Genetic Epidemiologic Studies Of Plasma Fatty Acids, Hemostatic Factors, And Abdominal Aortic Aneurysm

Abstract

Plasma fatty acids and hemostatic factors are biochemical measurements and associated with the risk of venous thromboembolism (VTE) or abdominal aortic aneurysm (AAA), which are important public health issues. Current research has identified genes and variants for these diseases but they only explain a small amount of disease risk. We used three approaches to evaluate the genetic influences on these diseases or their biochemical measurements and the interactions between genetic variants and gender. In the first manuscript, we tested gene-by-gender interactions on plasma phospholipid polyunsaturated fatty acid (PUFA) levels in 8,962 individuals of European ancestry (EA) from 5 cohorts, using meta-analysis data for selected plasma PUFA-related single nucleotide polymorphisms (SNPs). A few nominally significant interactions with gender were observed (p<0.005). Additionally, three novel loci on chromosome 3, 17, and 18 were genome-wide significant (p < 5 x 10-8) for plasma eicosapentaenoic acid (EPA) when both main genetic effect and SNP-by-gender interaction were considered. Findings from this study suggested the possibility of gene-by-gender interaction on plasma phospholipid PUFA levels in EA populations. In the second manuscript, we aimed to identify common genetic variants for plasma levels of PUFA and hemostatic factors. Focusing on 15 SNPs of 9 independent signals previously identified for PUFAs, our study identified novel associations between hemostatic factors and the variants in JMJD1c, SYCP2L, and PPT2 in 9,035 European Americans (EAs) from the Atherosclerosis Risk in Communities (ARIC) study. Using a Mendelian randomization (MR) approach, our study suggested that higher adrenic acid (AdrA) leads to a lower factor VII level, and a higher dihomo-gamma-linolenic acid (DGLA) leads to a lower activated partial thromboplastin time (aPTT) level in EAs. The third manuscript aimed to investigate the causal relationship between plasma lipid levels and risk of AAA by a MR approach in 9,035 EAs of the ARIC study. Using SNPs related to plasma lipid levels as instruments, our study identified a borderline significant association of instrumented total cholesterol with clinical AAA risk. This association became stronger after we removed users of lipid-lowering medications. These findings suggested a causal link between higher total cholesterol level and increased risk of AAA.