Lack of associations of ten candidate coronary heart disease risk genetic variants and subclinical atherosclerosis in four U.S. populations: The Population Architecture using Genomics and Epidemiology (PAGE) study

Abstract

Background A number of genetic variants have been discovered by recent genome-wide association studies for their associations with clinical coronary heart disease (CHD). However, it is unclear whether these variants are also associated with the development of CHD as measured by subclinical atherosclerosis phenotypes, ankle brachial index (ABI), carotid artery intima-media thickness (cIMT) and carotid plaque. Methods Ten CHD risk single nucleotide polymorphisms (SNPs) were genotyped in individuals of European American (EA), African American (AA), American Indian (AI), and Mexican American (MA) ancestry in the Population Architecture using Genomics and Epidemiology (PAGE) study. In each individual study, we performed linear or logistic regression to examine population-specific associations between SNPs and ABI, common and internal cIMT, and plaque. The results from individual studies were meta-analyzed using a fixed effect inverse variance weighted model. Results None of the ten SNPs was significantly associated with ABI and common or internal cIMT, after Bonferroni correction. In the sample of 13,337 EA, 3,809 AA, and 5,353 AI individuals with carotid plaque measurement, the GCKR SNP rs780094 was significantly associated with the presence of plaque in AI only (OR = 1.32, 95% confidence interval: 1.17, 1.49, P = 1.08 × 10−5), but not in the other populations (P = 0.90 in EA and P = 0.99 in AA). A 9p21 region SNP, rs1333049, was nominally associated with plaque in EA (OR = 1.07, P = 0.02) and in AI (OR = 1.10, P = 0.05). Conclusions We identified a significant association between rs780094 and plaque in AI populations, which needs to be replicated in future studies. There was little evidence that the index CHD risk variants identified through genome-wide association studies in EA influence the development of CHD through subclinical atherosclerosis as assessed by cIMT and ABI across ancestries.

Modulation of Glucokinase Regulatory Protein: A Double-Edged Sword?

“…One sufficiently powered population-based study, including 22 513 participants, did observe a positive association between the GCKR minor allele (rs780094) and carotid artery plaques, albeit only in Native Americans [67].…”

Association Between Coronary Artery Disease Genetic Variants and Subclinical Atherosclerosis: An Association Study and Meta-analysis

“…We finally included 9 manuscripts, [28][29][30][31][32][33][34][35][36] and the number of Table 4 Age-and Sex-adjusted Analysis Across Genotype Groups participants included in the meta-analysis ranged from 6676 (rs17465637 and rs10455872) to 32056 (rs1333049). The results reported in the studies included in the meta-analysis are shown in Table 3 of the supplementary material.…”

Cardiovascular dynamics of Canadian Indigenous peoples

“…Similarities in resting cardiovascular structure and function between Indigenous and European-descendant young adults suggest that subclinical cardiovascular disease development may occur similarly across ethnicities. These similarities in cardiovascular structure and function may seem counterintuitive given the greater experiences of obesity, diabetes and cardiovascular disease among Indigenous populations [2,36]; however, similar or more favourable vascular structure and function have been previously identified among Indigenous populations compared to European descent [37–39]. Similarities in cardiovascular structure and function, combined with previous similarities in vascular structure and function [37–39], suggest that the differences in cardiovascular disease are rooted outside of cardiovascular physiology and genetics, as previously suggested [40,41].…”

“…These similarities in cardiovascular structure and function may seem counterintuitive given the greater experiences of obesity, diabetes and cardiovascular disease among Indigenous populations [2,36]; however, similar or more favourable vascular structure and function have been previously identified among Indigenous populations compared to European descent [37–39]. Similarities in cardiovascular structure and function, combined with previous similarities in vascular structure and function [37–39], suggest that the differences in cardiovascular disease are rooted outside of cardiovascular physiology and genetics, as previously suggested [40,41]. Alternatively, while ethnic differences in resting cardiovascular dynamics were not identified, ethnic differences may be more apparent when evaluating ECG during maximal or near-maximal exercise stress tests which are prognostic for identifying cardiac arrhythmias and abnormalities among asymptomatic individuals with underlying cardiovascular disease [42].…”