별히 한정되지 않으며 폴리클로날 항체, 모노클로날 항체 또는 항원 결합성을 갖는 것이면 그것의 일부도 포함되고 모든 면역글로불린 항체가 포함될 수 있으며, 나아가, 인간화 항체 등의 특수항체도 포함될 수 있다. 일 양태에 따른 항체는 2개의 전체 길이의 경쇄 및 2개의 전체 길이의 중쇄를 가지는 완전한 형태뿐만 아니라 항체 분자의 기능적인 단편을 포함할 수 있다. 항체 분자의 기능적인 단편은 적어도 항원 결합기능을 보유하고 있는 단편을 의미하며, 예를 들어, Fab, F(ab'), F(ab')2, Fv, scFv 등일 수 있다.As used herein, the term "antibody" is a term known in the art and may refer to a specific protein molecule directed against an antigenic site. The type of antibody according to one aspect is not particularly limited, and polyclonal antibodies, monoclonal antibodies, or any immunoglobulin antibody may be included as long as it has antigen binding properties, and furthermore, special antibodies such as humanized antibodies may be included. Antibodies may also be included. Antibodies according to one embodiment may include functional fragments of the antibody molecule as well as complete forms having two full-length light chains and two full-length heavy chains. A functional fragment of an antibody molecule refers to a fragment having at least an antigen-binding function, and may be, for example, Fab, F(ab'), F(ab')2, Fv, scFv, and the like.
본 명세서에서, 크로마토그래피는 가스 크로마토그래피(Gas Chromatography), 액체-고체 크로마토그래피 (Liquid-Solid Chromatography, LSC), 종이 크로마토그래피(Paper Chromatography, PC), 박층 크로마토그래피 (Thin-Layer Chromatography, TLC), 기체-고체 크로마토그래피(Gas-Solid Chromatography, GSC), 액체-액체 크로마토그래피(Liquid-Liquid Chromatography, LLC), 포말 크로마토그래피(Foam Chromatography, FC), 유화 크로마토그래피(Emulsion Chromatography, EC), 기체-액체 크로마토그래피(Gas-Liquid Chromatography, GLC), 이온 크로마토그래피(Ion Chromatography, IC), 겔 여과 크로마토그래피(Gel Filtration Chromatograhy, GFC) 또는 겔 투과 크로마토그래피(Gel Permeation Chromatography, GPC)를 포함하나, 이에 한정되지 않고, 당업계에서 통상적으로 사용되는 모든 정량용 크로마토그래피를 사용할 수 있다. 바람직하게는, 본 발명에서 이용되는 크로마토그래피는 가스 크로마토그래피이다. 바람직하게는, 본 발명에서 이용되는 질량분석기는 MALDI-TOF MS 또는 TOF MS이고, 보다 바람직하게는 TOF MS이다.In this specification, chromatography is gas chromatography (Gas Chromatography), liquid-solid chromatography (Liquid-Solid Chromatography, LSC), paper chromatography (Paper Chromatography, PC), thin-layer chromatography (Thin-Layer Chromatography, TLC) , Gas-Solid Chromatography (GSC), Liquid-Liquid Chromatography (LLC), Foam Chromatography (FC), Emulsion Chromatography (EC), Gas -Including liquid chromatography (Gas-Liquid Chromatography, GLC), Ion Chromatography (IC), Gel Filtration Chromatography (GFC) or Gel Permeation Chromatography (GPC), It is not limited thereto, and all quantitative chromatography commonly used in the art may be used. Preferably, the chromatography used in the present invention is gas chromatography. Preferably, the mass spectrometer used in the present invention is MALDI-TOF MS or TOF MS, more preferably TOF MS.
본 발명은 또 다른 관점에서, 상기 조성물을 포함하는, 식품 알레르기 지속성 판단용 키트에 관한 것이다.In another aspect, the present invention relates to a kit for determining the persistence of food allergy, including the composition.
본 발명에 있어서, 상기 키트는 일 양태로서, 경쟁적 효소 결합 면역 흡착 분석용 (competitive enzyme-linked immuno-sorbent assay) 키트일 수 있고, 다른 양태로서 정량적 샌드위치 ELISA 키트 (Quantitative Sandwich ELISA kit)일 수 있으며, 또 다른 양태로서, PAF의 수준을 측정하는 크로마토그래피 및/또는 질량분석용 키트일 수 있으며, 또 다른 양태로서, 혈소판 활성화 인자 아세틸 가수분해 효소 (platelet activating factor acetylhydrolase, PAFAH)의 활성 측정용 키트일 수 있다.In the present invention, the kit may be a competitive enzyme-linked immuno-sorbent assay kit in one aspect, and a quantitative sandwich ELISA kit in another aspect. , In another embodiment, it may be a chromatography and / or mass spectrometry kit for measuring the level of PAF, and in another embodiment, a kit for measuring the activity of platelet activating factor acetylhydrolase (PAFAH) can be
본 발명에서, 상기 키트는 항체, 항체의 면역학적 검출을 위하여 기질, 적합한 완충용액, 발색 효소 또는 형광물질로 표지된 2차 항체, 또는 발색 기질을 포함할 수 있다. 상기 키트는 압타머, 프라미어, 프로브 또는 올리고뉴클레오티드를 포함할 수 있다. In the present invention, the kit may include an antibody, a substrate for immunological detection of the antibody, a suitable buffer, a secondary antibody labeled with a chromogenic enzyme or a fluorescent substance, or a chromogenic substrate. The kit may include an aptamer, primer, probe or oligonucleotide.
예컨대, 본 발명에서 경쟁적 효소 결합 면역 흡착 분석용 (competitive enzyme-linked immuno-sorbent assay) 키트는 항체 코팅된 웰 플레이트, 비오틴-표지 PAF, HRP-접합 시약 및 TMB 기질로 구성된 군에서 선택되는 하나 이상을 포함할 수 있으나, 이에 한정되지는 않는다. For example, in the present invention, the competitive enzyme-linked immuno-sorbent assay kit is one or more selected from the group consisting of antibody-coated well plate, biotin-labeled PAF, HRP-conjugated reagent, and TMB substrate. It may include, but is not limited to.
본 발명에 있어서, 상기 키트는 또 다른 양태로서, 혈소판 활성화 인자 아세틸 가수분해 효소 (platelet activating factor acetylhydrolase, PAFAH)의 서브유닛인 PAFAH1B1의 SNP(rs2290925) 판별용 키트일 수 있다. In the present invention, as another aspect, the kit may be a kit for determining SNP (rs2290925) of PAFAH1B1, which is a subunit of platelet activating factor acetylhydrolase (PAFAH).
본 발명에 있어서, 상기 키트는 본원의 SNP, 폴리뉴클레오티드, cDNA 등뿐만 아니라 분석 방법에 적합한 다른 구성 성분 조성물, 용액 또는 장치가 포함될 수 있다.In the present invention, the kit may include not only the SNP, polynucleotide, cDNA, etc. of the present application, but also other component compositions, solutions or devices suitable for the analysis method.
본 발명에 있어서, 상기 키트는 PCR 키트, RT-PCR 키트 또는 DNA 칩 키트일 수 있으나, 이에 한정되지는 않는다.In the present invention, the kit may be a PCR kit, RT-PCR kit or DNA chip kit, but is not limited thereto.
상기 키트는 완충액(lysis buffer)을 더 포함할 수 있다. 상기 완충액은 상용화된 제품 등 다양한 물질을 포함할 수 있다. 상기 완충액은 HEPES, MgCl2, NaCl, 이미다졸, DNAse 및 β이 포함될 수 있고, 단백질의 분해를 방지하기 위해 프로테이즈 저해제인 PMSF (phenylmethanesulfonylfluoride)가 첨가될 수 있으나, 이에 한정되지 않는다.The kit may further include a lysis buffer. The buffer solution may include various materials such as commercially available products. The buffer may include HEPES, MgCl 2 , NaCl, imidazole, DNAse, and β, and a protease inhibitor PMSF (phenylmethanesulfonylfluoride) may be added to prevent protein degradation, but is not limited thereto.
상기 키트는 유전자 또는 단백질을 분해 (Digestion)하는 시약을 더 포함할 수 있다. 상기 유전자 분해 시약은 제한효소 등을 포함할 수 있다. 상기 단백질 분해 시약은 트립신, 트립신/EDTA, 또는 TrypLE 등을 포함할 수 있으나, 상기 유전자 또는 단백질 분해 시약은 이에 한정되지 않는다.The kit may further include a reagent for digesting genes or proteins. The gene degradation reagent may include a restriction enzyme or the like. The proteolytic reagent may include trypsin, trypsin/EDTA, or TrypLE, but the gene or proteolytic reagent is not limited thereto.
상기 키트는 동위원소로 라벨링된 표준 펩타이드(Isotope labeled standard peptide) 혼합물을 더 포함할 수 있다.The kit may further include a mixture of isotope labeled standard peptides.
상기 키트는 데이터 분석 또는 통계처리를 할 수 있는 프로그램을 더 포함할 수 있다. 상기 프로그램은 유전자 또는 단백질의 발현 수준을 분석하는 것일 수 있다. 상기 데이터 분석 또는 통계처리 프로그램은 Skyline Software, ProteoWizard Software, SCIEX OS Software, SPSS Statistics Software, MedCalc Software, MultiQuant Software, MasterView Software 또는 Cliquid Software 중에서 선택된 하나 이상일 수 있으나, 이에 한정되지 않는다.The kit may further include a program capable of data analysis or statistical processing. The program may analyze the expression level of a gene or protein. The data analysis or statistical processing program may be one or more selected from Skyline Software, ProteoWizard Software, SCIEX OS Software, SPSS Statistics Software, MedCalc Software, MultiQuant Software, MasterView Software, or Cliquid Software, but is not limited thereto.
상기 키트는 RT-PCR(Reverse transcription polymerase chain reaction) 키트, DNA 칩 키트, ELISA(Enzyme linked immunosorbent assay) 키트, 단백질 칩 키트, 래피드(rapid) 키트 또는 MRM(Multiple reaction monitoring) 키트일 수 있다.The kit may be a reverse transcription polymerase chain reaction (RT-PCR) kit, a DNA chip kit, an enzyme linked immunosorbent assay (ELISA) kit, a protein chip kit, a rapid kit, or a multiple reaction monitoring (MRM) kit.
본 발명의 일 양태로서, 상기 PCR 키트는 PCR을 수행하기 위해 필요한 필수 요소를 포함하는 키트일 수 있다. PCR 키트는, 상기 SNP에 대한 특이적인 폴리뉴클레오티드, 프라이머 또는 프로브 외에도 테스트 튜브 또는 다른 적절한 컨테이너, 반응 완충액 (pH 및 마그네슘 농도는 다양), 데옥시뉴클레오타이드(dNTPs), Taq-폴리머라아제 및 역전사효소와 같은 효소, DNase, RNAse 억제제, DEPC-수 (DEPC-water) 및 멸균수 등을 포함할 수 있다.As one aspect of the present invention, the PCR kit may be a kit including essential elements required to perform PCR. The PCR kit contains, in addition to polynucleotides, primers or probes specific for the SNP, a test tube or other suitable container, reaction buffer (with varying pH and magnesium concentration), deoxynucleotides (dNTPs), Taq-polymerase and reverse transcriptase enzymes such as, DNase, RNAse inhibitors, DEPC-water and sterile water, and the like.
