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Genome-wide association study of coronary artery calcification in asymptomatic Korean populations.

ABSTRACT: Epidemiologic evidence indicates that the prevalence and severity of coronary artery disease vary depending on ethnicity. In this study, a genome-wide association study for coronary artery calcification (CAC) was performed in a Korean population-based sample of 400 subjects without prior coronary artery disease and replicated in another of 1,288 subjects. CAC score, as assessed by multi-detector computed tomography, was evaluated in volunteers for screening purposes as part of a routine health examination. CAC score greater than the 90th percentile across the age in each sex group was considered severe CAC. Single nucleotide polymorphisms (SNPs) associated with severe CAC after adjusting for age, sex, hypertension, and diabetes were investigated using the additive model of logistic regression. One SNP (rs10757272 in the intronic region of the CDKN2B-AS1 gene in chromosome 9p21.3) met Bonferroni correction in the discovery set (p = 7.55E-08) and was also significant in the validation set by TaqMan assay (p = 0.036). Subjects with rs10757272 were found to have an increased odds ratio (OR) of having severe CAC in multivariate logistic regression analysis after adjusting for age, sex, hypertension, and diabetes (adjusted OR 3.24 and 95% CI 2.11-4.97). In conclusion, SNP rs10757272 in chromosome 9p21.3 was associated with severe CAC based on age and sex in an asymptomatic community-based Korean population. Therefore, it was associated with promotion of coronary artery calcification in subclinical state.

SUBMITTER: Choi SY

PROVIDER: S-EPMC6438465 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Genome-wide association study of coronary artery calcification in asymptomatic Korean populations.

Choi Su-Yeon SY Shin Eunsoon E Choe Eun Kyung EK Park Boram B Lee Heesun H Park Hyo Eun HE Lee Jong-Eun JE Choi Seung Ho SH

PloS one 20190328 3

Epidemiologic evidence indicates that the prevalence and severity of coronary artery disease vary depending on ethnicity. In this study, a genome-wide association study for coronary artery calcification (CAC) was performed in a Korean population-based sample of 400 subjects without prior coronary artery disease and replicated in another of 1,288 subjects. CAC score, as assessed by multi-detector computed tomography, was evaluated in volunteers for screening purposes as part of a routine health e ...[more]

PMID: 30921371

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Project description:Many GWAS have identified novel loci associated with common diseases, but have focused only on main effects of individual genetic variants rather than interactions with environmental factors (GxE). Identification of GxE interactions is particularly important for coronary heart disease (CHD), a major preventable source of morbidity and mortality with strong non-genetic risk factors. Atherosclerosis is the major cause of CHD, and coronary artery calcification (CAC) is directly correlated with quantity of coronary atherosclerotic plaque. In the current study, we tested for genetic variants influencing extent of CAC via interaction with smoking (GxS), by conducting a GxS discovery GWAS in Genetic Epidemiology Network of Arteriopathy (GENOA) sibships (N = 915 European Americans) followed by replication in Framingham Heart Study (FHS) sibships (N = 1025 European Americans). Generalized estimating equations accounted for the correlation within sibships in strata-specific groups of smokers and nonsmokers, as well as GxS interaction. Primary analysis found SNPs that showed suggestive associations (p≤10(-5)) in GENOA GWAS, but these index SNPs did not replicate in FHS. However, secondary analysis was able to replicate candidate gene regions in FHS using other SNPs (+/-250 kb of GENOA index SNP). In smoker and nonsmoker groups, replicated genes included TCF7L2 (p = 6.0×10(-5)) and WWOX (p = 4.5×10(-6)); and TNFRSF8 (p = 7.8×10(-5)), respectively. For GxS interactions, replicated genes included TBC1D4 (p = 6.9×10(-5)) and ADAMTS9 (P = 7.1×10(-5)). Interestingly, these genes are involved in inflammatory pathways mediated by the NF-κB axis. Since smoking is known to induce chronic and systemic inflammation, association of these genes likely reflects roles in CAC development via inflammatory pathways. Furthermore, the NF-κB axis regulates bone remodeling, a key physiological process in CAC development. In conclusion, GxS GWAS has yielded evidence for novel loci that are associated with CAC via interaction with smoking, providing promising new targets for future population-based and functional studies of CAC development.

