The Genetics of Insulin Resistance: Analysis of the Peroxisome Proliferator-Activated Receptor Pathway

Polycystic ovary syndrome (PCOS) is a heterogeneous familial disorder characterized by insulin resistance and an increased risk of type 2 diabetes mellitus (T2DM), a disorder with epidemic public health significance. The aim of this dissertation was to determine the risk of T2DM among Caucasian and African American women with PCOS compared to controls and to assess potential genetic variants that may affect development of T2DM. T2DM was defined as a fasting plasma glucose level >=126 mg/dL or self-report of physician diagnosis. Genetic variants analyzed for association with PCOS and subclinical coronary heart disease (CHD) risk measures were the peroxisome proliferator-activated receptor-gamma (PPAR-gamma) single nucleotide polymorphism (SNP) P12A, insulin receptor substrate-1 (IRS-1) SNP G972R, one novel SNP of lipoprotein lipase (LPL), and three novel SNPs from acetyl-CoA carboxylase-beta (ACC-beta). Significant association of genotype frequency with PCOS was determined by Pearson chi-square tests. Generalized linear modeling was utilized to test for association of genotype with subclinical measures of CHD, including insulin resistance (HOMA-IR) and C-reactive protein (CRP). The 8-year prevalence of T2DM was 13.4% in PCOS cases and 5.8% in controls. After adjusting for age and BMI, women with PCOS had an estimated 2-fold risk of developing T2DM compared to normal control women. When stratified by body mass index (BMI) and controlling for age, PCOS cases with BMI > 35 kg/m2 were estimated to have 5x higher risk of developing T2DM. There were no significant associations between genotype frequencies and PCOS for Caucasian or African American subjects. However, the G972R variant of IRS-1 and PCOS significantly interacted to affect CRP concentrations indicating that cases with the R allele had significantly elevated CRP compared to all other permutations of G972R and PCOS status interaction. The final CRP model explained 22% of variability in CRP concentrations. In conclusion, the significant risk of T2DM attributed to women by PCOS was not explained by genetic SNPs analyzed here, however, a significant association of G972R and G972RxPCOS interaction with CRP concentrations was found, further supporting the growing body of evidence of associations between insulin resistance and systemic inflammation