Identification of susceptibility loci for cardiovascular disease in adults with hypertension, diabetes, and dyslipidemia

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.

Keywords: Cardiovascular disease; Diabetes mellitus; Dyslipidemia; Genome-wide association studies; Hypertension.

Fig. 1

Study Design. Flow diagram illustrating the study sample selection process and overall study design

Fig. 2

Manhattan Plots Showing Association Results of the GWASs. Manhattan plots showing association results from the GWASs of CVD in the HTN(A–C), DM(D–F), and DL(G–I) groups within the City Cohort: a HTN-CAD (816 CAD cases and 15,488 controls), b HTN-IS (398 IS cases and 15,909 controls), c HTN-CCD (1,185 CCD cases and 15,117 controls), d DM-CAD (361 CAD cases and 5,161 controls), e DM-IS (153 IS cases and 5,161 controls), f DM-CCD (497 CCD cases and 4,815 controls), g DL-CAD (768 CAD cases and 19,999 controls), h DL-IS (295 IS cases and 20,474 controls), and i DL-CCD (1,039 CCD cases and 19,727 controls). Each tested SNP is visualized as a dot with a location on the genome shown on the x-axis and log10- transformed p values on the y-axis. Results for all chromosomes within the consensus threshold for genome-wide significance (5 × 10⁻⁸) are marked with a horizontal line in red and suggestive significance (1 × 10^–5) in blue