CN102876794A - Application of mononucleotide polymorphic rs6871626 in detection of susceptibility genes of lepriasis - Google Patents
Application of mononucleotide polymorphic rs6871626 in detection of susceptibility genes of lepriasis Download PDFInfo
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Abstract
The invention discloses application of mononucleotide polymorphic rs6871626 in detection of susceptibility genes of the lepriasis and provides application of polymorphic or genetic substances for detecting the rs 6871626 in genomes of humans in preparation and detection of mononucleotide polymorphic products relevant to the lepriasis. The polymorphic substances or other substances detecting the rs 6871626 (or detecting other mononucleotide polymorphic substances relevant to the lepriasis) are combined to prepare products forexamining patients with the lepriasis.
Description
Technical field
The present invention relates to the application of single nucleotide polymorphism rs6871626 in detecting the leprosy tumor susceptibility gene.
Background technology
Single nucleotide polymorphism (single nucleotide polymorphism, SNP) refers to the variation of genome single core thuja acid, and it is the most small variation unit, is to displacement, transversion, insertion or lack formed variant form by the single core thuja acid.Single nucleotide polymorphism is highdensity genetic marker on the genome, and the SNP quantity of having found in human genome surpasses 30,000,000.As third generation genetic marker SNP One's name is legion, densely distributed, be easy to detect, thereby be desirable gene type target.The SNP somatotype detects at disease genome (such as disease susceptibility), is significant in the researchs such as Drug Discovery (drug effect, drug metabolism difference and untoward reaction) and Swarm Evolution.
At present existing several different methods can be used for SNP and detects, such as dna sequencing, Restriction fragment length polymorphism, single strand conformation polymorphism, sex change high performance liquid chromatography, SNP chip.Wherein, the SNP chip comprises chip based on nucleic acid hybridization reaction, based on the chip of single base extension, based on the chip of allele-specific primers extension, based on the chip of " single stage method " reaction, based on the chip of the chip of primer ligation, the reaction of constraint based restriction endonuclease, based on the chip of protein D NA association reaction, and based on the chip (Zhang Xiaoyan etc. of fluorescence molecule DNA association reaction.With genechip detection single nucleotide polymorphism reaction principle.Chinese biological engineering magazine.2005,25(11):52～56）。
Leprosy is a kind of chronic infectious disease due to being infected by Mycobacterium leprae, and this remains a serious health problem in developing country, and annual global new cases number is 250000.Main infringement skin and peripheral nerve, and cause the nerve function lesion of non-reversibility and chronic teratogenesis to be disabled.This has been proved to be in the in the groove environmental factors of leprosy and host genetic factor and has played vital effect, estimates that inherited genetic factors is up to 57%.
The scheme of the World Health Organization is divided into tuberculosis type and knurl type to the clinical manifestation of leprosy, and respectively corresponding Th1(is cell-mediated) and Th2(body fluid mediate) immunne response of the human body of tissue.The multifarious clinical manifestation of leprosy reflects human body to two kinds of distinct immunne responses of allogenic disease substance, and this just illustrates the importance of genetic predisposition in the leprosy morbidity.The result of genetic research shows that heredity is all relevant with the disease progression of vulnerability to leprosy and its clinical subtype.
Summary of the invention
Technical problem to be solved by this invention provides the new purposes of single nucleotide polymorphism rs6871626 aspect leprosy.