본 발명의 일 양태로서, 상기 DNA 칩 키트는 DNA 칩을 수행하기 위해 필요한 필수 요소를 포함하는 키트일 수 있으며, DNA 칩 키트는 상기 SNP에 대한 특이적인 폴리뉴클레오티드, 프라이머 또는 프로브가 부착되어 있는 기판을 포함하고 기판은 정량 대조구 유전자 또는 그의 단편에 해당하는 핵산을 포함할 수 있다.As one aspect of the present invention, the DNA chip kit may be a kit including essential elements required to perform DNA chip, and the DNA chip kit may include a substrate to which a polynucleotide, primer or probe specific for the SNP is attached. And the substrate may include a nucleic acid corresponding to a quantitative control gene or a fragment thereof.
본 발명의 일 양태로서, 상기 RT-PCR 키트는 RT-PCR을 수행하기 위해 필요한 필수 요소를 포함하는 키트일 수 있으며, RT-PCR 키트는, 상기 SNP에 대한 특이적인 각각의 프라이머 외에도 테스트 튜브 또는 다른 적절한 컨테이너, 반응 완충액(pH 및 마그네슘 농도는 다양), 디옥시뉴클레오타이드(dNTPs), 디디옥시뉴클레오타이드(ddNTPs), Taq-폴리머라아제 및 역전사효소와 같은 효소, DNase, RNAse 억제제, DEPC-수(DEPC-water), 멸균수 등을 포함할 수 있다.As one aspect of the present invention, the RT-PCR kit may be a kit including essential elements required to perform RT-PCR, and the RT-PCR kit, in addition to each primer specific for the SNP, a test tube or Other suitable containers, reaction buffers (pH and magnesium concentrations vary), deoxynucleotides (dNTPs), dideoxynucleotides (ddNTPs), enzymes such as Taq-polymerase and reverse transcriptase, DNase, RNAse inhibitors, DEPC-water ( DEPC-water), sterile water, and the like.
또 다른 관점에서, 본 발명은 식품 알레르기를 가지는 대상체에서 분리된 샘플에서 In another aspect, the present invention relates to a sample isolated from a subject having a food allergy.
(i) 혈소판 활성화 인자 (platelet activating factor, PAF)의 수준을 측정; 및/또는(i) measuring the level of platelet activating factor (PAF); and/or
(ii) 혈소판 활성화 인자 아세틸 가수분해 효소 (platelet activating factor acetylhydrolase, PAFAH)의 활성을 측정; 하는 단계를 포함하는, 식품 알레르기 지속성 여부 예측을 위한 정보 제공 방법에 관한 것이다.(ii) measuring the activity of platelet activating factor acetylhydrolase (PAFAH); It relates to a method for providing information for predicting whether food allergy persists, including the step of doing.
본 발명에 있어서, 상기 (i) 혈소판 활성화 인자 (platelet activating factor, PAF)의 수준은 면역블로팅, 효소 결합 면역흡착 분석법(Enzyme-Linked Immunosorbent Assay: ELISA), 면역 조직 화학 염색, 단백질 칩, 면역침강, 질량분석, 크로마토그래피 또는 이들의 조합으로 수행되는 것을 특징으로 할 수 있으나, 이에 한정되지는 않는다.In the present invention, the level of (i) platelet activating factor (PAF) is determined by immunoblotting, enzyme-linked immunosorbent assay (ELISA), immunohistochemical staining, protein chip, immunohistochemistry It may be characterized as being performed by sedimentation, mass spectrometry, chromatography, or a combination thereof, but is not limited thereto.
본 발명에 있어서, 상기 (ii) 혈소판 활성화 인자 아세틸 가수분해 효소 (platelet activating factor acetylhydrolase, PAFAH)의 활성은 비색 분석법으로 측정하는 것을 특징으로 할 수 있으나, 이에 한정되지는 않는다.In the present invention, the activity of (ii) platelet activating factor acetylhydrolase (PAFAH) may be measured by a colorimetric assay, but is not limited thereto.
본 발명은 식품 알레르기를 가지는 대상체에서 분리된 샘플에서 In a sample isolated from a subject with food allergy, the present invention
(iii) 혈소판 활성화 인자 아세틸 가수분해 효소 (platelet activating factor acetylhydrolase, PAFAH)의 서브유닛인 PAFAH1B1의 SNP (rs2290925)를 판별;하는 단계를 포함하는 식품 알레르기 지속성 여부 예측을 위한 정보 제공 방법에 관한 것이다.(iii) determining the SNP (rs2290925) of PAFAH1B1, a subunit of platelet activating factor acetylhydrolase (PAFAH);
본 발명에 있어서, 상기 (iii) 혈소판 활성화 인자 아세틸 가수분해 효소 (platelet activating factor acetylhydrolase, PAFAH)의 서브유닛인 PAFAH1B1의 SNP(rs2290925)는 , 시퀀싱 분석, 파이로시퀀싱(pyrosequencing), 마이크로어레이에 의한 혼성화, PCR-RELP(restriction fragment length polymorphism)법, PCR-SSCP(single strand conformation polymorphism)법, PCR-SSO(specific sequence oligonucleotide)법, PCR-SSO법과 도트 하이브리드화법을 조합한 ASO(allele specific oligonucleotide) 하이브리드화법, TaqMan-PCR법, MALDI-TOF/MS법, RCA(rolling circle amplification)법, HRM(high resolution melting)법, 프라이머 신장법, 서던 블롯 하이브리드화법, 도트 하이브리드화법 또는 이들의 조합으로 판별되는 것을 특징으로 할 수 있으나, 이에 한정되지는 않는다.In the present invention, the SNP (rs2290925) of PAFAH1B1, which is a subunit of (iii) platelet activating factor acetylhydrolase (PAFAH), is determined by sequencing analysis, pyrosequencing, and microarray. Hybridization, PCR-RELP (restriction fragment length polymorphism) method, PCR-SSCP (single strand conformation polymorphism) method, PCR-SSO (specific sequence oligonucleotide) method, ASO (allele specific oligonucleotide) combining PCR-SSO method and dot hybridization method Hybridization method, TaqMan-PCR method, MALDI-TOF / MS method, RCA (rolling circle amplification) method, HRM (high resolution melting) method, primer extension method, Southern blot hybridization method, dot hybridization method, or a combination thereof It may be characterized by, but is not limited thereto.
본 발명에 있어서, 상기 샘플은 혈액, 혈장, 혈청, 소변, 점액, 타액, 눈물, 객담, 척수액, 흉수, 유두 흡인물, 림프액, 기도액, 장액, 비뇨생식관액, 모유, 림프계 체액, 정액, 뇌척수액, 기관계내 체액, 복수, 낭성 종양 체액, 양수액 또는 이들의 조합인 것을 특징으로 할 수 있으나, 이에 한정되지는 않는다.In the present invention, the sample is blood, plasma, serum, urine, mucus, saliva, tears, sputum, spinal fluid, pleural fluid, nipple aspirate, lymph fluid, airway fluid, serous fluid, genitourinary tract fluid, breast milk, lymphatic body fluid, semen, It may be characterized as cerebrospinal fluid, organ system fluid, ascites, cystic tumor fluid, amniotic fluid, or a combination thereof, but is not limited thereto.
본 발명에 있어서, 바람직하게는 상기 (i) 혈소판 활성화 인자 (platelet activating factor, PAF)의 수준이 126 pg/mL 이상인 경우, 바람직하게는, 127 pg/mL 이상인 경우, 더 바람직하게는 128 pg/mL 이상인 경우, 더욱 바람직하게는 129 pg/mL 이상인 경우, 가장 바람직하게는 130 pg/mL 이상이 경우, 상기 대상체는 알레르기가 지속될 것으로 예측하는 것을 특징으로 할 수 있다.In the present invention, preferably, the (i) platelet activating factor (PAF) level is 126 pg/mL or more, preferably, 127 pg/mL or more, more preferably 128 pg/mL If it is greater than or equal to mL, more preferably greater than or equal to 129 pg/mL, and most preferably greater than or equal to 130 pg/mL, the subject may be characterized as predicting that the allergy will persist.
본 발명에 있어서, 바람직하게는 상기 (ii) 혈소판 활성화 인자 아세틸 가수분해 효소 (platelet activating factor acetylhydrolase, PAFAH)의 활성이 0.008 μmol/min/mL 이하인 경우, 바람직하게는, 0.0078 μmol/min/mL 이하인 경우, 상기 대상체는 알레르기가 지속될 것으로 예측하는 것을 특징으로 할 수 있다. In the present invention, preferably, when the activity of (ii) platelet activating factor acetylhydrolase (PAFAH) is 0.008 μmol/min/mL or less, preferably, 0.0078 μmol/min/mL or less In this case, the subject may be characterized as predicting that the allergy will persist.
본 발명에 있어서, 바람직하게는 상기 식품 알레르기는 달걀 알레르기이고, 혈소판 활성화 인자의 수준이 126 pg/mL, 바람직하게는 130 pg/mL 이상인 경우, 상기 대상체는 달걀 알레르기가 지속될 것으로 예측하는 것을 특징으로 할 수 있다.In the present invention, preferably, the food allergy is egg allergy, and when the level of platelet activating factor is 126 pg/mL, preferably 130 pg/mL or more, the subject predicts that egg allergy will persist can do.
본 발명에 있어서, 상기 혈소판 활성화 인자의 수준은 Platelet Activating Factor (PAF) ELISA Kit (Cat. No: abx150368, Abbexa Biologics, Arlington, Texas, USA)를 이용하여 측정하는 것일 수 있으나, 이에 한정되지는 않는다. In the present invention, the level of the platelet activating factor may be measured using a Platelet Activating Factor (PAF) ELISA Kit (Cat. No: abx150368, Abbexa Biologics, Arlington, Texas, USA), but is not limited thereto .
본 발명에 따른 상기 정보 제공 방법에서, 상기 결과들은 당업계에서 일반적으로 사용되는 통계학적 분석 방법을 이용하여 통계처리 할 수 있으며, 예를 들어, 스튜던트 t-검정(Student's t-test), 카이-스퀘어 검정(Chi-square test), 선형 회귀선 분석(linear regression line analysis), 다변량 로지스틱 회귀분석(multiple logistic regression analysis), 메타 분석(meta-analysis) 등을 통해 얻은 연속 변수(continuous variables), 절대 변수 (categorical variables), 대응비(odds ratio, OR) 및 95% 신뢰구간(confidence interval, CI) 등의 변수를 이용하여 분석할 수 있다.In the information providing method according to the present invention, the results can be statistically processed using statistical analysis methods commonly used in the art, for example, Student's t-test, chi- Continuous variables and absolute variables obtained through chi-square test, linear regression line analysis, multiple logistic regression analysis, meta-analysis, etc. It can be analyzed using variables such as categorical variables, odds ratio (OR), and 95% confidence interval (CI).
본 명세서에서 용어, "대상체"는 식품 알레르기를 가지는 모든 생물체를 의미하며, 구체적인 예로, 마우스, 원숭이, 소, 돼지, 미니돼지, 가축, 인간 등을 포함하는 포유동물을 포함할 수 있으나, 이에 한정되는 것은 아니다.As used herein, the term "subject" refers to any organism having a food allergy, and may include mammals, including mice, monkeys, cows, pigs, mini-pigs, livestock, humans, etc. as specific examples, but is limited thereto. it is not going to be
본 발명에 있어서, 상기 대상체는 인간일 수 있으며, 구체적으로 한국인 또는 아시아인일 수 있으나, 이에 한정되는 것은 아니다.In the present invention, the subject may be a human, specifically Korean or Asian, but is not limited thereto.
