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.

The genetic case for cardiorespiratory fitness as a clinical vital sign and the routine prescription of physical activity in healthcare

“…Previous notable associations with these ten functional candidates include disease (Parkinson’s disease [ 70 ], hypertrophic cardiomyopathy [ 71 ], ischaemic stroke, diabetes mellitus and coronary artery disease [ 72 ]) anthropometrics (BMI-adjusted waist-hip to ratio, BMI [ 73 ]), blood phenotypes (haemoglobin measurement [ 55 ], red blood cell density, haematocrit [ 57 ], eosinophil count and systolic blood pressure [ 54 ]), lung function (FVC [ 54 ], FEV1 [ 51 ]), and heart and electrocardiography measures (QRS measures [ 52 ], and cardiac arrhythmia [ 53 ]).…”

“…For PA, the functional candidates on 17q21.31 ( MAPT , LRRC37A2 , LRRC37A , KANSL1 , CRHR1 , ARL17A and ARHGAP27 ) and 22q13.2 ( L3MBTL2 ) with a high probability of the same variant driving PA association and expression in the adipose, brain, heart, lung and muscle; have previously been associated with disease (Parkinson’s disease [ 70 ], hypertrophic cardio myopathy [ 71 ], ischaemic stroke, diabetes mellitus and coronary artery disease [ 72 ]) anthropometrics (BMI-adjusted waist hip to ratio, BMI [ 73 ]), blood phenotypes (haemoglobin measurement [ 55 ], red blood cell density, haematocrit [ 57 ], eosinophil count and systolic blood pressure [ 54 ]), lung function (FVC [ 54 ], FEV1 [ 51 ]), and heart and electrocardiography measures (QRS measures [ 52 ], cardiac arrhythmia [ 53 ]). We found PA functional candidates enriched in Parkinson’s and Alzheimer’s disease, noteworthy given their underlying insulin resistance pathology (although the insulin resistance link is controversial for Alzheimer’s disease), idiopathic pulmonary fibrosis, multiple system atrophy and primary biliary cirrhosis.…”

The genetic case for cardiorespiratory fitness as a clinical vital sign and the routine prescription of physical activity in healthcare

“…Previous notable associations with these ten functional candidates include disease (Parkinson’s disease (70), hypertrophic cardio myopathy (71), ischaemic stroke, diabetes mellitus and coronary artery disease (72)) anthropometrics (BMI-adjusted waist hip to ratio, BMI (73)), blood phenotypes (haemoglobin measurement (55), red blood cell density, hematocrit (57), eosinophil count and systolic blood pressure (54)), lung function (FVC (54), FEV1 (51)), and heart and electrocardiography measures (QRS measures (52), cardiac arrhythmia (53)).…”

“…For PA, the functional candidates on 17q21.31 ( MAPT, LRRC37A2, LRRC37A, KANSL1, CRHR1, ARL17A , and ARHGAP27 ) and 22q13.2 ( L3MBTL2 ) with a high probability of the same variant driving PA association and expression in adipose, brain, heart, lung and muscle, have previously been associated with disease (Parkinson’s disease (70), hypertrophic cardio myopathy (71), ischaemic stroke, diabetes mellitus and coronary artery disease (72)) anthropometrics (BMI-adjusted waist hip to ratio, BMI (73)), blood phenotypes (haemoglobin measurement (55), red blood cell density, hematocrit (57), eosinophil count and systolic blood pressure (54)), lung function (FVC (54), FEV1 (51)), and heart and electrocardiography measures (QRS measures (52), cardiac arrhythmia (53)). We found PA functional candidates enriched in Parkinson’s and Alzheimer’s disease, noteworthy given their underlying insulin resistance pathology (although the insulin resistance link is controversial for Alzheimer’s disease), idiopathic pulmonary fibrosis, multiple system atrophy and primary biliary cirrhosis.…”

Potential Regulatory Role of lncRNA-miRNA-mRNA in Coronary Artery Disease (CAD)

“…29) Actually, hypertension, diabetes, or dyslipidemia has been considered to be a risk factor for CAD. 30) A previous study has revealed 225 DE lncRNAs and 473 DE mRNAs in the submandibular gland of rats with spontaneous hypertension compared with that of Wistar-Kyoto rats. 31) As an obesity-related gene, FAIM2 is regulated by nutritional state and the methylation levels of the FAIM2 promoter are significantly associated with obesity.…”