New purposes provided by the present invention is following 1)-9) at least a:
1) polymorphism of rs6871626 or the application of genotypic material in the product of the preparation detection single nucleotide polymorphism relevant with leprosy in the detection human genome;
2) detect the application in the product of characterization or the assistant identification single nucleotide polymorphism relevant with leprosy of the polymorphism of rs6871626 in the human genome or genotypic material;
3) polymorphism of rs6871626 or the genotypic material application in preparation examination leper product in the detection human genome;
4) polymorphism of rs6871626 or the genotypic material application in preparation detection leprosy susceptibility product in the detection human genome;
5) application of the single nucleotide polymorphism in the human genome in the product of preparation detection leprosy tumor susceptibility gene, wherein, described single nucleotide polymorphism is that refSNP ID is the dna sequence polymorphism of rs6871626;
6) application of the single nucleotide polymorphism in the human genome in the product of characterization or assistant identification leprosy tumor susceptibility gene, wherein, described single nucleotide polymorphism is that refSNP ID is the dna sequence polymorphism of rs6871626;
7) application of the polymorphism of rs6871626 in preparation examination leper product in the human genome;
8) application of the polymorphism of rs6871626 in preparation detection leprosy susceptibility product in the human genome;
9) comprise the product that detects the material of rs6871626 polymorphism in the human genome, be any product in a)-d):
The product of the single nucleotide polymorphism that a) detection is relevant with leprosy,
The product of the single nucleotide polymorphism that b) evaluation or assistant identification are relevant with leprosy,
C) examination leper product,
D) detect leprosy susceptibility product.
In an embodiment of the present invention, described leprosy is specially China Han and the crowd of ethnic minority leprosy.
Rs6871626 is the SNP site of two equipotential polymorphisms on the human chromosome 5q33, and this variation is conversion (A/C then is T/G on its complementary strand).Described rs6871626 genotype is AA, AC or CC.Described AA is that the rs6871626 site is the homozygous of A, and described CC is that the rs6871626 site is the homozygous of C, and described AC is that the rs6871626 site is the heterozygous of A and C.The polymorphism of rs6871626 or genotype specifically can be the Nucleotide kind that detects rs6871626 in the described detection human genome.
The P value that experiment showed, the case-control colony that rs6871626 forms in the case colony that is comprised of 5503 lepers with by 4971 normal peoples is 3.95 * 10
-18, relative risk is 0.75, illustrates that rs6871626 is the single nucleotide polymorphism relevant with leprosy.
Experiment showed, that in three genotype of rs6871626, the ratio of the genotypic individuality of CC in normal people colony is 45.5%, is starkly lower than the ratio 51.5% in the leper colony.In actual applications, material and other material (as detecting other the material of relevant single nucleotide polymorphism with the leprosy) gang that detects the polymorphism of rs6871626 can be prepared examination leper's product.
Wherein, the material of the polymorphism of rs6871626 can be required reagent and/or the instrument of polymorphism of determining rs6871626 by following at least a method in the detection human genome: dna sequencing, Restriction fragment length polymorphism, single strand conformation polymorphism, sex change high performance liquid chromatography and SNP chip.Wherein, the SNP chip comprises chip based on nucleic acid hybridization reaction, based on the chip of single base extension, based on the chip of allele-specific primers extension, based on the chip of " single stage method " reaction, based on the chip of the chip of primer ligation, the reaction of constraint based restriction endonuclease, based on the chip of protein D NA association reaction, and based on the chip of fluorescence molecule DNA association reaction.
Described product can be reagent or test kit, also can be the combined prod of reagent or test kit and instrument, such as the combined prod that is formed by primer and DNA sequencer, and the combined prod that is formed by PCR reagent and dna sequencing reagent and DNA sequencer.
In one embodiment of the present of invention, adopt the PCR primer amplification to comprise the genomic DNA fragment of rs6871626, take the pcr amplification product that obtains as template, adopt the single-basic extension primer to carry out single base extension, sequence to the extension products that obtains detects, and determines polymorphism and the genotype of rs6871626.Described PCR primer does not have particular requirement in sequence, as long as can amplify the genomic DNA fragment that comprises rs6871626, specifically can be the single stranded DNA shown in sequence 1 and the sequence 2.Described extension primer designs according to rs6871626 upstream in the human genome (not comprising this SNP site), front 1 Nucleotide of last 1 Nucleotide correspondence of described extension primer rs6871626 in human genome, extend as described primer and specifically can be the strand DMNA shown in the sequence 5 in the sequence table, certainly also can be with the above Nucleotide of downstream sequence prolongation according to rs6871626 in the human genome of the single stranded DNA shown in the sequence 5, or according to above Nucleotide of the downstream sequence of rs6871626 in human genome disappearance, as long as can make 3 ' end of this single-basic extension primer extend the Nucleotide in rs6871626 site.