이하, 실시예를 통하여 본 발명을 더욱 상세히 설명하고자 한다. 이들 실시예는 오로지 본 발명을 예시하기 위한 것으로서, 본 발명의 범위가 이들 실시예에 의해 제한되는 것으로 해석되지 않는 것은 당업계에서 통상의 지식을 가진 자에 있어서 자명할 것이다.Hereinafter, the present invention will be described in more detail through examples. These examples are only for exemplifying the present invention, and it will be apparent to those skilled in the art that the scope of the present invention is not to be construed as being limited by these examples.
실시예 1. 연구 모집단 및 샘플 수집Example 1. Study Population and Sample Collection
1-1. 연구 모집단 1-1. study population
두 개의 독립적인 코호트, 즉 식별 코호트 (identification cohort)와 정량 코호트 (quantification cohort)가 식품 알레르기 아동의 대사 프로파일을 연구하는데 사용되었다. Two independent cohorts, an identification cohort and a quantification cohort, were used to study the metabolic profiles of children with food allergy.
식별 코호트는 식품 알레르기 아동 20명과 건강한 대조군 20명으로 구성되었다. 식품 알레르기는 하나 이상의 특정 식품 알레르겐에 대한 특정 IgE 수치 > 0.7 kU/L와 식품 섭취 2시간 이내에 발생하는 IgE 매개 증상의 병력을 포함하여, 확인된 알레르기 과민 반응의 조합을 기반으로 의사에 의해 진단되었다. 식품 알레르기의 해소(resoultion)는 이전에 식품 알레르기를 일으켰던 모든 식품 알레르겐에서 발생하는 국소 및 전신 증상의 상실로 정의되었으며, 해소는 해당 음식 섭취를 시도해보거나 간병인의 관찰로 확인되었다. 식품 알레르기 소아에 대해 진단 당시와 추적 관찰시 혈청을 채취하였다. 식품 알레르기 해소가 확인된 대상체 (subject)와 식품 알레르기가 지속되는 대상체에 대해 각각 동일한 시간 경과에 따른 추적 관찰이 수행되었다. 지속성은 식품 알레르기 진단 기준과 동일한 기준으로 진료실에서 확인되었다. 대사체 프로파일링이 수행될 때까지 샘플은 -20 ℃에서 보관하였다. 식품 알레르기가 지속되는 대상체와 식품 알레르기가 해소된 대상체에 대한 식품 알레르기 및 아토피 피부염의 중증도는 각각 B. Niggemann et al (Allergy 2016; 71:135-6) 및 SCORing Atopic Dermatitis(SCORAD) (Dermatology 1993; 186:23-31)에 의해 확립된 등급 시스템을 사용하여 평가되었다. 대조군은 알레르기 질환의 병력이나 알레르기 과민증의 증상이 없는 대상체로 선정하였다. 유전자형 분석을 위해 상기 40명의 피험자로부터 추가로 전혈 샘플을 수집하였다. The identification cohort consisted of 20 children with food allergy and 20 healthy controls. Food allergy was diagnosed by a physician based on a combination of identified allergic hypersensitivity reactions, including a specific IgE level >0.7 kU/L to one or more specific food allergens and a history of IgE-mediated symptoms occurring within 2 hours of ingesting the food . Resoultion of food allergy was defined as the loss of local and systemic symptoms from any food allergen that previously caused a food allergy, and resolution was confirmed by attempting to eat the food or observation by a caregiver. Serum was collected at diagnosis and at follow-up for children with food allergy. Follow-up over the same time was conducted for subjects whose food allergy was resolved and subjects whose food allergy persisted. Persistence was confirmed in the clinic using the same criteria as for food allergy diagnosis. Samples were stored at -20 °C until metabolomic profiling was performed. The severity of food allergy and atopic dermatitis for subjects with persistent food allergy and subjects with resolved food allergy were evaluated by B. Niggemann et al (Allergy 2016; 71:135-6) and SCORing Atopic Dermatitis (SCORAD) (Dermatology 1993; 186:23-31). The control group was selected as a subject without a history of allergic disease or symptoms of allergic hypersensitivity. Additional whole blood samples were collected from these 40 subjects for genotyping.
정량 코호트는 식품 알레르기가 있는 48명의 대상체와 30명의 건강한 대조군으로 구성되었다. 피험자(즉, 대상체)는 식별 코호트와 동일한 포함 기준으로 모집되었으며, 혈청 샘플을 사용하여 선택된 대사체를 정량화하였다. 모든 피험자는 상호 관계가 없었고, 서면 동의서를 제공받아 실험이 진행되었다. 모든 연구는 세브란스병원 기관심사위원회(서울, 한국, IRB 번호 4-2019-1271)의 승인을 받아 진행되었다.The quantification cohort consisted of 48 subjects with food allergy and 30 healthy controls. Subjects (i.e., subjects) were recruited with the same inclusion criteria as the identification cohort, and serum samples were used to quantify selected metabolites. All subjects were unrelated, and the experiment was conducted after providing written informed consent. All studies were conducted with the approval of the Institutional Review Board of Severance Hospital (Seoul, Korea, IRB No. 4-2019-1271).
1-2. 임상평가1-2. clinical evaluation
식품 알레르기로 진단하기 위해 확인된 식품 알레르기(FA) 증상에는 입안의 따끔 거림 또는 가려움증; 두드러기; 얼굴, 입 또는 기타 신체 부위의 붓기; 천명; 호흡 곤란; 메스꺼움; 구토; 복통; 설사가 포함되었다. 식품 알레르기가 있는 일부 대상체는 여러 음식에 알레르기가 있었고, 모든 대상체는 달걀 알레르기가 있었다. 우유와 견과류에 대한 알레르기는 다중 알레르기가 있는 대상체에게 가장 흔하게 나타났다. 비-IgE 매개 또는 만성 염증성 위장 장애의 병력과 지난 6주 이내에 면역억제제 사용한 병력이 있는 대상체는 피험자에서 제외되었다. Food allergy (FA) symptoms identified for diagnosis of food allergy include tingling or itching in the mouth; hives; swelling of the face, mouth, or other body parts; appointment; shortness of breath; sickness; throw up; colic; Diarrhea was included. Some subjects with food allergies had allergies to multiple foods, and all subjects had egg allergies. Allergies to milk and nuts were most common in subjects with multiple allergies. Subjects with a history of non-IgE mediated or chronic inflammatory gastrointestinal disorders and the use of immunosuppressants within the past 6 weeks were excluded from subjects.
1-3. 샘플 준비 및 대상체 분석1-3. Sample preparation and subject analysis
식품 알레르기가 있는 대상체로부터 20개의 쌍을 이룬 혈청 샘플과 대조군으로부터 20개의 쌍을 이루지 않은 혈청 샘플을 수집하였다. 식별 코호트에 대한 정보는 표 1에 요약되어 있다.20 paired serum samples from subjects with food allergy and 20 unpaired serum samples from controls were collected. Information on identification cohorts is summarized in Table 1.
데이터는 n (%) 또는 평균 ± 표준 편차로 제공됨Data are given as n (%) or mean ± standard deviation
* 식품 알레르기 해소에 대한 정보가 충분하지 못한 2명을 제외하고, 식품 알레르기를 가지는 총 18명을 대상으로 계산한 비율임* Rate calculated for a total of 18 people with food allergy, excluding 2 people with insufficient information on food allergy relief
** 카테고리 값에 대한 카이 제곱 검정 및 연속 값에 대한 Welch의 t-검정으로 계산된 p-값** p-value calculated by chi-square test for categorical values and Welch's t-test for continuous values
피험자들의 평균 연령은 2.72세 (표준 편차: 2.29)였으며 식품 알레르기를 가지는 대상체와 대조군 간에 유의한 연령 차이는 없었다. 총 혈청 IgE 수치는 예상한 바와 같이 식품 알레르기를 가지는 대상체에서 대조군보다 평균적으로 더 높았다. 진단 당시 식품 알레르기 환자들은 원인이 되는 알레르겐을 피하는 식사를 하고 있었다 (표 2). The average age of the subjects was 2.72 years (standard deviation: 2.29), and there was no significant age difference between subjects with food allergies and controls. Total serum IgE levels were higher on average in subjects with food allergy than in controls, as expected. At the time of diagnosis, food allergy patients were on a diet avoiding the causative allergen (Table 2).
식품 알레르기 환자 중 10명은 지속적인 증상을 보였고, 8명은 식품 알레르기가 해소되었다. 2명의 피험자는 예후에 대한 정보가 충분하지 않아 식품 알레르기 해소 여부에 대한 분석에서 제외시켰다. 이들 대상체에 대한 추적 관찰 기간 및 질병 속성은 표 3에 요약되어 있다. Ten of the food allergy patients showed persistent symptoms, and food allergy resolved in eight. Two subjects were excluded from the analysis of food allergy resolution due to insufficient prognostic information. The follow-up period and disease attributes for these subjects are summarized in Table 3.
(n = 10)food allergy persists
(n = 10)
(n = 8)food allergy relief
(n = 8)
SCORAD, SCORing Atopic DermatitisSCORAD, SCORing Atopic Dermatitis
데이터는 n (%) 또는 평균 ± 표준 편차로 제공됨Data are given as n (%) or mean ± standard deviation
* 카테고리 값에 대한 카이 제곱 검정 및 연속 값에 대한 Welch의 t-검정으로 계산된 p-값* p-value calculated by chi-square test for categorical values and Welch's t-test for continuous values
진단을 위한 샘플 수집과 추적 관찰 사이의 평균 시간 간격은 16.5개월이었고, 추적 관찰 시 아동은 4세에서 5세 사이였다. 대상체들은 식품 알레르기의 심각도에서 유사한 분포를 보였다. 지속적인 식품 알레르기를 나타내는 7명의 대상체와 식품 알레르기가 해소된 6명의 대상체는 2A 등급(피부 또는 위장관 침범을 동반한 경증에서 중등도의 전신 반응)을 나타내었다. 지속적인 식품 알레르기를 나타내는 2명의 대상체와 식품 알레르기가 해소된 1명의 대상체는 심각한 전신 반응을 경험하였다. 아토피 피부염을 동반하는 대상체들은 모두 경증 또는 중등도의 아토피 피부염 증상을 경험하였으며 그룹 간에 SCORAD에 유의한 차이는 없었다.The average time interval between diagnostic sample collection and follow-up was 16.5 months, and the children were between 4 and 5 years of age at follow-up. Subjects showed a similar distribution in severity of food allergy. Seven subjects with persistent food allergy and six subjects with resolution of food allergy presented Grade 2A (mild to moderate systemic reaction with cutaneous or gastrointestinal involvement). Two subjects with persistent food allergy and one subject whose food allergy resolved experienced severe systemic reactions. Subjects with atopic dermatitis all experienced mild or moderate symptoms of atopic dermatitis, and there was no significant difference in SCORAD between groups.
정량 코호트는 식품 알레르기가 지속되는 25명, 식품 알레르기가 해소된 23명, 대조군 30명으로 구성되었다 (표 4). 평균 연령과 총 혈청 IgE 수치는 동일 집단의 IgE 수치와 유사하였다. 식품 알레르기 해소 여부를 추적하는데 소요된 평균 추적 기간은 18.5개월이었다.The quantitative cohort consisted of 25 subjects with persistent food allergy, 23 subjects with resolution of food allergy, and 30 subjects in the control group (Table 4). Mean age and total serum IgE levels were similar to those of the same population. The average follow-up period for food allergy resolution was 18.5 months.
