WO2019225803A1 - Association entre un polymorphisme de nucléotide simple de rnf213 et un risque de développer une maladie de moyamoya chez les coréens - Google Patents

Association entre un polymorphisme de nucléotide simple de rnf213 et un risque de développer une maladie de moyamoya chez les coréens Download PDF

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WO2019225803A1
WO2019225803A1 PCT/KR2018/007327 KR2018007327W WO2019225803A1 WO 2019225803 A1 WO2019225803 A1 WO 2019225803A1 KR 2018007327 W KR2018007327 W KR 2018007327W WO 2019225803 A1 WO2019225803 A1 WO 2019225803A1
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polymorphism
primer
risk
rnf213
seq
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Korean (ko)
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김남근
박영석
김옥준
김정오
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의료법인 성광의료재단
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    • 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
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6813—Hybridisation assays
    • C12Q1/6827—Hybridisation assays for detection of mutation or polymorphism
    • C12Q1/683—Hybridisation assays for detection of mutation or polymorphism involving restriction enzymes, e.g. restriction fragment length polymorphism [RFLP]
    • 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
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • 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
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/156—Polymorphic or mutational markers

Definitions

  • the present invention relates to the relationship between RNF213 monobasic polymorphism and the risk of Korean moyamoya disease. Specifically, a method of determining rs371441113 monobasic polymorphism from a DNA sample of a subject in order to provide information necessary for predicting the risk of moyamoya disease in Koreans. And rs371441113 relates to a kit for predicting the risk of occurrence of moyamoya disease in Koreans comprising means for detecting a single nucleotide polymorphism.
  • MMD Moyamoya disease
  • MMD represents the age distribution of the dichotomy for the maximum frequency of occurrence, with children around five years of age and adults in their mid-40s highest. Most children with MMD have a transient ischemic attack or cerebral infarction, while adults with MMD are more likely to have a hemorrhagic stroke. This suggests the possibility of alteration or damage of the gene sequence in the same MMD. Most MMD cases are sporadic, although familial MMD cases account for about 9.15% of all cases. Genetic associations of positions on chromosomes 3, 6, 8, 10, and 17 with specific human leukocyte antigen (HLA) haplotypes have been reported, but questions remain.
  • HLA human leukocyte antigen
  • Diagnosis of MMD can be used to confirm cerebral blood flow reduction on CT / MRI, SPECT or cerebral perfusion CT, or to reduce cerebral perfusion pressure on PET or cerebral perfusion MRI, to increase cerebral blood flow, and to increase cerebral oxygen extraction. It is used.
  • cerebral angiography is used to confirm the diagnosis. In the cerebral angiography, the distal and anterior cerebral arteries or the proximal or proximal cerebral arteries are narrowed or blocked, and these arteries are blocked or narrowed. Confirmation with MMD when abnormal blood vessels (moyamoya vessels) appear near the site.
  • RNF213 located on chromosome 17q25, is recognized as a major susceptibility gene for MMD in Asians as well as Caucasians and East / South Asians. Although there has been an association between p.R4810K polymorphism and intracranial major artery stenosis / arterial atresia in Japanese and Koreans, this genetic variation associated with MMD has been observed in non-MMD intracranial stenosis patients. The link between clinical symptoms of MMD is uncertain.
  • RNF213 variant p.R4810K (c.14429G> A, rs112735431) was first reported to have a high association with MMD.
  • RNF213 variants R4859K and R4810K correspond to rs112735431, while R4859K is based on computer predictive open reading frames on the database.
  • the present inventors have developed a new marker associated with MMD to improve the accuracy of MMD, especially Korean MMD risk prediction.
  • the main object of the present invention is to provide a method of using a new marker related to the risk of MMD in Korean in order to provide information necessary for predicting the risk of Korean's moyamoya disease.
  • Another object of the present invention to provide a kit useful for predicting the risk of MMD in Korean using the marker.
  • the present invention provides a method for determining rs371441113 single nucleotide polymorphism from a DNA sample of a subject in order to provide information necessary for predicting the risk of moyamoya disease in Koreans.
  • At least one monobasic polymorphism selected from rs148731719 monobasic polymorphism, rs112735431 monobasic polymorphism and rs760732823 monobasic polymorphism.
  • the present invention provides a kit for predicting the risk of moyamoya disease in Korean, comprising a means for detecting rs371441113 monobasic polymorphism.
  • the means for detecting the rs371441113 monobasic polymorphism is a primer for amplifying a continuous 50 to 10,000 bp region including the rs371441113 monobasic polymorphism site on human genomic DNA and the rs371441113 monobasic polymorphism site.
  • the base is a primer-limiting enzyme set comprising a restriction enzyme capable of cleaving DNA of either case of guanine or adenine.
  • the primer comprises an oligonucleotide represented by the nucleotide sequence of SEQ ID NO: 5 and an oligonucleotide represented by the nucleotide sequence of SEQ ID NO: 6, wherein the restriction enzyme is preferably BssS I.
  • kit of the present invention it is preferable to further include means for detecting at least one monobasic polymorphism selected from rs148731719 monobasic polymorphism, rs112735431 monobasic polymorphism and rs760732823 monobasic polymorphism.
