Gene-By-Diet Interactions And Obesity Among Yup'ik People Living In Southwest Alaska

• Main Author: Lemas, Dominick
• Other Authors: Boyer, Bert B., O'Brien, Diane M., Schulte, Marvin K., Tiwari, Hemant K.
• Format: Doctoral or Postdoctoral Thesis
• Language: unknown
• Published: 2012
• Subjects: Epidemiology; Genetics; Biostatistics; Fairbanks; Yup'ik; Alaska
• Online Access: http://hdl.handle.net/11122/9157

Dissertation (Ph.D.) University of Alaska Fairbanks, 2012 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 ...