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


      • We examine the associations between CAD risk SNPs and subclinical atherosclerosis.
      • We include large samples of African Americans, Mexican Americans, and American Indians.
      • SNP rs780094 is significantly associated with plaque in American Indians.
      • Lack of association between CAD risk SNPs with ABI and cIMT.



      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.


      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.


      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, 3809 AA, and 5353 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).


      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.


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          Genetic and molecular epidemiology identifies genes and biomarkers associated with disease, and provides means to extrapolate from controlled animal experiments to the human situation. However, genetic epidemiological studies only demonstrate associations between the studied genetic variations and the studied disease, and thus provide no causal evidence regarding the underlying causal relationships or the mechanism of action. Likewise, even prospective studies of the association of biomarkers with later occurrence of disease do not provide evidence of causality.
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