  • the means for detecting the rs148731719 monobasic polymorphism is a primer for amplifying a continuous 50 to 10,000 bp region comprising the rs148731719 monobasic polymorphism site on the human genomic DNA and the rs148731719 monobasic polymorphism
  • a primer-limiting enzyme set comprising a restriction enzyme capable of cleaving DNA in any of the cases where the base of the site is guanine or adenine
  • the means for detecting rs112735431 monobasic polymorphism is human genomic DNA
  • a primer-limiting enzyme set comprising: c) the r
  • the primer of a) comprises an oligonucleotide represented by the nucleotide sequence of SEQ ID NO: 7 and an oligonucleotide represented by the nucleotide sequence of SEQ ID NO: 8, wherein the restriction enzyme of a) is Alu I
  • the primer of b) comprises an oligonucleotide represented by the nucleotide sequence of SEQ ID NO: 9 and an oligonucleotide represented by the nucleotide sequence of SEQ ID NO: 10, wherein the restriction enzyme of b) is Hpy 188I
  • the primer of c) comprises an oligonucleotide represented by the nucleotide sequence of SEQ ID NO: 11 and an oligonucleotide represented by the nucleotide sequence of SEQ ID NO: 12, wherein the restriction enzyme of c) is preferably Hpy 188I.
  • the present invention by determining the rs371441113 single nucleotide polymorphism, or rs148731719 single nucleotide polymorphism, rs112735431 single nucleotide polymorphism, and rs760732823 single nucleotide polymorphism, it can provide useful information for predicting the risk of moyamoya disease in Koreans. In particular, when using the kit of the present invention can be provided with such information more easily.
  • rs371441113 d
  • rs148731719 a
  • rs112735431 b
  • rs760732823 c
  • M molecular weight marker
  • GG GG genotype
  • GA GA genotype
  • AA AA genotype.
  • 'SNP' SNPs that can be expressed in human ring finger protein 213 (RNF213) genes.
  • the rs371441113 SNP can be identified as the 26th base in the human DNA region represented by SEQ ID NO: 1, which may be adenine, cytosine or guanine, but is rare in cytosine.
  • the rs148731719 SNP can be classified as the 26th base in the DNA region of human represented by SEQ ID NO: 2, and this base may be adenine or guanine.
  • the rs112735431 SNP can be identified as the 26th base in the human DNA site represented by SEQ ID NO: 3, which may be adenine, cytosine, or guanine, but is rare in cytosine.
  • the rs760732823 SNP can be identified as the 26th base in the human DNA region represented by SEQ ID NO: 4, which may be adenine, cytosine, or guanine, but is rare in cytosine.
  • the SNP can be determined by performing polymerase chain reaction- restriction fragment length polymorphism (PCR-RFLP) or sequencing.
  • PCR-RFLP polymerase chain reaction- restriction fragment length polymorphism
  • Polymerase chain reaction-limiting enzyme fragment length formation method is to amplify a target gene or DNA site by performing polymerase chain reaction, and the restriction enzyme recognizes or digests when treated with a specific restriction enzyme. It is a method of distinguishing polymorphism, deletion, addition or substitution of base by distinguishing whether or not digestion is performed.
  • the DNA amplification and digestion by restriction enzymes can be confirmed by electrophoresis using agarose gel.
  • a primer for amplifying a continuous 50 to 10,000 bp region including each SNP region and a restriction enzyme capable of cleaving DNA when each SNP region is a specific base are used. Can be.
  • amplification primers and restriction enzymes can be used.
  • DNA fragments of 188 bp are amplified by polymerase chain reaction, and when the restriction enzymes are processed, 162 bp and 26 bp DNA fragments in the GG genotype, 188 bp, 162 bp and the G genotype.
  • 230 bp DNA fragments are amplified by the polymerase chain reaction, and when the restriction enzymes are treated, 135 bp and 95 bp DNA fragments in the GG genotype, 230 bp, 135 bp and A 95 bp DNA fragment, 230 bp DNA fragment is generated.
  • DNA fragments of 151 bp are amplified by polymerase chain reaction, and DNA fragments of GG genotype 104 bp, 42 bp and 5 bp DNA fragments, 146 bp if GA genotypes are processed. DNA fragments of 104, 42 and 5 bp, 146 and 5 bp DNA fragments for the AA genotype are generated.
  • DNA fragments of 867bp are amplified by polymerase chain reaction, and the restriction enzymes process the DNA fragments of 867bp for the GG genotype, and 867bp, 719bp and 148bp for the GG genotype. DNA fragments, 719 bp and 148 bp DNA fragments are generated for the AA genotype.
  • the haplotype according to the combination of each SNP can be determined without performing a separate analysis method when the combined polymorphism is homozygous, otherwise it can be determined by performing a continuous sequencing method.
  • the present invention it is possible to determine each SNP of the RNF213 gene by the above method and to provide information for predicting the risk of moyamoya disease in Korean based on this. This is due to the significant difference (p ⁇ 0.05) confirmed by comparative analysis of the patients with moyamoya disease.
  • the risk of occurrence of moyamoya disease can be predicted as follows based on the SNP discrimination results of the RNF213 gene.
  • the risk of maternal morbidity is higher than that of other rs148731719 / rs112735431 / rs760732823 / rs371441113 haplotypes.
  • the risk of moyamoya disease is higher than that of other rs148731719 / rs112735431 / rs371441113 haplotypes.
  • the risk of moyamoya disease is higher than that of other rs112735431 / rs760732823 / rs371441113 haplotypes.
  • the GA genotype of rs371441113 was found to be significant in the patient group of ischemic moyamoya disease. Therefore, the rs371441113 genotyping method is more efficient for predicting the risk of ischemic moyamoya disease.