(n = 25)food allergy persists
(n = 25)
(n = 23)food allergy relief
(n = 23)
(n = 30)control group
(n = 30)
* 진단과 가장 최근의 해소 또는 지속 확인 사이의 시간*Time between diagnosis and most recent resolution or persistence check
데이터는 n (%) 또는 평균 ± 표준 편차로 제공됨Data are given as n (%) or mean ± standard deviation
실시예 2. 대사체 프로파일링Example 2. Metabolite profiling
두 가지 모드(양이온 및 음이온 대사 산물)에서 LC-MS(liquid chromatography-tandem mass spectrometry)를 사용하여 식별 코호트의 혈청 샘플로부터 대사체 프로파일링을 수행하였다.Metabolomic profiling was performed from serum samples from a discrete cohort using liquid chromatography-tandem mass spectrometry (LC-MS) in two modes (cationic and anionic metabolites).
LC-MS 분석을 위해 각 100 μL 샘플을 내부 표준물질을 함유한 메탄올 (0.1% 포름산 포함) 300 μL 와 혼합하고 원심분리(9,100 x g, 4℃, 10분)하였다. 다음으로, 250 μL의 상청액과 550 μL의 0.1% 포름산 수용액을 혼합하고 SPE 컬럼 (MonoSpin C18, 5010-2170, GL Sciences Inc., Tokyo, Japan)을 사용하여 여과하였다. 여과액을 0.1% 포름산 용액 및 0.1% 포름산 - 25% 메탄올 용액으로 정제하였다. 정제된 지질 대사체는 측정 직전 메탄올(0.1% 포름산 포함) 200 μL에 용해하였다. LC-MS 분석에서 검출된 피크는 m/z, 머무름 시간 및 피크 면적을 포함한 정보를 얻기 위해 자동 통합 소프트웨어 MultiQuant(AB Sciex, Framingham, MA, USA)를 사용하여 추출되었다. 그런 다음 피크 면적을 상대 피크 면적으로 변환하고 표준 라이브러리 (Human Metabolome Technologies, Inc., Tsuruoka, Japan)를 사용하여 다음과 같이 주석을 달았다: [생화학적 분류] [아실 사슬 탄소 원자의 수]:[지방산 부분의 이중 결합 수]. For LC-MS analysis, each 100 μL sample was mixed with 300 μL of methanol (with 0.1% formic acid) containing the internal standard and centrifuged (9,100 x g, 4° C., 10 min). Next, 250 μL of the supernatant and 550 μL of 0.1% formic acid aqueous solution were mixed and filtered using an SPE column (MonoSpin C18, 5010-2170, GL Sciences Inc., Tokyo, Japan). The filtrate was purified with a 0.1% formic acid solution and a 0.1% formic acid-25% methanol solution. The purified lipid metabolite was dissolved in 200 μL of methanol (including 0.1% formic acid) immediately before measurement. Peaks detected in the LC-MS analysis were extracted using the automatic integration software MultiQuant (AB Sciex, Framingham, MA, USA) to obtain information including m/z, retention time and peak area. Peak areas were then converted to relative peak areas and annotated using a standard library (Human Metabolome Technologies, Inc., Tsuruoka, Japan) as follows: [Biochemical classification] [Number of acyl chain carbon atoms]:[ number of double bonds in the fatty acid moiety].
유리지방산 (free fatty acid), 아실카르니틴 (acylcarnitine), 옥시리핀 (oxylipin), 리소포스파티딜콜린 (lysophosphatidylcholine), 리소포스파티딜에탄올아민 (lysophosphatidylethanolamine), 리소포스파티딜이노시톨 (lysophosphatidyllinositol), 리소포스파티딜세린 (lysophosphatidylserine), 리소포스파티딜글리세롤 (lysophosphatidylglycerol), 리소포스파티딘산 (lysophosphatidic acid), 혈소판 활성화 인자 (platelet-activating factor), 아실에탄올아민 (acylethanolamine), 스핑가닌 (sphinganine), 스핑고신 (sphingosine), 강글리오사이드 (ganglioside), 글루코실세라마이드 (glucosylceramide), 락토실세라마이드 (lactosylceramide), 세라마이드-1P (ceramide-1P) 및 스테로이드 (steroid)를 포함한 여러 클래스의 총 344개 대사체가 확인되었다. Free fatty acid, acylcarnitine, oxylipin, lysophosphatidylcholine, and lysophosphatidylethanola MINE), Lysophosphatidyrinositol, Lysophosphatidylserine, Lysopos Party Deal Glycerol (lysophosphatidylglycerol), lysophosphatidic acid, platelet-activating factor, acylethanolamine, sphinganine, sphingosine, ganglioside, gluco A total of 344 metabolites from several classes were identified, including glucosylceramide, lactosylceramide, ceramide-1P and steroids.
대사체 수준에 대해 결측값 대치 (missing value imputation) 및 일반 품질 관리 절차를 수행하였다. 각 대사체와 대상체 연령 간의 상관 관계는 진단 시 건강한 대조군과 식품 알레르기 대상체의 로그 변환 대사체 데이터를 사용하여 Pearson의 상관 관계를 계산하여 결정되었다. 연령과 유의하게 관련된 대사체 (p-값 < 0.05) (표 5 참조)는 추가 분석에서 제외되었다 . Metabolite levels were subjected to missing value imputation and general quality control procedures. Correlations between each metabolite and subject age were determined by calculating Pearson's correlation using log-transformed metabolome data from healthy controls and food allergy subjects at diagnosis. Metabolites significantly associated with age (p-value < 0.05) (see Table 5) were excluded from further analysis.
LPS, 리소포스파티딜세린; GM3, 모노시알로디헥소실강글리오시드; TXB2, 트롬복산 B2; FFA, 유리 지방산; LPE, 리소포스파티딜에탄올아민; HETE, 히드록시에이코사테트라엔산; LPA, 리소포스파티딘산; PAF, 혈소판 활성화 인자; LPG, 리소포스파티딜글리세롤; AC, 아실카르니틴; LPC, 리소포스파티딜콜린LPS, lysophosphatidylserine; GM3, monosialodihexosylganglioside; TXB2, thromboxane B2; FFA, free fatty acid; LPE, lysophosphatidylethanolamine; HETE, hydroxyeicosatetraenoic acid; LPA, lysophosphatidic acid; PAF, platelet activating factor; LPG, lysophosphatidylglycerol; AC, acylcarnitine; LPC, lysophosphatidylcholine
대사체 데이터의 품질 관리를 위하여, 샘플의 10% 이상에서 정량되지 않은 대사체는 배제하였다. 대사체에 대한 누락 값은 k-최근접 이웃 알고리즘 (k-nearest neighbor algorith)을 사용하여 대체하였다. 10개의 가장 근접한 이웃의 중앙값이 계산에 사용되었다. 대사체 데이터의 정규화에는 확률 지수 정규화법 (probabilistic quotient normalization method)이 사용되었다. For quality control of metabolome data, metabolites that were not quantified in more than 10% of the samples were excluded. Missing values for metabolites were replaced using the k-nearest neighbor algorithm. The median of the 10 nearest neighbors was used for the calculation. A probabilistic quotient normalization method was used to normalize the metabolomic data.
데이터 패턴을 관찰하기 위해 진단 당시 식품 알레르기를 가지는 대상체와 대조군에서 얻은 대사체 데이터에 대해 MetaboAnalyst를 사용하여 희소 부분 최소 제곱 판별 분석 (sparse partial least-squares discriminant analysis, sPLS-DA)을 수행하였다. sPLS-DA 모델의 희소성을 제어하기 위해 5가지 구성요소를 사용하고 예측 능력을 평가하기 위해 5중 교차 검증을 사용하였다. sPLS-DA 모델의 처음 5개 구성요소를 연령과의 상관관계에 대해 테스트하여 연령이 그룹 분리에 미치는 영향을 평가하였다. In order to observe data patterns, sparse partial least-squares discriminant analysis (sPLS-DA) was performed using MetaboAnalyst on the metabolomic data obtained from subjects with food allergy at the time of diagnosis and controls. Five components were used to control the sparsity of the sPLS-DA model, and five-fold cross-validation was used to evaluate the predictive ability. The first five components of the sPLS-DA model were tested for correlation with age to evaluate the effect of age on group segregation.
식품 알레르기를 가지는 그룹과 대조군, 또는 식품 알레르기가 지속 또는 식품 알레르기가 해소되는 그룹 사이에서 상이하게 발현되는 대사체를 확인하기 위하여, 식품 알레르기 해소와 유의하게 연관된 오메가-3 대사체에 대하여 진단에서 추적 관찰까지 paired t-test 또는 Wilcoxon 부호 순위 테스트를 수행하였다. 0.05 미만의 p-값이 통계적으로 유의한 것으로 간주되었다. MetaboAnalyst를 사용하여 트리 수를 500으로 설정하고 각 분할에서 시도된 변수 수를 7로 설정한 Random Forest 모델로 발현 수준이 유의하게 상이한 대사체가 구축되었다. ROC (Receiver operating characteristic) 곡선은 균형 잡힌 하위 샘플링 (balanced sub-sampling)을 사용하여 Monte Carlo 교차 검증에 의해 생성되었다. To identify metabolites that are differentially expressed between a group with food allergy and a control group, or a group in which food allergy persists or resolves, omega-3 metabolites significantly associated with resolution of food allergy are tracked at diagnosis. Paired t-test or Wilcoxon signed rank test was performed until observation. A p-value of less than 0.05 was considered statistically significant. Using MetaboAnalyst, metabolites with significantly different expression levels were constructed with a Random Forest model in which the number of trees was set to 500 and the number of variables tried in each partition was set to 7. Receiver operating characteristic (ROC) curves were generated by Monte Carlo cross-validation using balanced sub-sampling.
또한, 선형 혼합 모델(LMM)을 사용하여 평균 대사체 수준에서 지속적인 식품 알레르기가 있는 대상체와 식품 알레르기가 해소된 대상체 간의 경향 변화를 평가하였다. LMM에는 구조화되지 않은 공분산 행렬이 적용되었다. In addition, a linear mixed model (LMM) was used to evaluate changes in trends between subjects with persistent food allergy and subjects with resolved food allergy at the average metabolite level. An unstructured covariance matrix was applied to the LMM.
