Metabolic Syndrome(대사증후군)의 주요 유형과 SNP와의 관련성 연구

Abstract

[한글]

본 연구는 한국인 대상의 심혈관계 질환 환자를 중심으로 한 가계자료를 이용하여 Metabolic Syndrome(대사증후군)과 SNP의 연관성 분석을 통해 관련 유전자를 발굴하기 위한 연구이다.

연구 대상자는 혈압이 외래에서 측정하여 160

90mmHg 이상인 고혈압 환자이거나 이미 고혈압으로 진단받고 약물투여중인 환자들(Proband)과 그 가족들(Non-probnad)이며, 이렇게 수집된 심혈관계 질환 유전체 연구센터의 가계자료는 535 family, 총 2100명 (남성 992명, 여성 1108명)이었다. Metabolic Syndrome criteria NCEP-ATPⅢ(단, 허리둘레 APC)에 따라 Metabolic Syndrome으로 진단된 경우 환자군, Metabolic syndrome이 아닌 경우 대조군으로 정의하였다.

설문지를 통하여 관련 변수를 수집하고, 혈액을 채취하여 유전자를 추출, genotyping을 하였으며, 심혈관계 질환과 연관성을 보이는 7개 유전자 ABCA1, ACE, AGT, ApoB, CETP, GPIIB, PON1의 11개 SNP를 대상으로 Metabolic Syndrome 발생과의 관련성을 분석하였다. 특히, Metabolic Syndrome의 5가지 구성 요소별, 주요 다빈도 유형별 assocoation 분석을 실시하였으며, haplotype 분석도 함께 시행하였다. SAS

Genetics 9.1.2로 통계 분석하였다.

연구의 결과는 다음과 같다.

1. Metabolic Syndrome의 발생은 NCEP-ATPⅢ 기준(단, 허리둘레 APC 적용)에 의해 전체 36.17%, 남성 36.13%, 여성 36.20%의 유병률을 보였으며, Metabolic Syndrome과 유전자의 환자대조군 분석을 한 결과 유전자 AGT의 A-20C SNP가 유의한 차이를 보였다.

2. Metabolic Syndrome을 결정짓는 주요 대사 요소 5가지를 각각 요소별로 유전자(SNP)와의 관련성을 분석한 결과, Waist level에서 ABCA1, ApoB, PON1, Blood Pressure level에서 ACE, AGT, Triglyceride level에서 AGT, CETP, Glucose level에서 GPIIB, HDL-cholesterol level에서 ABCA1, ACE가 각각 유의한 차이를 나타냈다.

3. 한국인에서 나타나는 Metabolic Syndrome의 주요 다빈도 유형은 Blood Pressure+Triglyceride+HDL-Cholesterol의 3가지 요소를 포함한 유형이었다. 이 유형을 구성하는 3가지 요소는 다음 순위의 다빈도 유형에서도 주요 요소로 포함되어, 한국인에서의 Metabolic Syndrome을 결정짓는 주요 요소들로 보여진다.

4. Metabolic Syndrome의 주요 유형과 SNP와의 연관성을 분석한 결과, 전체에서 유전자 AGT의 A-217T, G-6A가 유의한 결과를 보였으며, Proband에서 AGT(A-20C), Non-proband에서 AGT(G-217T)가 매우 유의하게 나타났다. 따라서, 유전자 AGT가 Metabolic Syndrome과 연관성이 있음을 확인하였다.

5. 1q42-3에 위치한 AGT 유전자의 4개 SNP G-217T, A-20C, G-6A, M235T에 대해 Allele association을 통한 Haplotype 분석을 실시하였으며, 두 군에서 공통적으로 G-C-A-C, G-T-G-T, G-T-A-C, A-T-A-C 등의 일배체형이 전체 분포의 99%정도를 차지하고 있었다. Proband와 Non-proband, Metabolic Syndrome 발현-비발현으로 나누어 환자-대조군 연구를 한 결과, 전체적으로 모두 유의한 차이를 보이지 않았다. 그러나 각각 haplotype 별로 차이를 비교하였을 때에는, Proband와 Non-proband에서 G-C-A-C와 G-T-G-C haplotype, 환자대조군에서 G-C-A-C, A-T-G-C, G-T-A-T, A-T-A-T haplotype이 유의한 차이를 나타냈다.

