Examination of the contribution of differences in disease architecture and epistasis to type 2 diabetes risk in African Americans.

摘要

Diabetes is a major global health problem. In the United States alone, 29.1 million people, or 9.3% of the population, have diabetes. Type 2 diabetes (T2D) is the most common form of the disease and represents 90-95% of all diagnosed cases. This form of the disease is characterized by high blood sugar resulting from defects in insulin secretion in pancreatic beta cells and defects in insulin action in hepatic, skeletal muscle, and other peripheral tissues. The most recent data shows that the prevalence of diabetes is much higher among African Americans (13.2%) compared to European Americans (7.6%). This dissertation examines genetic causes of disparity in T2D prevalence between African Americans and European Americans through an investigation of differences in disease architecture and an evaluation of heritable risk not captured in previous genetic studies.;Herein, differences in T2D disease architecture that may explain disparities in disease prevalence between African Americans and European Americans are explored through an examination of population-specific genetic burden of alleles contributing to disease risk. This project compared risk allele burden between 1,990 African Americans (n=963 T2D cases, 1,027 controls) and 1,644 European Americans (n=719 T2D cases, 925 controls) across 43 established T2D single nucleotide polymorphisms (SNPs). Analyses include a comparison of mean risk allele burden as well as association of a genetic risk score (GRS) summarizing the 43 SNPs in each population.;The major part of this thesis explores T2D risk as a result of gene-gene interaction, which is a type of heritable risk not captured in genome-wide association studies (GWAS). These projects examine genome-wide interactions with an established insulin secretion SNP, rs10830963 in the gene MTNR1B, which explains variation in insulin secretion, both statistically and functionally, as well as additional variants associated with acute insulin response to glucose (AIRg), a dynamic measure of first-phase insulin secretion, and variants associated with fasting plasma glucose levels. Additional analyses explore interactions with GRSs summarizing these variants. Study subjects include ∼7,000 African American participants from the Atherosclerosis Risk in Communities Study (ARIC; n=955 T2D cases, 414 controls), Coronary Artery Risk Development in Young Adults (CARDIA; n=94 T2D cases, 654 controls), Jackson Heart Study (JHS; n=333 T2D cases, 1,450 controls), Multi-Ethnic Study of Atherosclerosis (MESA; n=411 T2D cases, 793 controls), and the Wake Forest School of Medicine (WFSM; n=932 T2D cases, 856 controls) cohorts for a total of 2,725 T2D cases and 4,167 controls.;The results presented here illuminate differences in T2D disease architecture between African Americans and European Americans and show that novel genetic factors contributing to T2D risk can be identified through analyses of gene-gene interaction. These results underscore the necessity for further study of genetic variation underlying T2D risk in African Americans as a mean to improve the overall quality of genetic research of this disease.