품질 관리 결과에 따라 또는 대상체 연령과 관련된 대사체를 제거한 후, 총 275개의 대사체가 확인되었다. 도 1은 식품 알레르기 및 식품 알레르기 해소된 그룹의 지도모델(supervised model)에서 데이터 패턴과 함께 sPLS-DA 플롯을 보여준다. sPLS-DA 모델에서 처음 두 구성 요소의 가중치는 식품 알레르기 그룹의 경우 16.5% 및 13%, 식품 알레르기가 해소된 그룹의 경우 9.5% 및 8.4%였다. 식품 알레르기 그룹과 식품 알레르기가 해소된 그룹에 대한 대상체의 클러스터링은 그룹 간 분리되는 경향을 보였고, 특히, 식품 알레르기가 해소된 그룹과 식품 알레르기가 지속된 그룹의 경계는 약간만 오버랩되며 뚜렷하게 구별되었다. 도 1c는 세 그룹을 모두 사용하여 확인된 sPLS-DA 모델에 대한 점수 플롯을 보여준다. 대조군과 식품 알레르기가 지속된 그룹이 상대적으로 잘 분리되는 것과 비교하여 식품 알레르기가 해소된 그룹은 다른 그룹의 경계 내에 위치하여, 식품 알레르기가 해소되는 경우는 식품 알레르기가 지속되는 경우 및 대조군에서의 대사 특징 모두와 오버랩 된다는 것을 알 수 있었다. 모든 플롯에서, 대상체의 분포는 연령별 클러스터링을 나타내지 않았으며 처음 5개 구성요소 중 어느 것도 연령과 유의한 상관관계가 없었다 (p-값 > 0.05).A total of 275 metabolites were identified according to quality control results or after removing metabolites related to subject age. Figure 1 shows the sPLS-DA plot with data patterns in the supervised model of food allergy and food allergy resolved groups. In the sPLS-DA model, the weights of the first two components were 16.5% and 13% for the food allergy group and 9.5% and 8.4% for the food allergy resolved group. The clustering of the subjects for the food allergy group and the food allergy resolved group showed a tendency to separate between the groups, and in particular, the boundary between the food allergy resolved group and the food allergy sustained group overlapped only slightly and was clearly distinguished. Figure 1c shows the score plot for the sPLS-DA model identified using all three groups. Compared to the relatively good separation between the control group and the group with continued food allergy, the group with resolved food allergy was located within the boundaries of the other groups, so that the case in which food allergy was resolved was the case with continued food allergy and the metabolism in the control group. It was found that it overlapped with all of the features. In all plots, the distribution of subjects did not show clustering by age and none of the first 5 components were significantly correlated with age (p-value > 0.05).
식품 알레르기를 가지는 대상체와 대조군을 비교한 결과, 식품 알레르기를 가지는 대상체에서 유의하게 높은 수준의 8개 대사체와 유의하게 낮은 수준의 8개 대사체가 확인되었다. 도 2a는 생화학적 클래스에 따른 분류와 함께 이러한 대사체 중 12가지를 보여준다. 모든 스핑고지질 대사 산물의 수준은 대조군보다 식품 알레르기를 가지는 대상체에서 일관되게 더 높게 나타났다. 탄소 수가 많고 이중 결합이 적은 6개의 아실카르티닌(acylcarnitine) 대사체는 대조군보다 식품 알레르기를 가지는 대상체에서 더 낮은 수준을 보이는 경향이 일반적이었다. 두 개의 리소포스파티딘산 (lysophosphatidic acid) 수준은 식품 알레르기를 가지는 대상체에서 더 높았다. As a result of comparing the subjects with food allergy and the control group, 8 metabolites with significantly high levels and 8 metabolites with significantly low levels were identified in subjects with food allergies. Figure 2a shows 12 of these metabolites with classification according to biochemical class. Levels of all sphingolipid metabolites were consistently higher in subjects with food allergies than in controls. Six acylcarnitine metabolites with high carbon numbers and low double bonds tended to have lower levels in subjects with food allergies than in controls. Levels of both lysophosphatidic acids were higher in subjects with food allergies.
도 2b는 식품 알레르기가 지속되는 대상체보다 식품 알레르기가 해소된 대상체에서 8개의 대사체가 유의하게 더 높고 4개의 대사체가 유의하게 더 낮음을 보여준다. 4가지 오메가-3 대사체, 특히 식품 알레르기가 해소된 대상체에서 히드록시도코사헥사엔산(HDoHE)의 지속적으로 더 높은 수치가 관찰되었다. 식품 알레르기가 해소된 대상체의 오메가-3 대사산물 수준은 식품 알레르기가 지속되는 대상체보다 평균 1.66배 높았다. 2개의 리소포스파티딜콜린(LPC) 수치도 식품 알레르기가 해소된 피험자에서 더 높게 나타났다. 반대로, PAF(16:1)의 수준은 1.2의 배수 변화로 식품 알레르기가 해소된 대상체에서 유의하게 낮았다. 식품 알레르기 및 식품 알레르기 해소와 관련된 대사체의 전체 목록은 표 6과 같다.Figure 2b shows that 8 metabolites were significantly higher and 4 metabolites were significantly lower in subjects with resolving food allergy than in subjects with persistent food allergy. Consistently higher levels of the four omega-3 metabolites, particularly hydroxydocosahexaenoic acid (HDoHE), were observed in subjects whose food allergy resolved. The levels of omega-3 metabolites in subjects whose food allergy resolved were on average 1.66 times higher than those in subjects whose food allergy persisted. Levels of the two lysophosphatidylcholines (LPCs) were also higher in subjects whose food allergy resolved. Conversely, the level of PAF(16:1) was significantly lower in subjects whose food allergy resolved with a fold change of 1.2. A full list of metabolites related to food allergy and resolution of food allergy is shown in Table 6.
FA, 식품 알레르기; LPG, 리소포스파티딜글리세롤; AC, 아실카르니틴; LPA, 리소포스파티딘산; PGH2, 프로스타글란딘 H2; diHETE, 디히드록시이코사테트라엔산; LPC, 리소포스파티딜콜린; LPE, 리소포스파티딜에탄올아민; HDoHE, 히드록시도코사헥사엔산; PAF, 혈소판 활성화 인자; LPS, 리소포스파티딜세린FA, food allergy; LPG, lysophosphatidylglycerol; AC, acylcarnitine; LPA, lysophosphatidic acid; PGH2, prostaglandin H2; diHETE, dihydroxyicosatetraenoic acid; LPC, lysophosphatidylcholine; LPE, lysophosphatidylethanolamine; HDoHE, hydroxydocosahexaenoic acid; PAF, platelet activating factor; LPS, lysophosphatidylserine
* 정규 분포 데이터에 대한 Welch의 t-검정 및 비모수 데이터에 대한 Mann-Whitney U 검정으로 계산된 p-값.*p-value calculated by Welch's t-test for normally distributed data and Mann-Whitney U test for nonparametric data.
다음으로 분류의 정확성을 평가하기 위하여 유의하게 연관된 대사체를 사용하여 Random Forest 모델을 구축하였다 (도 3). 식품 알레르기 모델의 ROC 곡선 아래 면적은 0.708 (95% CI: 0.483 - 0.926)이고 식품 알레르기 해소 모델의 면적은 0.947 (95% CI: 0.748 - 1)이다. 식품 알레르기 해소 모델은 식품 알레르기 모델보다 더 높은 민감도와 전반적으로 더 나은 성능을 보였다. 식품 알레르기 해소의 대사 프로파일은 식품 알레르기 모델보다 더 독특하고 표현형에 더 특이적일 수 있음을 시사한다. Next, a random forest model was constructed using significantly related metabolites to evaluate the accuracy of classification (FIG. 3). The area under the ROC curve of the food allergy model was 0.708 (95% CI: 0.483 - 0.926) and the area under the food allergy resolution model was 0.947 (95% CI: 0.748 - 1). The food allergy resolution model showed higher sensitivity and overall better performance than the food allergy model. It suggests that the metabolic profile of food allergy resolution may be more unique and phenotype-specific than food allergy models.
실시예 3. 식품 알레르기 지속성 여부에 따른 PAF 수준 차이Example 3. PAF level difference according to persistence of food allergy
식품 알레르기 해소와 관련된 대사체 중 특히 혈소판 활성화 인자는 식품 알레르기가 해소된 대상체와 식품 알레르기가 지속되는 대상체들 간에 유의한 차이가 있었다. 식품 알레르기 해소 및 식품 알레르기 지속 대상체들 간의 혈소판 활성화 인자 수준 차이를 확인하기 위하여, 정량 코호트의 대상체로부터 수집된 혈청에서 혈소판 활성화 인자 수준을 정량하고 PAFAH (platelet activating factor acetylhydrolase) 활성을 측정하였다. PAFAH는 혈소판 활성화 인자를 촉매하여 염증 유발 효과를 종결시키는데 필수적인 동종효소(isoenzyme)이다. Among the metabolites related to resolution of food allergy, platelet activating factor, in particular, showed a significant difference between subjects whose food allergy was resolved and subjects whose food allergy persisted. In order to confirm the difference in platelet activating factor levels between subjects who resolved food allergy and continued food allergy, platelet activating factor levels were quantified and platelet activating factor acetylhydrolase (PAFAH) activity was measured in the serum collected from the subjects of the quantitative cohort. PAFAH is an essential isoenzyme that catalyzes platelet activating factor to terminate its pro-inflammatory effect.
정량 코호트의 혈청 샘플을 사용하여 효소 결합 면역 흡착 분석 (ELISA)을 수행하여 제조사의 지침에 따라 혈소판 활성화 인자 (Abbexa Biologics)의 수준을 측정하였다. 혈소판 활성화 인자 아세틸하이드롤라제(PAFAH)의 효소 활성은 비색 분석(Cayman Chemical, Ann Arbor, MI, USA)으로 측정되었다. 한 샘플에서 음성 분석 결과가 나오면 추가 분석에서 배제하였다. 그룹 간의 대사체 수준과 효소 활성의 차이를 평가하기 위하여 데이터의 정규성에 따라 Welch의 2-표본 t-검정 또는 Mann-Whitney U 검정을 사용하였다. 대사체 수준과 식품 알레르기 중앙 표현형 간의 상관관계를 조사하기 위하여 데이터 분포에 따라 Pearson의 상관분석 또는 Spearman의 상관분석을 사용하여 총 혈청 IgE 수준을 평가하였다. 데이터의 정규성은 Shapiro-Wilk 테스트를 사용하여 확인되었다. An enzyme-linked immunosorbent assay (ELISA) was performed using serum samples from the quantification cohort to determine levels of platelet activating factor (Abbexa Biologics) according to the manufacturer's instructions. The enzymatic activity of platelet activating factor acetylhydrolase (PAFAH) was measured by a colorimetric assay (Cayman Chemical, Ann Arbor, MI, USA). A negative assay result in one sample was excluded from further analysis. Welch's two-sample t-test or Mann-Whitney U test was used according to the normality of the data to evaluate the differences in metabolite levels and enzyme activity between groups. Total serum IgE levels were evaluated using Pearson's correlation analysis or Spearman's correlation analysis according to data distribution to investigate the correlation between metabolomic levels and food allergy central phenotypes. The normality of the data was confirmed using the Shapiro-Wilk test.
그 결과는 도 4에서 볼 수 있듯이, 혈소판 활성화 인자 수준과 PAFAH 활성 모두에서 식품 알레르기가 해소된 대상체와 식품 알레르기가 지속된 대상체 간에 상당한 차이가 있었다. 식품 알레르기가 지속된 대상체에서 PAF의 중앙값은 130.3 pg/mL(IQR: 100.5 - 143.7)인 반면, 식품 알레르기가 해소된 대상체에서 PAF의 중앙값은 125.8 pg/mL (IQR: 113.8 - 159.9) 으로 나타나 통계적으로 유의한 차이가 있는 것으로 확인되었다. 대조군에서 PAF 수준의 중앙값은 식품 알레르기가 해소된 대상체 보다 낮았지만 대조군에서 더 넓은 범위의 값을 나타내었다. As can be seen in FIG. 4, there was a significant difference between subjects whose food allergy was resolved and subjects whose food allergy persisted in both platelet activating factor levels and PAFAH activity. In subjects with persistent food allergy, the median value of PAF was 130.3 pg/mL (IQR: 100.5 - 143.7), whereas in subjects with resolved food allergy, the median value of PAF was 125.8 pg/mL (IQR: 113.8 - 159.9), showing statistical significance. was found to have a significant difference. The median level of PAF in the control group was lower than in the subjects with resolved food allergy, but showed a wider range of values in the control group.