The present invention finds that in a sample from Chinese population (5503 leper with 4971 healthy persons) rs6871626 is the single nucleotide polymorphism relevant with leprosy.Material and other material (as detecting other the material of relevant single nucleotide polymorphism with the leprosy) gang that detects the polymorphism of rs6871626 can be prepared examination leper's product.
Description of drawings
Fig. 1 is the associated region of rs2058660.
The left side longitudinal axis is shown as the P value of SNP, and the right side longitudinal axis is shown as recombination fraction, and transverse axis shows its physical location.SNP and this relation conefficient (r2) of testing positive SNP site rs2058660 are used the different colours mark in each zone, arrow indication be P value minimum SNP site in the positive SNP rs2058660 of this experiment, the zone and the SNP that in the past reported, the minimum SNP site rs1916307 of P value, the report site rs3771166 relevant with asthma all tested positive SNP site rs2058660 onrelevant with this in the past, and site rs917997, the rs13015714 relevant with celiac disease and positive site be related (r by force
2＞0.8).The estimation of recombination fraction is based on China in thousand human genomes and Japanese population sample.The gene of note comes from (http://genome.ucsc.edu/) among the figure.
Fig. 2 is the associated region of rs6871626.
The left side longitudinal axis is shown as the P value of SNP, and the right side longitudinal axis is shown as recombination fraction, and transverse axis shows its physical location.SNP and this are tested the relation conefficient (r of positive SNP site rs6871626 in each zone
2) use the different colours mark, arrow indication be P value minimum SNP site in the positive SNP rs6871626 of this experiment, the zone and the SNP that in the past reported, site rs1422877 and the rs10045431 relevant with Crohn disease that the P value is minimum, the rs2546890 that multiple sclerosis is relevant, rs2546890, rs3213094, rs2082412 that psoriatic is relevant, the rs12188300 that arthropathic psoriasis is relevant, the relevant rs6556416 of ankylosing spondylitis all with positive SNP site rs6871626 onrelevant (r
2＜0.01).The estimation of recombination fraction is based on China in thousand human genomes and Japanese population sample.The gene of note comes from (http://genome.ucsc.edu/) among the figure.
Embodiment
Following embodiment is convenient to understand better the present invention, but does not limit the present invention.Experimental technique among the following embodiment if no special instructions, is ordinary method.
Used material, reagent etc. if no special instructions, all can obtain from commercial channels among the following embodiment.
Contriver place research group adopted genome-wide association study (GWAS) to find 7 tumor susceptibility genes (CCDC122, C13orf31, NOD2, TNFSF15 of leprosy in Chinese han population in 2009, HLA-DR, RIPK2 and LRRK2), wherein 5 genes are set up signal path (Zhang, F.R., a Huang centered by NOD2, W., Chen, S, M., Sun, L.D., Liu, H., Li, Y., Cui, Y., Yan, X.X., Yang, H.T., Yang, R.D.et al. (2009) Genomewide association study of leprosy.N.Engl.J.Med., 361,2609-2618.), behind GWAS, found again 2 vulnerability to leprosy genes (IL23R and RAB32) (Zhang, F. in 2011, Liu, H., Chen, S., Low, H., Sun, L., Cui, Y., Chu, T., Li, Y., Fu, X., Yu, Y.et al. (2011) Identification of two new loci at IL23R and RAB32that influence).The Complex Diseases that leprosy concurs as a plurality of minor genes of a class, 9 susceptibility locis finding at present only are the tips of the iceberg of its tumor susceptibility gene spectrum, and more vulnerability to leprosy gene waits further discovery.