  • the GA genotype of rs371441113 was found to be more significant in the adult MMD patient group. Therefore, when the subject is rs371441113 GA genotype, it can be predicted that there is a high risk of moyamoya disease when adults 18 years of age or older than other rs371441113 genotype.
  • the material commonly used for the detection of SNP for example, primers for PCR, primers and restriction enzymes for PCR-RFLP, DNA-DNA hybridization probes and the like can be used.
  • kit of the present invention may further include reagents, instruments, and the like used for detecting SNPs.
  • rs371441113 is expressed as 'RNF213 4950G> A', rs148731719 as 'RNF213 4448G> A', rs112735431 as 'RNF213 4810G> A', and rs760732823 as 'RNF213 4863G> A'.
  • MMD Moyamoya disease
  • the control group consisted of 253 patients (mean age 25.60 ⁇ 16.98 years; 145 women (57.3%); 108 men (42.7%) with the same regional background as MMD patients. Severance Hospital, Bundang Cha Hospital, and Chungbuk National University Hospital recruited outpatients according to age and gender. Table 1 shows the demographic characteristics of the patient and control groups. MMD patients were divided into pediatric (under 18 years old) and adult (over 18 years old) groups, and further MMD patients were divided into ischemic or hemorrhagic groups according to clinical and MRI findings.
  • PCR-RFLP polymerase chain reaction-restriction fragment length polymorphism
  • RNF213 4448G> A polymorphism was PCR using forward primer (5'-TTG CCA ACT AAG CCC TCG AAA CAA-3 ') and reverse primer (5'-CAA CAA TGG CAC AGA ATT GTC-3'), PCR product (230 bp) was detected by treatment with 5 U Alu I. When the PCR product was treated with Alu I, only 230 bp fragments were generated, and AA genotypes, 230 bp, 135 bp, and 95 bp fragments were generated. G genotypes, 135 bp, and 95 bp fragments were generated, indicating the GG genotype. .
  • RNF213 4810G> A polymorphism was PCR using forward primers (5'-AGC AGA GCT GAG GCT GGT AA-3 ') and reverse primers (5'-CTG TCA GAG CAG AGC CAC AC-3') and PCR products ( 151 bp) was detected by treatment with 3U Hpy 188I.
  • PCR products were treated with Hpy 188I, fragments of 146 bp and 5 bp produced AA genotypes, fragments of 146 bp, 104 bp, 42 bp and 5 bp produced GA genotypes, and fragments of 104 bp, 42 bp and 5 bp showed GG genotypes. See b of FIG. 1).
  • RNF213 4863G> A polymorphism was PCR using forward primer (5'-TGT GTG TGG AGC TGA TGG CT-3 ') and reverse primer (5'-AGG GAG GAG ATA CAG ACC AGA CT-3'), PCR product (867bp) was detected by treatment with 5U Hpy 188I. When the PCR product was treated with Hpy 188I, only 867 bp fragments were generated, resulting in the GG genotype, 867 bp, 719 bp, and 148 bp fragments, which resulted in the GA genotype, 719 bp and 148 bp fragments.
  • RNF213 4950G> A polymorphism was PCR using forward primer (5'-GGT GGA GGA GGG CAG AGA GAC CGT GCA CGA-3 ') and reverse primer (5'-CTT CCC TCT CTC GAG AAA CAC ACC AA-3') PCR products (188 bp) were detected by treatment with 3U BssS I. When the PCR product was treated with BssS I, fragments of 162 bp and 26 bp produced GG genotypes, 188 bp, 162 bp and 26 bp fragments were produced. .
  • Genotype frequencies for the RNF213 polymorphism were compared using the Hardy-Weinberg equilibrium (HWE) test. Mann-Whitney and chi-square tests were used for continuous and categorical data, respectively, to analyze the demographic characteristics of MMD. The relationship between RNF213 and MMD patients (child or adult) was calculated according to odds ratio (OR) and 95% confidence intervals (CI) using Fisher's exact test. Corrected odds ratios (AOR) for the four polymorphisms of the RNF213 gene were calculated using multiple logistic regression analysis with gender and age. Hardy-Weinberg equilibrium was considered in the genotype distribution.
  • HWE Hardy-Weinberg equilibrium
  • Table 2 shows the demographic characteristics of MMD patients in this study. Genotype frequencies between MMD patients and controls of RNF213 4448G> A, RNF213 4810G> A, RNF213 4863G> A and RNF213 4950G> A polymorphisms are shown in Table 3. There were statistically significant differences between MMD patients and controls in the RNF213 4810G> A and RNF213 4950G> A polymorphisms.
  • the GA genotype of RNF213 4810G> A was more frequent in the MMD patient group (p ⁇ 0.001, GG vs. GA), and the comparison of the GA + AA genotype and the GG genotype also showed significant differences in MMD patients.
  • the genotype of RNF213 polymorphism was analyzed to be ischemic and hemorrhagic in MMD disease.
  • the GA genotype of RNF213 4950G> A was more frequent in the ischemic type, and the GA genotype of RNF213 4810G> A was It is frequent in both ischemic and hemorrhagic types of MMD (see Table 4).
  • MMD patients were divided into pediatric (less than 18 years old) and adult (over 18 years old) haplotype analyzes (see Tables 9-12).
  • GGAG 0.005
  • GAGG p ⁇ 0.0001
  • GAAG 0.033
  • haplotypes in RNF213 4448/4810/4863/4950 haplotypes are associated with MMD risk in the pediatric group
  • GAGA p Haplotypes increased the risk of MMD in the adult group.
  • Table 13 and 14 show the results of genotype combination frequency analysis of RNF213 in MMD patient group and control group.
  • RNF213 4448G> A / 4810G> A combination genotype the GG / GA combination genotype was more frequent in the MMD patient group
  • RNF213 4810G> A / 4863G> A combination genotype for the GA / GG and GA / GA combination genotype RNF213 4810G
  • Table 15 shows the major and small allele frequencies of RNF213 polymorphism in different global populations according to the 1000 Genome Project Database (http://www.internationalgenome.org/), and the RNF213 4448G> A of the control and MMD patient groups investigated in the present invention. , 4810G> A, 4863G> A and 4950G> A allele frequencies.