PAFAH 활성은 PAF를 분해하는 역할에서 예상되는 바와 같이 PAF 수준에 대한 경향과 반대로 확인되었다. 효소 활성 속도는 식품 알레르기가 지속된 대상체 (중앙값: 0.0078 μmol/min/mL)보다 식품 알레르기 해소된 대상체 (중앙값: 0.0087 μmol/min/mL)에서 유의하게 더 높았다. 총 혈청 IgE 수준 간의 상관 관계를 평가할 때 log 변환된 PAF 수준 또는 PAFAH 활성 수준과의 상관 관계는 발견되지 않았다 (도 5). PAFAH activity was confirmed to reverse the trend for PAF levels, as would be expected from a role in degrading PAF. The rate of enzyme activity was significantly higher in subjects whose food allergy resolved (median: 0.0087 μmol/min/mL) than in subjects whose food allergy persisted (median: 0.0078 μmol/min/mL). When evaluating the correlation between total serum IgE levels, no correlation was found with log transformed PAF levels or PAFAH activity levels (FIG. 5).
실시예 4. PAF 발현 수준에 대한 PAFAH의 SNP의 영향Example 4. Effect of SNPs of PAFAH on PAF expression levels
PAF와 식품 알레르기 해소 사이의 연관성을 고려하여, 식별 코호트에서 파생된 데이터를 사용하여 유전자형 변이 및 PAF (16:1) 수준에 대한 정량적 특성 연관성 분석을 진행하였다. PAFAH의 서브유닛인 PAFAH1B1 및 그 근처에 위치한 SNP에 중점을 두어 분석을 진행하였다. Considering the association between PAF and resolution of food allergy, a quantitative trait association analysis was conducted for genotypic variation and PAF (16:1) levels using data derived from the identification cohort. The analysis was conducted focusing on PAFAH1B1, a subunit of PAFAH, and SNPs located nearby.
유전자형 분석은 식별 코호트의 전혈 샘플을 이용하여 Infinium Omni5Exome-4 BeadChip(Illumina Inc., San Diego, CA, USA)로 수행되었다. 품질 관리 후 얻은 1,841,897 SNP에서 PLINK v.1.0712를 사용하여 4개의 오메가-3 대사 산물에 대한 Wald 테스트를 사용하여 정량적 형질 연관 분석을 수행하였다. 0.05 미만의 Bonferroni 보정 p-값이 통계적으로 유의한 것으로 간주되었다. 다음으로 혈소판 활성화 인자(PAF)(16:1) 수준과 PAFAH1B1에 위치한 SNP 간의 연관성을 유전자의 양쪽에 있는 500kb 측면을 포함하는 영역을 기준으로 분석하였다. 유전자형 데이터의 품질 관리를 위하여 결측률이 5% 보다 높거나, Hardy-Weinberg 평형 p-값이 10-5 미만인 경우, 사례와 대조군 간의 결측률이 유의하게 다르거나(p-값 < 0.001), 소수 대립 유전자 빈도가 1% 미만인 경우는 SNP에서 배제하였다. 데이터는 R 버전 3.3(R Foundation for Statistical Computing, Vienna, Austria) 및 SAS 버전 9.4(SAS Institute Inc., Cary, NC, USA)를 사용하여 분석하였다. Genotyping was performed with an Infinium Omni5Exome-4 BeadChip (Illumina Inc., San Diego, CA, USA) using whole blood samples from an identified cohort. Quantitative trait association analysis was performed using the Wald test for four omega-3 metabolites using PLINK v.1.0712 in 1,841,897 SNPs obtained after quality control. A Bonferroni corrected p-value of less than 0.05 was considered statistically significant. Next, the association between the platelet activating factor (PAF) (16:1) level and the SNP located in PAFAH1B1 was analyzed based on a region containing 500 kb flanking on both sides of the gene. For quality control of genotyping data, if the missing rate is higher than 5%, or the Hardy-Weinberg equilibrium p-value is less than 10 -5 , the missing rate is significantly different between cases and controls (p-value < 0.001), or a small number SNPs were excluded if the allele frequency was less than 1%. Data were analyzed using R version 3.3 (R Foundation for Statistical Computing, Vienna, Austria) and SAS version 9.4 (SAS Institute Inc., Cary, NC, USA).
PAFAH1B1의 3' 측면 영역에 위치한 하나의 SNP(rs2290925)는 PAF(16:1) 수준 (Bonferroni 수정된 p-값 = 0.0384)(표 7)과 유의한 연관성을 나타내었다. SNP에서 이형접합체를 가진 피험자의 평균 PAF(16:1) 수준은 0.001583이었고 주요 대립유전자 A의 동형접합체를 갖는 대상체의 평균은 0.0008364으로 나타났다. One SNP (rs2290925) located in the 3' flanking region of PAFAH1B1 showed a significant association with the PAF (16: 1) level (Bonferroni corrected p-value = 0.0384) (Table 7). The mean PAF(16:1) level of subjects heterozygous for the SNP was 0.001583 and the mean of subjects homozygous for major allele A was 0.0008364.
* Bonferroni 수정된 p-값 < 0.05SNP, * Bonferroni corrected p-value < 0.05 SNP,
단일 뉴클레오티드 다형성; MAF, 마이너 대립유전자 빈도single nucleotide polymorphism; MAF, minor allele frequency
SNP 위치는 GRCh38/hg38 게놈 어셈블리에 해당함SNP positions correspond to the GRCh38/hg38 genome assembly
실시예 5. PAF 정량 분석Example 5. PAF quantitative analysis
달걀 알레르기를 가지는 소아에서 PAF 발현량을 ELISA로 분석하고, PAF 발현량에 따른 달걀 알레르기 지속성 여부의 판별이 가능한지 확인하였다. 이를 위하여, 총 50개의 식품 알레르기가 있는 대상체의 혈청 샘플과 총 30개의 건강한 대상체의 혈청 샘플로 실험을 진행하였으며, 제조사의 지침에 따라 ELISA kit (Abbexa Biologics, Arlington, Texas, USA)를 이용하여 PAF 발현량을 확인하였다. 매개변수 통계와 함께 Welch의 2-표본 t-검정 및 비모수 통계량에 대한 Mann-Whitney U 검정을 사용하여 그룹을 비교하였다. p-값이 0.05 미만인 경우 통계적으로 유의한 것으로 간주되었다.PAF expression level in children with egg allergy was analyzed by ELISA, and it was confirmed whether egg allergy persistence could be determined according to the PAF expression level. To this end, experiments were conducted with serum samples from a total of 50 food allergic subjects and serum samples from a total of 30 healthy subjects, and PAF was performed using an ELISA kit (Abbexa Biologics, Arlington, Texas, USA) according to the manufacturer's instructions. The expression level was confirmed. Welch's 2-sample t-test with parametric statistics and Mann-Whitney U test for nonparametric statistics were used to compare groups. A p-value of less than 0.05 was considered statistically significant.
그 결과, 달걀 알레르기가 지속된 경우와 달걀 알레르기가 해소된 경우의 PAF 발현량에 유의한 차이가 있는 것으로 확인되었는데 (도 6), 구체적으로, 달걀 알레르기가 지속된 대상체에서의 PAF 발현량은 평균 141.04 pg/mL로 확인되었고, 달걀 알레르기가 해소된 대상체에서의 PAF 발현량은 평균 121.23 pg/mL로 확인되었다. As a result, it was confirmed that there was a significant difference in PAF expression level between egg allergy persistence and egg allergy resolution (FIG. 6). Specifically, the PAF expression level in subjects with continued egg allergy was average It was confirmed as 141.04 pg/mL, and the PAF expression level in subjects whose egg allergy was resolved was found to be 121.23 pg/mL on average.
이상으로 본 발명 내용의 특정한 부분을 상세히 기술하였는바, 당업계의 통상의 지식을 가진 자에게 있어서, 이러한 구체적 기술은 단지 바람직한 실시양태일 뿐이며, 이에 의해 본 발명의 범위가 제한되는 것이 아닌 점은 명백할 것이다. 따라서 본 발명의 실질적인 범위는 첨부된 청구항들과 그것들의 등가물에 의하여 정의된다고 할 것이다.As above, specific parts of the present invention have been described in detail, and for those skilled in the art, it is clear that these specific descriptions are only preferred embodiments, and the scope of the present invention is not limited thereby. something to do. Accordingly, the substantial scope of the present invention will be defined by the appended claims and their equivalents.