The selection of candidate gene and SNP
12 CD(Crohn's diseases have been consulted in the GWAS official website (http://www.genome.gov/26525384) of contriver by PUBMED) GWAS research and 2 UC(ulcerative colitiss) GWAS study.Therefrom select 155 of being positioned on 118 genes and CD or UC or SNPs(p that both are relevant＜5.0 * 10
-8).Get rid of 7 SNP and 15 SNPs that are positioned on 5 known vulnerability to leprosy genes (NOD2, TNFSF15, IL23R, C13ORF31 and LRRK2) of being positioned at the MHC zone.Remaining 133 SNPs comprise the related SNP s of 75 CD, 54 SNPs that UC is relevant, 41 IBD(MIM266600) (CD and UC) relevant SNPs.These are named a person for a particular job and are verified in 4 independent samples from Chinese population.
The ethics statement
The approval of Ethics Committee of Dermatology and Venereology research institution of Shandong Academy of Medical Sciences has been passed through in this research, and all lepers and normal healthy controls person have all signed Informed Consent Form.
Research object
From four independent samples of Chinese population, have 4971 lepers in these four independent samples, 5503 normal healthy controls persons.They are the independent individual of consanguinity-less relation.The information exchanges such as clinical classification, family history situation and age of onset are crossed the case history collection.Sample standard deviation is by the Quality Control of sample.Leper's diagnosis is made a definite diagnosis (clinical foundation comprises claw hand, reel foot and pathology foundation etc.) simultaneously by two experts of Dermatology Department at least.Normal healthy controls person all personally discusses the disease medical history without leprosy family history and other.
Wherein, leprosy in China patient's Case definition be meet in following 4 more than 2 or 2, or meet the 3rd person and establish diagnosis: 1, skin decreases with sensory disturbance and closes sweat, or numb district is arranged; 2, peripheral nerve is got involved, and shows as the thick companion's corresponding function of nerve trunk obstacle; 3, skin damage tissue slice or tissue juice smear are found leprosy bacillus; 4, the pathology visible features sexually revises.
Normal healthy controls person's Case definition: without leprosy medical history and other transmissible disease medical histories, without other autoimmune disorder medical history and family history.
Table 1 has shown the essential information of sample 1-4.
Table 1,4971 leprosy in China patients and 5503 normal healthy controls persons' basic condition
aSample is from Shandong, Anhui and the Wuhan province in Chinese East China
bSample is from Shandong, Anhui and the Jiangsu Province in Chinese East China
cSample is from Yunnan, Guizhou and the Fujian Province of In South China
dSample is from Yunnan, Guizhou and the Fujian Province of In South China.
The present invention uses the genotype that Sequenom MassARRAY SNP genotyping technique (San Diego, USA) is analyzed 4 groups of independence leprosy samples.In fs, to having carried out gene type from 1504 lepers of north of China and 133 SNPs of 1502 normal healthy controls persons, 119 successful somatotypes of quilt wherein.The p value of 19 SNPs comprises the SNPs of 9 CD less than 0.05, the SNPs of the SNPs of 8 UC and 2 IBD.In the subordinate phase, 19 above-mentioned SNPs independently are verified in the Chinese population at another.This crowd is divided into 3 groups: 1) from 1154 lepers and 2605 normal healthy controls persons of Northern Han Nationality; 2) from 1165 lepers and 648 normal healthy controls persons of Han nationality in southern China; 3) from 1148 lepers and 748 normal healthy controls person's (Zhuangs: 358 lepers and 323 normal healthy controls persons of southern china ethnic minority; Miao ethnic group: 277 lepers and 190 collators; The Yi nationality, distributed over Yunnan, Sichuan and Guizhou: 366 lepers and 182 normal healthy controls persons; Other nationality: 147 lepers and 53 normal healthy controls persons).
In 4 groups of independent samples (p of its genetic heterogeneity〉0.05), found 2 new relevant SNPs, namely be positioned at the rs2058660 and the rs6871626 that is positioned at 5q33.3 of 2q12.1.Behind all samples of analysis-by-synthesis (4971 lepers and 5503 normal healthy controls persons), the p value that draws 2 SNPs is respectively 4.57 * 10
-19With 3.95 * 10
-18, the OR value is respectively 1.30 and 0.75.
