CYP7A1 Variants Are Associated with Postabsorptive Endogenous Glucose Production: A Genome-Wide Association Study in Nondiabetic Pima Indians

Increased post-absorptive endogenous glucose production (PEGP) is a major contributor to fasting hyperglycemia in individuals with type 2 diabetes (T2D). As compared to individuals with fasting normoglycemia, PEGP is increased at higher fasting glucose concentrations, suggesting that elevated PEGP is a marker of hyperglycemia and may be a metabolic risk factor for T2D. The aim of this study was to identify genetic variants associated with PEGP in non-diabetic Pima Indians, an ethnic group with high prevalence and heritability of T2D. A genome-wide association study (GWAS) was performed in a cohort of 552 non-diabetic Pima Indians (323M/229F, mean±SD, age: 27±6 yr, body fat: 32±8%, fasting glucose=89±10 mg/dL) using an Affymetrix Axiom Custom Array including 489,397 single-nucleotide polymorphisms (SNPs) selected to tag common variation (minor allele frequency≥5%, r2≥0.85) detected in Pima sequence data. PEGP was measured after an overnight fast by infusion of 3-[3H] glucose for 120 minutes before a hyperinsulinemic-euglycemic glucose clamp, and expressed per kg of fat free mass (FFM) estimated by hydrodensitometry or DXA. No SNP achieved genome-wide statistical significance (p=5x10-8), with the smallest 10 p-values ranging from 7x10-7 to 2x10-5. The top GWAS signal for PEGP, rs2162459 (p=7x10-7, with genomic control, adjusted for age, gender, percent body fat, heritage), maps to an intron in CYP7A1, and the G allele (frequency=0.23) is associated with higher PEGP (b=+0.09 mg/kg FFM/min per allele copy). This variant accounts for 5% of PEGP variance. CYP7A1 encodes the cholesterol 7α-hydroxylase which is the key regulatory enzyme converting cholesterol into bile acids in the liver. Increased expression of hepatic CYP7A1 improves insulin resistance in transgenic mice on a high-fat diet. However, rs2162459 is not associated with whole-body insulin action in Pima Indians (p=0.98). Our results suggest that common variation in CYP7A1 may influence PEGP in non-diabetic Pima Indians.