FA: 식품 알레르기 (food allergy)
IgE: 면역글로불린 E (immunoglobulin E)
IgE: 면역글로불린 E (immunoglobulin E)
SNP: 단일 염기 다형성 (single nucleotide polymorphism)
LC-MS: 액체 크로마토그래피-질량 분석법 (liquid chromatography-mass spectrometry)
sPLS-DA: 희소 부분 최소 제곱 판별 분석 (sparse partial least squares-discriminant analysis)
ROC: 수신자 조작 특성 (receiver operating characteristic)
LMM: 선형 혼합 모델 (linear mixed model)
PAF: 혈소판 활성화 인자 (platelet-activating factor)
PAFAH1B1: 혈소판 활성화 인자 아세틸하이드롤라제 1b 조절 서브유닛 1 (platelet-activating factor acetylhydrolase 1b regulatory subunit 1)
ELISA: 효소 면역 분석법 (enzyme-linked immunosorbent assay)
PAFAH: 혈소판 활성화 인자 아세틸하이드롤라제 (platelet-activating factor acetylhydrolase)
SD: 표준편차 (standard deviation)
HDoHE: 하이드록시도코사헥사엔산 (hydroxydocosahexaenoic acid)
LPC: 리소포스파티딜콜린 (lysophosphatidylcholine)
CI: 신뢰 구간 (confidence interval)
AD: 아토피 피부염 (atopic dermatitis)FA: food allergy
IgE: Immunoglobulin E
IgE: Immunoglobulin E
SNP: single nucleotide polymorphism
LC-MS: liquid chromatography-mass spectrometry
sPLS-DA: sparse partial least squares-discriminant analysis
ROC: receiver operating characteristic
LMM: linear mixed model
PAF: platelet-activating factor
PAFAH1B1: platelet-activating factor acetylhydrolase 1b
ELISA: enzyme-linked immunosorbent assay
PAFAH: platelet-activating factor acetylhydrolase
SD: standard deviation
HDoHE: hydroxydocosahexaenoic acid
LPC: lysophosphatidylcholine
CI: confidence interval
AD: atopic dermatitis
<110> Industry Academic Cooperation Foundation <120> Use of platelet activating factor as a biomarker for determining persistancy of food allergy <130> 1069854 <160> 2 <170> KoPatentIn 3.0 <210> 1 <211> 410 <212> PRT <213> Homo sapiens <400> 1 Met Val Leu Ser Gln Arg Gln Arg Asp Glu Leu Asn Arg Ala Ile Ala 1 5 10 15 Asp Tyr Leu Arg Ser Asn Gly Tyr Glu Glu Ala Tyr Ser Val Phe Lys 20 25 30 Lys Glu Ala Glu Leu Asp Val Asn Glu Glu Leu Asp Lys Lys Tyr Ala 35 40 45 Gly Leu Leu Glu Lys Lys Trp Thr Ser Val Ile Arg Leu Gln Lys Lys 50 55 60 Val Met Glu Leu Glu Ser Lys Leu Asn Glu Ala Lys Glu Glu Phe Thr 65 70 75 80 Ser Gly Gly Pro Leu Gly Gln Lys Arg Asp Pro Lys Glu Trp Ile Pro 85 90 95 Arg Pro Pro Glu Lys Tyr Ala Leu Ser Gly His Arg Ser Pro Val Thr 100 105 110 Arg Val Ile Phe His Pro Val Phe Ser Val Met Val Ser Ala Ser Glu 115 120 125 Asp Ala Thr Ile Lys Val Trp Asp Tyr Glu Thr Gly Asp Phe Glu Arg 130 135 140 Thr Leu Lys Gly His Thr Asp Ser Val Gln Asp Ile Ser Phe Asp His 145 150 155 160 Ser Gly Lys Leu Leu Ala Ser Cys Ser Ala Asp Met Thr Ile Lys Leu 165 170 175 Trp Asp Phe Gln Gly Phe Glu Cys Ile Arg Thr Met His Gly His Asp 180 185 190 His Asn Val Ser Ser Val Ala Ile Met Pro Asn Gly Asp His Ile Val 195 200 205 Ser Ala Ser Arg Asp Lys Thr Ile Lys Met Trp Glu Val Gln Thr Gly 210 215 220 Tyr Cys Val Lys Thr Phe Thr Gly His Arg Glu Trp Val Arg Met Val 225 230 235 240 Arg Pro Asn Gln Asp Gly Thr Leu Ile Ala Ser Cys Ser Asn Asp Gln 245 250 255 Thr Val Arg Val Trp Val Val Ala Thr Lys Glu Cys Lys Ala Glu Leu 260 265 270 Arg Glu His Glu His Val Val Glu Cys Ile Ser Trp Ala Pro Glu Ser 275 280 285 Ser Tyr Ser Ser Ile Ser Glu Ala Thr Gly Ser Glu Thr Lys Lys Ser 290 295 300 Gly Lys Pro Gly Pro Phe Leu Leu Ser Gly Ser Arg Asp Lys Thr Ile 305 310 315 320 Lys Met Trp Asp Val Ser Thr Gly Met Cys Leu Met Thr Leu Val Gly 325 330 335 His Asp Asn Trp Val Arg Gly Val Leu Phe His Ser Gly Gly Lys Phe 340 345 350 Ile Leu Ser Cys Ala Asp Asp Lys Thr Leu Arg Val Trp Asp Tyr Lys 355 360 365 Asn Lys Arg Cys Met Lys Thr Leu Asn Ala His Glu His Phe Val Thr 370 375 380 Ser Leu Asp Phe His Lys Thr Ala Pro Tyr Val Val Thr Gly Ser Val 385 390 395 400 Asp Gln Thr Val Lys Val Trp Glu Cys Arg 405 410 <210> 2 <211> 441 <212> PRT <213> Homo sapiens <400> 2 Met Val Pro Pro Lys Leu His Val Leu Phe Cys Leu Cys Gly Cys Leu 1 5 10 15 Ala Val Val Tyr Pro Phe Asp Trp Gln Tyr Ile Asn Pro Val Ala His 20 25 30 Met Lys Ser Ser Ala Trp Val Asn Lys Ile Gln Val Leu Met Ala Ala 35 40 45 Ala Ser Phe Gly Gln Thr Lys Ile Pro Arg Gly Asn Gly Pro Tyr Ser 50 55 60 Val Gly Cys Thr Asp Leu Met Phe Asp His Thr Asn Lys Gly Thr Phe 65 70 75 80 Leu Arg Leu Tyr Tyr Pro Ser Gln Asp Asn Asp Arg Leu Asp Thr Leu 85 90 95 Trp Ile Pro Asn Lys Glu Tyr Phe Trp Gly Leu Ser Lys Phe Leu Gly 100 105 110 Thr His Trp Leu Met Gly Asn Ile Leu Arg Leu Leu Phe Gly Ser Met 115 120 125 Thr Thr Pro Ala Asn Trp Asn Ser Pro Leu Arg Pro Gly Glu Lys Tyr 130 135 140 Pro Leu Val Val Phe Ser His Gly Leu Gly Ala Phe Arg Thr Leu Tyr 145 150 155 160 Ser Ala Ile Gly Ile Asp Leu Ala Ser His Gly Phe Ile Val Ala Ala 165 170 175 Val Glu His Arg Asp Arg Ser Ala Ser Ala Thr Tyr Tyr Phe Lys Asp 180 185 190 Gln Ser Ala Ala Glu Ile Gly Asp Lys Ser Trp Leu Tyr Leu Arg Thr 195 200 205 Leu Lys Gln Glu Glu Glu Thr His Ile Arg Asn Glu Gln Val Arg Gln 210 215 220 Arg Ala Lys Glu Cys Ser Gln Ala Leu Ser Leu Ile Leu Asp Ile Asp 225 230 235 240 His Gly Lys Pro Val Lys Asn Ala Leu Asp Leu Lys Phe Asp Met Glu 245 250 255 Gln Leu Lys Asp Ser Ile Asp Arg Glu Lys Ile Ala Val Ile Gly His 260 265 270 Ser Phe Gly Gly Ala Thr Val Ile Gln Thr Leu Ser Glu Asp Gln Arg 275 280 285 Phe Arg Cys Gly Ile Ala Leu Asp Ala Trp Met Phe Pro Leu Gly Asp 290 295 300 Glu Val Tyr Ser Arg Ile Pro Gln Pro Leu Phe Phe Ile Asn Ser Glu 305 310 315 320 Tyr Phe Gln Tyr Pro Ala Asn Ile Ile Lys Met Lys Lys Cys Tyr Ser 325 330 335 Pro Asp Lys Glu Arg Lys Met Ile Thr Ile Arg Gly Ser Val His Gln 340 345 350 Asn Phe Ala Asp Phe Thr Phe Ala Thr Gly Lys Ile Ile Gly His Met 355 360 365 Leu Lys Leu Lys Gly Asp Ile Asp Ser Asn Val Ala Ile Asp Leu Ser 370 375 380 Asn Lys Ala Ser Leu Ala Phe Leu Gln Lys His Leu Gly Leu His Lys 385 390 395 400 Asp Phe Asp Gln Trp Asp Cys Leu Ile Glu Gly Asp Asp Glu Asn Leu 405 410 415 Ile Pro Gly Thr Asn Ile Asn Thr Thr Asn Gln His Ile Met Leu Gln 420 425 430 Asn Ser Ser Gly Ile Glu Lys Tyr Asn 435 440 <110> Industry Academic Cooperation Foundation <120> Use of platelet activating factor as a biomarker for determining persistancy of food allergy <130> 1069854 <160> 2 <170> KoPatentIn 3.0 <210> 1 <211> 410 <212> PRT <213> Homo sapiens <400> 1 Met Val Leu Ser Gln Arg Gln Arg Asp Glu Leu Asn Arg Ala Ile Ala 1 5 10 15 Asp Tyr Leu Arg Ser Asn Gly Tyr Glu Glu Ala Tyr Ser Val Phe Lys 20 25 30 Lys Glu Ala Glu Leu Asp Val Asn Glu Glu Leu Asp Lys Lys Tyr Ala 35 40 45 Gly Leu Leu Glu Lys Lys Trp Thr Ser Val Ile Arg Leu Gln Lys Lys 50 55 60 Val Met Glu Leu Glu Ser Lys Leu Asn Glu Ala Lys Glu Glu Phe Thr 65 70 75 80 Ser Gly Gly Pro Leu Gly Gln Lys Arg Asp Pro Lys Glu Trp Ile Pro 85 90 95 Arg Pro Pro Glu Lys Tyr Ala Leu Ser Gly His Arg Ser Pro Val Thr 100 105 110 Arg Val Ile Phe His Pro Val Phe Ser Val Met Val Ser Ala Ser Glu 115 120 125 Asp Ala Thr Ile Lys Val Trp Asp Tyr Glu Thr Gly Asp Phe Glu Arg 130 135 140 Thr Leu Lys Gly His Thr Asp Ser Val Gln Asp Ile Ser Phe Asp His 145 150 155 160 Ser Gly Lys Leu Leu Ala Ser Cys Ser Ala Asp Met Thr Ile Lys Leu 165 170 175 Trp Asp Phe Gln Gly Phe Glu Cys Ile Arg Thr Met His Gly His Asp 180 185 190 His Asn Val Ser Ser Val Ala Ile Met Pro Asn Gly Asp His Ile Val 195 200 205 Ser Ala Ser Arg Asp Lys Thr Ile Lys Met Trp Glu Val Gln Thr Gly 210 215 220 Tyr Cys Val Lys Thr Phe Thr Gly His Arg Glu Trp Val Arg Met Val 225 230 235 240 Arg Pro Asn Gln Asp Gly Thr Leu Ile Ala Ser Cys Ser Asn Asp Gln 245 250 255 Thr Val Arg Val Trp Val Val Ala Thr Lys Glu Cys Lys Ala Glu Leu 260 265 270 Arg Glu His Glu His Val Val Glu Cys Ile Ser Trp Ala Pro Glu Ser 275 280 285 Ser Tyr Ser Ser Ile Ser Glu Ala Thr Gly Ser Glu Thr Lys Lys Ser 290 295 300 Gly Lys Pro Gly Pro Phe Leu Leu Ser Gly Ser Arg Asp Lys Thr Ile 305 310 315 320 Lys Met Trp Asp Val Ser Thr Gly Met Cys Leu Met Thr Leu Val Gly 325 330 335 His Asp Asn Trp Val Arg Gly Val Leu Phe His Ser Gly Gly Lys Phe 340 345 350 Ile Leu Ser Cys Ala Asp Asp Lys Thr Leu Arg Val Trp Asp Tyr Lys 355 360 365 Asn Lys Arg Cys Met Lys Thr Leu Asn Ala His Glu His Phe Val Thr 370 375 380 Ser Leu Asp Phe His Lys Thr Ala Pro Tyr Val Val Thr Gly Ser Val 385 390 395 400 Asp Gln Thr Val Lys Val Trp Glu Cys Arg 405 410 <210> 2 <211> 441 <212> PRT <213> Homo sapiens <400> 2 Met Val Pro Pro Lys Leu His Val Leu Phe Cys Leu Cys Gly Cys Leu 1 5 10 15 Ala Val Val Tyr Pro Phe Asp Trp Gln Tyr Ile Asn Pro Val Ala His 20 25 30 Met Lys Ser Ser Ala Trp Val Asn Lys Ile Gln Val Leu Met Ala Ala 35 40 45 Ala Ser Phe Gly Gln Thr Lys Ile Pro Arg Gly Asn Gly Pro Tyr Ser 50 55 60 Val Gly Cys Thr Asp Leu Met Phe Asp His Thr Asn Lys Gly Thr Phe 65 70 75 80 Leu Arg Leu Tyr Tyr Pro Ser Gln Asp Asn Asp Arg Leu Asp Thr Leu 85 90 95 Trp Ile Pro Asn Lys Glu Tyr Phe Trp Gly Leu Ser Lys Phe Leu Gly 100 105 110 Thr His Trp Leu Met Gly Asn Ile Leu Arg Leu Leu Phe Gly Ser Met 115 120 125 Thr Thr Pro Ala Asn Trp Asn Ser Pro Leu Arg Pro Gly Glu Lys Tyr 130 135 140 Pro Leu Val Val Phe Ser His Gly Leu Gly Ala Phe Arg Thr Leu Tyr 145 150 155 160 Ser Ala Ile Gly Ile Asp Leu Ala Ser His Gly Phe Ile Val Ala Ala 165 170 175 Val Glu His Arg Asp Arg Ser Ala Ser Ala Thr Tyr Tyr Phe Lys Asp 180 185 190 Gln Ser Ala Ala Glu Ile Gly Asp Lys Ser Trp Leu Tyr Leu Arg Thr 195 200 205 Leu Lys Gln Glu Glu Glu Thr His Ile Arg Asn Glu Gln Val Arg Gln 210 215 220 Arg Ala Lys Glu Cys Ser Gln Ala Leu Ser Leu Ile Leu Asp Ile Asp 225 230 235 240 His Gly Lys Pro Val Lys Asn Ala Leu Asp Leu Lys Phe Asp Met Glu 245 250 255 Gln Leu Lys Asp Ser Ile Asp Arg Glu Lys Ile Ala Val Ile Gly His 260 265 270 Ser Phe Gly Gly Ala Thr Val Ile Gln Thr Leu Ser Glu Asp Gln Arg 275 280 285 Phe Arg Cys Gly Ile Ala Leu Asp Ala Trp Met Phe Pro Leu Gly Asp 290 295 300 Glu Val Tyr Ser Arg Ile Pro Gln Pro Leu Phe Phe Ile Asn Ser Glu 305 310 315 320 Tyr Phe Gln Tyr Pro Ala Asn Ile Ile Lys Met Lys Lys Cys Tyr Ser 325 330 335 Pro Asp Lys Glu Arg Lys Met Ile Thr Ile Arg Gly Ser Val His Gln 340 345 350 Asn Phe Ala Asp Phe Thr Phe Ala Thr Gly Lys Ile Ile Gly His Met 355 360 365 Leu Lys Leu Lys Gly Asp Ile Asp Ser Asn Val Ala Ile Asp Leu Ser 370 375 380 Asn Lys Ala Ser Leu Ala Phe Leu Gln Lys His Leu Gly Leu His Lys 385 390 395 400 Asp Phe Asp Gln Trp Asp Cys Leu Ile Glu Gly Asp Asp Glu Asn Leu 405 410 415 Ile Pro Gly Thr Asn Ile Asn Thr Thr Asn Gln His Ile Met Leu Gln 420 425 430 Asn Ser Ser Gly Ile Glu Lys Tyr Asn 435 440
Claims (13)
A composition for determining the persistence of food allergy, comprising an agent for measuring the level of platelet activating factor (PAF).