Table 2.rs2058660 is in the association analysis result of 4 independent samples and whole samples
aAllelotrope for assessment of the OR value.
bIn four independent samples, detect allelic average frequency.
Table 3.rs6871626 is in the association analysis result of 4 independent samples and whole samples
aAllelotrope for assessment of the OR value.
bIn four independent samples, detect allelic average frequency.
Then the GWAS data centralization formerly delivered of contriver has been studied relevant evidence (the Zhang FR of two genes at these two new locus near zones, Liu H, Chen S, Low H, Sun L, Cui Y, Chu T, Li Y, Fu X, Yu Y, et al. (2011) .Identification of two new loci at IL23R and RAB32that influence susceptibility to leprosy.Nat Genet.43,1247-1251).In order to cover to greatest extent this genovariation, the heritable variation data set that the invention people use from thousand human genome plans imports the GWAS data set, thousand human genome plans comprise and come from Africa (246 sample) that America (181 sample), Asia (286 samples) and Europe (379 sample) amount to the individuality of the dissimilar ancestor of 1092 samples.Guarantee idiotype probability＜90%, the importing of SNP＜80%, MAF＜5%, the individuality of miss rate＞1% is left out in next step analysis.In a word, there are 6593 samples (706 lepers and 5587 contrasts are individual) and 1,987,713SNP still to be retained in the correlation analysis by quality control.
Rs2058660 is positioned at the linkage disequilibrium zone of a 480kb of 2q12.1, and it comprises 5 gene IL1RL1, IL18RAP, IL18R1, SLC9A4 and SLC9A2 (Fig. 1).IL1RL1, IL18RAP and IL18R1 are parts that is positioned at the cytokine receptor bunch in 2q12 zone, IL1RL1 coding IL33 acceptor, IL18RAP and IL18R1 coding IL18 acceptor.IL33 in Th2 cell and mastocyte, and stimulates the generation of Th2 relevant cell factor as the part selective expression.
Rs6871626 is positioned at one of 5q33.3 and only has the very little LD zone (Fig. 2) of 40kb, only has the function of a gene (LOC285627) to there is no clearly in this zone.Yet IL12B is positioned near this LD zone, and is strong biology candidate gene.The p40 subunit of IL12B coding heterodimer interleukin I L-12 and IL-23.These two site prompting IL18RAP/IL18R1 of Rs2058660 and Rs6871626 and IL12B have participated in the regulate process of IFN-r transcriptional expression in the leprosy as the new tumor susceptibility gene of leprosy.
Wherein, the method for gene type is as follows:
133 SNPs adopt Sequenom MassArray (San Diego, USA) platform validation, and each sample is used 15ngDNA approximately.At first extract the genomic dna of peripheral blood, after the stdn, sample DNA increases through multi-PRC reaction and comprises the genomic DNA fragment in SNP site, and amplified production carries out the extension of the single chain of SNP locus specificity, and the extension products desalination is also transferred on the chip in 384 holes.Mass spectrograph (MALDI-TOF MS) carries out allelic detection, adopts Sequenom Mass ARRAY somatotype software that detected result is analyzed.
1, whole blood sample collection
In informed consent, and gather research object peripheric venous blood 5ml in the situation of signature written consent book, be positioned over EDTANa
2In the anticoagulant tube, putting-80 ℃ of refrigerator-freezers stores for future use.
2, the DNA concentration standard comprises the steps:
1) utilizes every a standardized sample DNA concentration and the OD ratio (A260/A280, A260/A230) of needing of NanoDrop-1000 concentration tester Accurate Determining.
2) set up electrical form, the DNA numbering that each sample aperture that is ranked need to add.
Carry out the sample of Sequenom MassArray somatotype, leave blank and repeated sample contrast at per 96 orifice plates.
3) according to the order of electrical form, add the DNA that has measured concentration.
