Abstract:
BACKGROUND: Molecular approaches have expedited the discovery of human obesity genes, however the heritability explained by these loci remains low (<2%). Gene-by-environment interactions may partially account for the "missing heritability" attributed to variation in obesity phenotypes. OBJECTIVE: The specific aims of this dissertation were to (i) identify genetic polymorphisms associated with obesity-related phenotypes in Yup'ik people and (ii) evaluate how n-3 polyunsaturated fatty acid (n-3 PUFA) intake modifies associations between genetic polymorphisms and obesity-related phenotypes in a population with widely varying intake of n-3 PUFAs. APPROACH: We genotyped genetic polymorphisms in (1) candidate genes with a strong physiological role in obesity pathophysiology; (2) candidate genes identified in obesity whole-genome linkage studies that were regulated by n-3 PUFAs; and (3) candidate genes reproducibly implicated in obesity genome-wide association studies (GWAS). DATA & ANALYSES: We used Center for Alaska Native Health Research (CANHR) data collected between 2001 and 2008. We estimated dietary intake of n-3 PUFA using nitrogen stable isotope ratios (delta15N) of red blood cells (RBC) and obesity-related phenotypes were obtained by trained staff. Genotype-phenotype analyses used generalized linear models that accounted for familial correlations. RESULTS: Our analyses of candidate genes based on physiology revealed a polymorphism called P479L in carnitine palmitoyltransferase 1A (CPT1A) that was associated with elevated fasting HDL-cholesterol and all obesity phenotypes. Our investigation of candidate genes that are regulated by n-3 PUFAs and implicated in obesity whole-genome linkage studies demonstrate that polymorphisms in stearoyl CoA desaturase (SCD) and steroyl regulatory element binding protein (SLC2A4) were associated with obesity-related phenotypes; however n-3 PUFA intake did not modify associations between SCD and SLC2A4 polymorphisms and obesity phenotypes. Finally, our investigation of candidate genes reproducibly implicated in obesity GWAS demonstrated that genetic predisposition to obesity is associated with adiposity and that interactions with n-3 PUFA intake accounted for more than twice the phenotypic variation in adiposity. CONCLUSION: Taken together, results from this dissertation suggest that selecting candidate genes based on large-scale genomic analyses, such as linkage analyses and GWAS, has the potential to identify gene-by-environment interactions that partially account for the "missing heritability" attributed to obesity.
