Youhyun Song1, Ja-Eun Choi2, Yu-Jin Kwon3, Hyuk-Jae Chang4, Jung Oh Kim2, Da-Hyun Park2, Jae-Min Park1, Seong-Jin Kim2, Ji Won Lee5, Kyung-Won Hong6. 1. Department of Family Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, 211, Eonju-ro, Gangnam-gu, Seoul, 06273, Korea. 2. Healthcare R&D Division, Theragen Bio Co., Ltd., Gwanggyo-ro 145, Suwon-si, Gyeonggi-do, 16229, Republic of Korea. 3. Department of Family Medicine, Yongin Severance Hospital, Yonsei University College of Medicine, 363, Dongbaekjukjeon-daero, Giheung-gu, Yongin-si, 16995, Gyeonggi-do, Korea. 4. Division of Cardiology, Severance Cardiovascular Hospital, Yonsei University College of Medicine, 50-1, Yonsei-ro, Seodaemun-gu, Seoul, 03722, Korea. 5. Department of Family Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, 211, Eonju-ro, Gangnam-gu, Seoul, 06273, Korea. indi5645@yuhs.ac. 6. Healthcare R&D Division, Theragen Bio Co., Ltd., Gwanggyo-ro 145, Suwon-si, Gyeonggi-do, 16229, Republic of Korea. kyungwon.hong@theragenbio.com.
Abstract
BACKGROUND: 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. METHODS: 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. RESULTS: 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 × 10-9]), 2 in DM (DM-IS: 4q32.3/MARCH1-LINC01207 [OR, 5.587; P = 1.34 × 10-8], and DM-CCD: 17q25.3/RPTOR [OR, 3.511; P = 1.99 × 10-8]), and 3 in DL (DL-CAD: 9q22.2/UNQ6494-LOC101927847 [OR, 2.282; P = 7.78 × 10-9], DL-IS: 3p22.1/ULK4 [OR, 2.162; P = 2.97 × 10-8], and DL-CCD: 2p22.2/CYP1B1-CYP1B1-AS1 [OR, 2.027; P = 4.24 × 10-8]). CONCLUSIONS: 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.
BACKGROUND: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 diseasepatients. METHODS: 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. RESULTS: 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 × 10-9]), 2 in DM (DM-IS: 4q32.3/MARCH1-LINC01207 [OR, 5.587; P = 1.34 × 10-8], and DM-CCD: 17q25.3/RPTOR [OR, 3.511; P = 1.99 × 10-8]), and 3 in DL (DL-CAD: 9q22.2/UNQ6494-LOC101927847 [OR, 2.282; P = 7.78 × 10-9], DL-IS: 3p22.1/ULK4 [OR, 2.162; P = 2.97 × 10-8], and DL-CCD: 2p22.2/CYP1B1-CYP1B1-AS1 [OR, 2.027; P = 4.24 × 10-8]). CONCLUSIONS: 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.
Entities:
Keywords:
Cardiovascular disease; Diabetes mellitus; Dyslipidemia; Genome-wide association studies; Hypertension
Authors: Jiu-Chang Zhong; Zhen-Zhou Zhang; Wang Wang; Shaun M K McKinnie; John C Vederas; Gavin Y Oudit Journal: Biochim Biophys Acta Mol Basis Dis Date: 2016-11-04 Impact factor: 5.187
Authors: Donald M Lloyd-Jones; Byung-Ho Nam; Ralph B D'Agostino; Daniel Levy; Joanne M Murabito; Thomas J Wang; Peter W F Wilson; Christopher J O'Donnell Journal: JAMA Date: 2004-05-12 Impact factor: 56.272
Authors: Katherine E Beaney; Claire E Ward; Dauda A S Bappa; Nadine McGale; Anna K Davies; Shashivadan P Hirani; KaWah Li; Philip Howard; Dwaine R Vance; Martin A Crockard; John V Lamont; Stanton Newman; Steve E Humphries Journal: Cardiovasc Diabetol Date: 2016-10-03 Impact factor: 9.951
Authors: Ken B Hanscombe; Elodie Persyn; Matthew Traylor; Kylie P Glanville; Mark Hamer; Jonathan R I Coleman; Cathryn M Lewis Journal: Genome Med Date: 2021-11-09 Impact factor: 11.117