The composition according to claim 1, wherein the preparation is a competitive enzyme-linked immuno-sorbent assay preparation.
The composition according to claim 1, characterized in that the preparation is a chromatography and/or mass spectrometry preparation for measuring the level of the PAF.
A composition for determining the persistence of food allergy, comprising an agent for measuring the activity of platelet activating factor acetylhydrolase (PAFAH).
According to claim 4, wherein the preparation is characterized in that the preparation for colorimetric analysis, the composition for determining the persistence of food allergy.
A kit for determining the persistence of food allergy, comprising the composition of any one of claims 1 to 5.
(i) 혈소판 활성화 인자 (platelet activating factor, PAF)의 수준을 측정; 및/또는
(ii) 혈소판 활성화 인자 아세틸 가수분해 효소 (platelet activating factor acetylhydrolase, PAFAH)의 활성을 측정; 하는 단계를 포함하는, 식품 알레르기 지속성 여부 예측을 위한 정보 제공 방법.
In samples isolated from subjects with food allergies
(i) measuring the level of platelet activating factor (PAF); and/or
(ii) measuring the activity of platelet activating factor acetylhydrolase (PAFAH); Information providing method for predicting whether food allergy persists, comprising the step of doing.
상기 (i) 혈소판 활성화 인자 (platelet activating factor, PAF)의 수준은 면역블로팅, 효소 결합 면역흡착 분석법(Enzyme-Linked Immunosorbent Assay: ELISA), 면역 조직 화학 염색, 단백질 칩, 면역침강, 질량분석, 크로마토그래피 또는 이들의 조합으로 수행되는 것을 특징으로 하는, 방법.
According to claim 7,
The level of (i) platelet activating factor (PAF) is determined by immunoblotting, enzyme-linked immunosorbent assay (ELISA), immunohistochemical staining, protein chip, immunoprecipitation, mass spectrometry, characterized in that it is carried out by chromatography or a combination thereof.
상기 (ii) 혈소판 활성화 인자 아세틸 가수분해 효소 (platelet activating factor acetylhydrolase, PAFAH)의 활성은 비색 분석법으로 측정하는 것을 특징으로 하는, 방법.
According to claim 7,
Wherein (ii) the activity of platelet activating factor acetylhydrolase (PAFAH) is measured by a colorimetric assay.
상기 샘플은 혈액, 혈장, 혈청, 소변, 점액, 타액, 눈물, 객담, 척수액, 흉수, 유두 흡인물, 림프액, 기도액, 장액, 비뇨생식관액, 모유, 림프계 체액, 정액, 뇌척수액, 기관계내 체액, 복수, 낭성 종양 체액, 양수액 또는 이들의 조합인 것을 특징으로 하는, 방법.
According to claim 7,
The sample is blood, plasma, serum, urine, mucus, saliva, tears, sputum, spinal fluid, pleural fluid, nipple aspirate, lymph fluid, airway fluid, serous fluid, genitourinary tract fluid, breast milk, lymphatic system fluid, semen, cerebrospinal fluid, intratracheal fluid , ascites, cystic tumor fluid, amniotic fluid, or a combination thereof.
상기 (i) 혈소판 활성화 인자 (platelet activating factor, PAF)의 수준이 126 pg/mL 이상인 경우, 상기 대상체는 알레르기가 지속될 것으로 예측하는 것을 특징으로 하는, 방법.
According to claim 7,
The method, characterized in that, when the level of (i) platelet activating factor (PAF) is 126 pg / mL or more, the subject is predicted to have an allergy.
상기 (ii) 혈소판 활성화 인자 아세틸 가수분해 효소 (platelet activating factor acetylhydrolase, PAFAH)의 활성이 0.008 μmol/min/mL 이하인 경우, 상기 대상체는 알레르기가 지속될 것으로 예측하는 것을 특징으로 하는, 방법.
According to claim 7,
When the activity of (ii) platelet activating factor acetylhydrolase (PAFAH) is 0.008 μmol/min/mL or less, the subject predicts that the allergy will persist.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR1020210150519A KR102596736B1 (en) | 2021-11-04 | 2021-11-04 | Use of platelet activating factor as a biomarker for determining persistancy of food allergy |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR1020210150519A KR102596736B1 (en) | 2021-11-04 | 2021-11-04 | Use of platelet activating factor as a biomarker for determining persistancy of food allergy |
Publications (2)
Publication Number | Publication Date |
---|---|
KR20230064910A true KR20230064910A (en) | 2023-05-11 |
KR102596736B1 KR102596736B1 (en) | 2023-10-31 |
Family
ID=86379056
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
KR1020210150519A KR102596736B1 (en) | 2021-11-04 | 2021-11-04 | Use of platelet activating factor as a biomarker for determining persistancy of food allergy |
Country Status (1)
Country | Link |
---|---|
KR (1) | KR102596736B1 (en) |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20090110675A1 (en) * | 2007-10-31 | 2009-04-30 | Peter Vadas | Use of platelet activating factor acetylhydrolase as biomarker for anaphylaxis |
US20110217290A1 (en) * | 2008-08-18 | 2011-09-08 | Manel Jordana | Treatment and/or prevention of peanut induced anaphylaxis |
US20210009678A1 (en) * | 2018-03-23 | 2021-01-14 | North Carolina State University | Methods and compositions for allergic disorders |
-
2021
- 2021-11-04 KR KR1020210150519A patent/KR102596736B1/en active IP Right Grant
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20090110675A1 (en) * | 2007-10-31 | 2009-04-30 | Peter Vadas | Use of platelet activating factor acetylhydrolase as biomarker for anaphylaxis |
US20110217290A1 (en) * | 2008-08-18 | 2011-09-08 | Manel Jordana | Treatment and/or prevention of peanut induced anaphylaxis |
US20210009678A1 (en) * | 2018-03-23 | 2021-01-14 | North Carolina State University | Methods and compositions for allergic disorders |
Non-Patent Citations (3)
Title |
---|
Foong RX et al., Pediatr Allergy Immunol 2021; 32:223-33 |
Fukuda Yoshiaki et al, European Journal of Pharmacology (2000.), vol 390.1-2, pp 203-207. * |
Vadas Peter et al, Annals of Allergy Asthma &Immunology (2016.), vol 117.5, pp 455-457. * |
Also Published As
Publication number | Publication date |
---|---|
KR102596736B1 (en) | 2023-10-31 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP3198023B1 (en) | Cardiovascular risk event prediction and uses thereof | |
RU2670148C2 (en) | Methods for predicting risk of interstitial pneumonia | |
Cronin et al. | Elevated serum angiogenin levels in ALS | |
US20150045245A1 (en) | Biomarkers and test panels useful in systemic inflammatory conditions | |
US20090042201A1 (en) | Biomarkers for multiple sclerosis and methods of use thereof | |
JP2009511911A (en) | Diabetes-related markers and uses thereof | |
CA3082591A1 (en) | Markers for the diagnosis and treatment of non-alcoholic steatohepatitis (nash) and advanced liver fibrosis | |
JP6691617B2 (en) | Methods and compositions for providing an assessment of preeclampsia | |
Maneerat et al. | Increased alpha-defensin expression is associated with risk of coronary heart disease: a feasible predictive inflammatory biomarker of coronary heart disease in hyperlipidemia patients | |
US20110086796A1 (en) | Methods for predicting the development and resolution of acute respiratory distress syndrome | |
Chiang et al. | The circulating level of MMP-9 and its ratio to TIMP-1 as a predictor of severity in patients with community-acquired pneumonia | |
WO2011044142A1 (en) | Peripheral blood biomarkers for idiopathic interstitial pneumonia and methods of use | |
CA2839207A1 (en) | Compositions and methods for diagnosing and monitoring hyperthyroidism in a feline | |
Guo et al. | Potential urine biomarkers for gestational hypertension and preeclampsia | |
AU2012351963A1 (en) | Identification of two novel biomarkers for Niemann-Pick disease type C | |
Ping et al. | Effects of variation in retinol binding protein 4 gene and adipose specific expression of gestational diabetes in Beijing, China | |
Mihajlovic et al. | Association among resistin, adenylate cyclase-associated protein 1 and high-density lipoprotein cholesterol in patients with colorectal cancer: A multi-marker approach, as a hallmark of innovative predictive, preventive, and personalized medicine | |
CN113774140A (en) | Product for predicting sensitivity of colorectal cancer to oxaliplatin treatment | |
KR102596736B1 (en) | Use of platelet activating factor as a biomarker for determining persistancy of food allergy | |
KR102554138B1 (en) | Use of Omega-3 metabolites as a biomarker for determining persistancy of food allergy | |
Al-Amodi et al. | Potential Value of TNF-α (–376 G/A) Polymorphism and Cystatin C (CysC) in the Diagnosis of Sepsis Associated Acute Kidney Injury (S-AK I) and Prediction of Mortality in Critically Ill patients | |
CN113817829A (en) | Use of biomarkers for the preparation of a product for predicting the sensitivity of colorectal cancer to treatment with oxaliplatin | |
WO2010136232A1 (en) | In vitro method suitable for patients suffering from cis for the early diagnosis or prognosis of multiple sclerosis | |
US20110177963A1 (en) | Variation in the CHI3L1 Gene Influences Serum YKL-40 Levels, Asthma Risk and Lung Function | |
US20070238124A1 (en) | Differentially expressed genes related to coronary artery disease |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
E902 | Notification of reason for refusal | ||
E701 | Decision to grant or registration of patent right | ||
GRNT | Written decision to grant |