Requiring experimental concentration for the sample that carries out Sequenom MassArray somatotype is 12-30ng/ μ l, generally take 18ng/ μ l as good.And A260/A280 ratio between 1.5-2.0, A260/230 is between 1.5-2.3, be higher than 18ng/ul such as DNA concentration and then add an amount of FG3, with the concentration mark to 18ng/ul; Be lower than 12ng/ul such as DNA concentration, then again extract qualified DNA from blood.Concentration directly adds between 12-18ng/ μ l.
Stick the viscosity masking foil after centrifugal, and put on the information such as sample plane label, sample type, source place with marker pen.
4) on dull and stereotyped whizzer, centrifugal 3 minutes of 3000g, deposit in-20 ℃ for subsequent use.
3, multiplex PCR
Wherein, amplification comprises that the primer of genomic DNA fragment of rs6871626 is as follows in the multiplex PCR:
Amplification comprises that the primer of genomic DNA fragment of rs2058660 is as follows in the multiplex PCR:
Sequence 3 in the ACGTTGGATGCAGCCCCATTAGCAGTAAAT(sequence table) and
Sequence 4 in the ACGTTGGATGAGCTCCACTTAACACCAGTC(sequence table).
4, the extension of the single chain of SNP locus specificity
Wherein, extend primer according to upstream, SNP site in the human genome (not comprising this SNP site) design, front 1 Nucleotide in last 1 Nucleotide correspondence of described extension primer this SNP site in human genome.The sequence of the extension primer of rs6871626 is the sequence 5 in the TGTCCTTCATCACTTGG(sequence table).The sequence of the extension primer of rs2058660 is the sequence 6 in the TGGCCCCATTAGCAGTAAATGCCCTTT(sequence table).
5, data quality control
1) call rate calculating is carried out in the SNP of somatotype, remove call rate＜95% SNP or SNPs of gene frequency＜0.01;
2) SNP is carried out genetic equilibrium check, remove the P of Hardy-Weinberg balance check in the SNP(check sample that departs from the law of genetic equilibrium＜=0.001).
3) in Sequenom MassArray system, check the somatotype dendrogram of SNP, remove dendrogram and divide heap unclear SNP.
4) sample Quality Control: the sample of directly removing the somatotype failure.
To carry out statistical study by sample and the SNP of Quality Control.
6, data statistic analysis
Utilize Plink1.07 software that somatotype success and the SNP by Quality Control are done the gene phenotype correlation analysis in case group and control group, check the genotype of each sample and the cognation of phenotype with Cochran-Armitage trend, then use the genotype of all samples of Cochran-Mantel-Haenszel analysis-by-synthesis and the dependency of phenotype.Check to estimate heterogeneity between individuality with Q, in this experiment, with p＜0.05 as inspection level.Multiple logistic regression analysis is for detection of the independence of the signal in the zone.Inspection level α take 0.05 divided by the SNP number by quality control as inspection level.The Q check has been considered as remarkable genetic heterogeneity to P value after the SNP correct detection less than 0.05 for assessment of the significance of genetic heterogeneity.
The genotype of rs6871626 and phenotype association study result are as shown in table 4, show that rs6871626 is the single nucleotide polymorphism relevant with leprosy.
Genotype and the phenotype association study result of table 4.rs6871626
The genotype of rs2058660 and phenotype association study result are as shown in table 5, show that rs2058660 is the single nucleotide polymorphism relevant with leprosy.
Genotype and the phenotype association study result of table 5.rs2058660
Claims (10)
1. the polymorphism of rs6871626 or the genotypic material application in the product of the preparation detection single nucleotide polymorphism relevant with leprosy in the detection human genome.
2. the polymorphism of rs6871626 or the genotypic material application in the product of characterization or the assistant identification single nucleotide polymorphism relevant with leprosy in the detection human genome.
3. the polymorphism of rs6871626 or the genotypic material application in preparation examination leper product in the detection human genome.
4. the polymorphism of rs6871626 or the genotypic material application in preparation detection leprosy susceptibility product in the detection human genome.
