Although genetic susceptibility indisputably increases the risk of type 2 diabetes, defining that risk has been challenging. These challenges are even greater for African American populations, where genetic diversity is higher, the risk of type 2 diabetes is greater, and the pathophysiology of type 2 diabetes and insulin resistance may differ from European populations. To address these gaps, we propose to investigate gene expression traits in adipose and muscle from non-diabetic individuals across a spectrum of weight and insulin sensitivity and who have previously had genome-wide association scans. We hypothesize that transcript profiles in adipose and muscle will correlate with insulin sensitivity, that a subset of these transcripts will be controlled by DNA sequence variants as expression quantitative traits, and that these variants will in turn be associated with type 2 diabetes or insulin resistance. To test these hypotheses we propose 4 aims. Aim 1 will recruit 250 previous participants in a genome wide association scan (GWAS) for African American type 2 diabetes genes, will characterize insulin secretion and sensitivity, and will obtain adipose and muscle samples. Aim 2 will characterize global transcript profiles in adipose and muscle from each participant, and will test for association of individual transcript levels with insulin sensitivity. Aim 3 will use these data and previously obtained GWAS on each individual to map expression quantitative traits, especially cis and trans acting variants for transcripts that associate with insulin sensitivity. Aim 4 will select single nucleotide polymorphisms (SNPs) that associate with type 2 diabetes or insulin sensitivity and associate with expression traits. These expression trait-SNP pairs will be validated for expression in adipose and muscle tissues, expression tested in lymphocytes, and SNPs tested for associations with type 2 diabetes and insulin sensitivity in extended populations. The top 10 cis acting associations will be fine mapped to identify the likely functional SNP or SNPs. As a small feasibility study, 50 individuals from years 1 and 2 of Aim 1 will be retested to characterize insulin sensitivity and glucose tolerance in years 4 and 5. The proposed studies will thus identify new SNPs that are associated with the intermediate phenotypes of insulin sensitivity and gene expression. The intermediate trait associations in turn will provide biological support for genetic association studies with type 2 diabetes. The proposed studies thus will complement ongoing GWAS studies as an alternative to extremely large sample sizes that cannot be easily achieved in minority populations, and will lead to an improved understanding of pathophysiology and new potential drug targets.

R01DK090111

2011-04-01

2019-03-31