Abstract

La présente invention concerne une association entre un polymorphisme de nucléotide simple RNF213 et le risque de développer la maladie de Moyamoya chez les coréens, et plus spécifiquement, une méthode de détermination d'un polymorphisme de nucléotide simple Rs371441113 à partir d'un échantillon d'ADN d'un sujet afin de fournir des informations nécessaires pour prédire le risque de développer une maladie de Moyamoya chez les coréens ; et un kit pour prédire le risque de développer une maladie de Moyamoya, le kit comprenant un moyen pour détecter un polymorphisme de nucléotide simple rs371441113. Selon la présente invention, il est possible de fournir des informations utiles pour prédire le risque de développer une maladie de Moyamoya chez les coréens par détermination du polymorphisme de nucléotide simple rs371441113 seul ou en combinaison avec un polymorphisme de nucléotide simple rs148731719, un polymorphisme de nucléotide simple rs112735431, et un polymorphisme de nucléotide simple rs760732823. En particulier, de telles informations peuvent être fournies de manière plus commode à l'aide du kit de la présente invention.
PCT/KR2018/007327 2018-05-25 2018-06-28 Association entre un polymorphisme de nucléotide simple de rnf213 et un risque de développer une maladie de moyamoya chez les coréens WO2019225803A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
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CN112941161A (zh) * 2019-12-11 2021-06-11 国立研究开发法人国立循环器病研究中心 评价脑梗死的风险的方法

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112941161A (zh) * 2019-12-11 2021-06-11 国立研究开发法人国立循环器病研究中心 评价脑梗死的风险的方法

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