Song Youhyun, Choi Ja-Eun, Kwon Yu-Jin, Chang Hyuk-Jae, Kim Jung Oh, Park Da-Hyun, Park Jae-Min, Kim Seong-Jin, Lee Ji Won, Hong Kyung-Won
Department of Family Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, 211, Eonju-ro, Gangnam-gu, Seoul, 06273, Korea.
Healthcare R&D Division, Theragen Bio Co., Ltd., Gwanggyo-ro 145, Suwon-si, Gyeonggi-do, 16229, Republic of Korea.
J Transl Med. 2021 Feb 25;19(1):85. doi: 10.1186/s12967-021-02751-3.
Hypertension (HTN), diabetes mellitus (DM), and dyslipidemia (DL) are well-known risk factors of cardiovascular disease (CVD), but not all patients develop CVDs. Studies have been limited investigating genetic risk of CVDs specific to individuals with metabolic diseases. This study aimed to identify disease-specific and/or common genetic loci associated with CVD susceptibility in chronic metabolic disease patients.
We conducted a genome-wide association study (GWAS) of a multiple case-control design with data from the City Cohort within Health EXAminees subcohort of the Korean Genome and Epidemiology Study (KoGES_HEXA). KoGES_HEXA is a population-based prospective cohort of 173,357 urban Korean adults that had health examinations at medical centers. 42,393 participants (16,309 HTN; 5,314 DM; 20,770 DL) were analyzed, and each metabolic disease group was divided into three CVD case-controls: coronary artery disease (CAD), ischemic stroke (IS), and cardio-cerebrovascular disease (CCD). GWASs were conducted for each case-control group with 7,975,321 imputed single nucleotide polymorphisms using the Phase 3 Asian panel from 1000 Genomes Project, by logistic regression and controlled for confounding variables. Genome-wide significant levels were implemented to identify important susceptibility loci.
Totaling 42,393 individuals, this study included 16,309 HTN (mean age [SD], 57.28 [7.45]; 816 CAD, 398 IS, and 1,185 CCD cases), 5,314 DM (57.79 [7.39]; 361 CAD, 153 IS, and 497 CCD cases), and 20,770 DL patients (55.34 [7.63]; 768 CAD, 295 IS, and 1,039 CCD cases). Six genome-wide significant CVD risk loci were identified, with relatively large effect sizes: 1 locus in HTN (HTN-CAD: 17q25.3/CBX8-CBX4 [OR, 2.607; P = 6.37 × 10]), 2 in DM (DM-IS: 4q32.3/MARCH1-LINC01207 [OR, 5.587; P = 1.34 × 10], and DM-CCD: 17q25.3/RPTOR [OR, 3.511; P = 1.99 × 10]), and 3 in DL (DL-CAD: 9q22.2/UNQ6494-LOC101927847 [OR, 2.282; P = 7.78 × 10], DL-IS: 3p22.1/ULK4 [OR, 2.162; P = 2.97 × 10], and DL-CCD: 2p22.2/CYP1B1-CYP1B1-AS1 [OR, 2.027; P = 4.24 × 10]).
This study identified 6 susceptibility loci and positional candidate genes for CVDs in HTN, DM, and DL patients using an unprecedented study design. 1 locus (17q25.3) was commonly associated with CAD. These associations warrant validation in additional studies for potential therapeutic applications.
高血压（HTN）、糖尿病（DM）和血脂异常（DL）是众所周知的心血管疾病（CVD）风险因素，但并非所有患者都会发生心血管疾病。针对患有代谢疾病个体的心血管疾病遗传风险的研究有限。本研究旨在确定慢性代谢疾病患者中与心血管疾病易感性相关的疾病特异性和/或常见基因位点。
我们采用多病例对照设计进行了一项全基因组关联研究（GWAS），数据来自韩国基因组与流行病学研究（KoGES_HEXA）的健康体检队列中的城市队列。KoGES_HEXA是一个基于人群的前瞻性队列，由173,357名韩国城市成年人组成，他们在医疗中心进行了健康检查。对42,393名参与者（16,309名高血压患者；5,314名糖尿病患者；20,770名血脂异常患者）进行了分析，每个代谢疾病组又分为三个心血管疾病病例对照：冠状动脉疾病（CAD）、缺血性中风（IS）和心脑血管疾病（CCD）。使用来自千人基因组计划的第3阶段亚洲面板的7,975,321个估算单核苷酸多态性，对每个病例对照组进行GWAS，采用逻辑回归并控制混杂变量。采用全基因组显著水平来确定重要的易感基因位点。
本研究共纳入42,393名个体，其中包括16,309名高血压患者（平均年龄[标准差]，57.28[7.45]；816例CAD，398例IS，1,185例CCD）、5,314名糖尿病患者（57.79[7.39]；361例CAD，153例IS,497例CCD）和20,770名血脂异常患者（55.34[7.63]；768例CAD，295例IS，1,039例CCD）。确定了6个全基因组显著的心血管疾病风险基因位点，效应大小相对较大：高血压组中有1个基因位点（HTN-CAD：17q25.3/CBX8-CBX4[比值比，2.607；P = 6.37×10]），糖尿病组中有2个（DM-IS：4q32.3/MARCH1-LINC01207[比值比，5.587；P = 1.34×10]，DM-CCD：17q25.3/RPTOR[比值比，3.511；P = 1.99×10]），血脂异常组中有3个（DL-CAD：9q22.2/UNQ6494-LOC101927847[比值比，2.282；P = 7.78×10]，DL-IS：3p22.1/ULK4[比值比，2.162；P = 2.97×10]，DL-CCD：2p22.2/CYP1B1-CYP1B1-AS1[比值比，2.027；P = 4.24×10]）。
本研究采用前所未有的研究设计，确定了高血压、糖尿病和血脂异常患者中6个心血管疾病的易感基因位点和定位候选基因。1个基因位点（17q25.3）与CAD普遍相关。这些关联值得在更多研究中进行验证，以用于潜在的治疗应用。