[영문]The aim of the study is to identify the SNPs related to Metabolic Syndrome through the analysis of the association between Metabolic Syndrome and SNPs, using the familial data on the patients of cardiovascular disease in Korea.

The subject of the study comprises hypertensive patients whose measured blood pressure exceeds 160

90mmHg or patients who have already been diagnosed as hypertensive and have been dosed with medicine (Proband), and their family members (Non-proband). The familial data gathered by the Yonsei Cardiovascular Center(Seoul, Korea) cover 535 families and 2100 family members in total (male 992, female 1108). Applying Metabolic Syndrome criteria NCEP-ATPⅢ(Waist level APC applied), when a subject was diagnosed as having Metabolic Syndrome, he or she was classified as belonging to the case group, whereas in the opposite case, the subject was classified as belonging to the control group.

Related variables were collected through questionnaires, and genes isolated from blood samples were genotyped. Analysis of the association between the occurrence of Metabolic Syndrome and the 11 SNPs from the 7 Genes, ABCA1, ACE, AGT, ApoB, CETP, GPIIB, PON1 that seem to be related to Cardiovascular disease, was conducted. Especially, the association analysis according to 5 components of Metabolic Syndrome and their frequency major types was conducted along with the haplotype analysis. The data were analyzed with the SAS/Genetics 9.1.2.

The results of the study are as follows:

1. The prevalence of Metabolic Syndrome, according to the NCEP-ATPⅢ criteria (Waist level APC applied) was 36.17% for total, 36.13% for male and 36.20% for female patients respectively, and the results from the case-control study of the relation between Metabolic Syndrome and genes(SNP) showed that there was a significant difference in A-20C SNP of the gene AGT.

2. The results from the analysis of the association between the SNPs and each of the 5 main metabolic components that determine Metabolic Syndrome showed that ABCA1, ApoB, PON1 showed a significant difference at the Waist level, ACE, AGT at the Blood Pressure level, AGT, CETP at the Triglyceride level, GPIIB at the Glucose level and ABCA1, ACE at the HDL-cholesterol level, respectively.

3. The major type of Metabolic Syndrome, found most frequently with Korean patients, is the type that combines the 3 components of Blood Pressure+Triglyceride+ HDL-Cholesterol. The three components that make up the type are also found in the next frequent types and seem to be the principal factors that determine Metabolic Syndrome for Korean.

4. The results from the analysis of the association between the major types of Metabolic Syndrome and SNPs, A-217T, G-6A of AGT showed a significant presence in all groups and AGT (A-20C) in Proband, AGT (G-217T) in Non-proband showed a significant presence respectively. Therefore, we confirmed that the gene AGT is related to Metabolic Syndrome.

5. The Haplotype analysis was conducted on the 4 SNPs of the gene AGT, G-217T, A-20C, G-6A, and M235T, which are located at 1q42-3, through Allele association. G-C-A-C, G-T-G-T, G-T-A-C, A-T-A-C haplotypes account for 99% of all distribution at two groups commonly. The analysis conducted separately on the Proband and Non-proband, and separately on the Metabolic syndrome diagnosis and non-diagnosis groups, showed no particular difference in total. However, when the differences according to haplotype were compared, G-C-A-C and G-T-G-C haplotype in Proband and Non-proband, G-C-A-C, A-T-G-C, G-T-A-T, A-T-A-T haplotype in Metabolic syndrome diagnosis and non-diagnosis groups respectively showed significant differences.