5. the application of the single nucleotide polymorphism in the human genome in the product of preparation detection leprosy tumor susceptibility gene, it is characterized in that: described single nucleotide polymorphism is that refSNP ID is the dna sequence polymorphism of rs6871626.
6. the application of the single nucleotide polymorphism in the human genome in the product of characterization or assistant identification leprosy tumor susceptibility gene is characterized in that: described single nucleotide polymorphism is that refSNP ID is the dna sequence polymorphism of rs6871626.
7. the application of the polymorphism of rs6871626 in preparation examination leper product in the human genome.
8. the application of the polymorphism of rs6871626 in preparation detection leprosy susceptibility product in the human genome.
9. contain the product that detects the material of rs6871626 polymorphism in the human genome, be any product in a)-d):
The product of the single nucleotide polymorphism that a) detection is relevant with leprosy;
The product of the single nucleotide polymorphism that b) evaluation or assistant identification are relevant with leprosy;
C) examination leper product;
D) detect leprosy susceptibility product.
10. product according to claim 9 is characterized in that: the material of the polymorphism of rs6871626 contains PCR primer and the single-basic extension primer that amplification comprises the genomic DNA fragment of rs6871626 in the described detection human genome.
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| CN104293948B (en) * | 2014-10-10 | 2016-03-23 | 山东省皮肤病性病防治研究所 | Single nucleotide polymorphism rs2221593 is detecting the application in susceptibility gene of leprosy |
| CN104293947A (en) * | 2014-10-10 | 2015-01-21 | 山东省皮肤病性病防治研究所 | Application of single nucleotide polymorphism rs58600253 in detection of leprosy susceptibility genes |
| CN104293952A (en) * | 2014-10-10 | 2015-01-21 | 山东省皮肤病性病防治研究所 | Application of single nucleotide polymorphism rs10817758 in detection of a lepriasis susceptibility gene |
| CN104293946A (en) * | 2014-10-10 | 2015-01-21 | 山东省皮肤病性病防治研究所 | Application of single nucleotide polymorphism rs663743 in detection of lepriasis susceptibility gene |
| CN104293949A (en) * | 2014-10-10 | 2015-01-21 | 山东省皮肤病性病防治研究所 | Application of single nucleotide polymorphism rs73058713 in detecting lepriasis predisposing gene |
| CN104293950A (en) * | 2014-10-10 | 2015-01-21 | 山东省皮肤病性病防治研究所 | Application of single nucleotide polymorphism rs77061563 in detecting leprosy susceptibility genes |
| CN104293947B (en) * | 2014-10-10 | 2016-03-23 | 山东省皮肤病性病防治研究所 | Single nucleotide polymorphism rs58600253 is detecting the application in susceptibility gene of leprosy |
| CN104293946B (en) * | 2014-10-10 | 2016-03-23 | 山东省皮肤病性病防治研究所 | Single nucleotide polymorphism rs663743 is detecting the application in susceptibility gene of leprosy |
| CN104293950B (en) * | 2014-10-10 | 2016-03-23 | 山东省皮肤病性病防治研究所 | Single nucleotide polymorphism rs77061563 is detecting the application in susceptibility gene of leprosy |
| CN104293949B (en) * | 2014-10-10 | 2016-03-23 | 山东省皮肤病性病防治研究所 | Single nucleotide polymorphism rs73058713 is detecting the application in susceptibility gene of leprosy |
| CN104293948A (en) * | 2014-10-10 | 2015-01-21 | 山东省皮肤病性病防治研究所 | Application of single nucleotide polymorphism rs2221593 in detecting leprosy susceptibility genes |
| CN111304323A (en) * | 2019-12-31 | 2020-06-19 | 中山大学肿瘤防治中心（中山大学附属肿瘤医院、中山大学肿瘤研究所） | SNP markers related to evaluation of NK/T cell lymphoma onset risk and application thereof |
| CN111647659A (en) * | 2020-06-30 | 2020-09-11 | 北京泱深生物信息技术有限公司 | New application of LOC285627 |
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