Project description:Coronary artery disease (CAD), one of the leading causes of death globally, is influenced by both environmental and genetic risk factors. Gene-centric genome-wide association studies (GWAS) involving cases and controls have been remarkably successful in identifying genetic loci contributing to CAD. Modern in silico platforms, such as candidate gene prediction tools, permit a systematic analysis of GWAS data to identify candidate genes for complex diseases like CAD. Subsequent integration of drug-target data from drug databases with the predicted candidate genes can potentially identify novel therapeutics suitable for repositioning towards treatment of CAD.Previously, we were able to predict 264 candidate genes and 104 potential therapeutic targets for CAD using Gentrepid (http://www.gentrepid.org), a candidate gene prediction platform with two bioinformatic modules to reanalyze Wellcome Trust Case-Control Consortium GWAS data. In an expanded study, using five bioinformatic modules on the same data, Gentrepid predicted 647 candidate genes and successfully replicated 55% of the candidate genes identified by the more powerful CARDIoGRAMplusC4D consortium meta-analysis. Hence, Gentrepid was capable of enhancing lower quality genotype-phenotype data, using an independent knowledgebase of existing biological data. Here, we used our methodology to integrate drug data from three drug databases: the Therapeutic Target Database, PharmGKB and Drug Bank, with the 647 candidate gene predictions from Gentrepid. We utilized known CAD targets, the scientific literature, existing drug data and the CARDIoGRAMplusC4D meta-analysis study as benchmarks to validate Gentrepid predictions for CAD.Our analysis identified a total of 184 predicted candidate genes as novel therapeutic targets for CAD, and 981 novel therapeutics feasible for repositioning in clinical trials towards treatment of CAD. The benchmarks based on known CAD targets and the scientific literature showed that our results were significant (p < 0.05).We have demonstrated that available drugs may potentially be repositioned as novel therapeutics for the treatment of CAD. Drug repositioning can save valuable time and money spent on preclinical and phase I clinical studies.

Project description:BackgroundDyslipidemia is a well-known risk factor for cardiovascular disease (CVD). Recently, atherogenic index of plasma (AIP) has been proposed as a novel predictive marker for CVD, and few cross sectional studies have demonstrated a relationship between AIP and coronary artery disease. The present study investigated the association between AIP and the progression of coronary artery calcification (CAC) in Korean adults without CVD.MethodsA total of 1124 participants who had undergone CAC measurement at least twice by multi-detector computed tomography (CT) at a health check-up center were enrolled. Their anthropometric measurements and various cardiovascular risk factors were assessed. AIP was defined as the base 10 logarithm of the ratio of the concentration of triglyceride (TG) to high-density lipoprotein-cholesterol (HDL-C). CAC progression was defined as either incident CAC in a CAC-free population at baseline, or an increase of ≥2.5 units between the square roots of the baseline and follow-up coronary artery calcium scores (CACS) in subjects with detectable CAC at baseline.ResultsCAC progression was observed in 290 subjects (25.8%) during the mean follow-up of 4.2 years. All subjects were stratified into three groups according to AIP. There were significant differences in cardiovascular parameters among groups at baseline. The follow-up CAC and the incidence of CAC progression increased gradually with rising AIP tertiles. In logistic regression analysis, the odds ratio for CAC progression was 2.27 when comparing the highest to the lowest tertile of AIP (95% CI: 1.61-3.19; P for trend < 0.01). However, this association was attenuated after adjustment for multiple risk factors (P for trend = 0.67).ConclusionsThere is a significant correlation between AIP and the progression of CAC in subjects without CVD. Although AIP was not an independent predictor of CAC progression, AIP should be considered when estimating the current as well as future CVD risk, along with other traditional risk factors.

Dataset Information

Genome-wide association study of coronary artery calcification in asymptomatic Korean populations.

Publications

Genome-wide association study of coronary artery calcification in asymptomatic Korean populations.

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