Assessing FOXO1A as a Potential Susceptibility Locus for Type 2 Diabetes and Obesity in American Indians

OBJECTIVE: A prior genome-wide association study (GWAS) in Pima Indians identified variation within FOXO1A that modestly associated with early-onset (onset age<25years) type 2 diabetes (T2D). FOXO1A encodes the forkhead transcription factor involved in pancreatic β-cell growth and hypothalamic energy balance; therefore, FOXO1A was analyzed as a candidate gene for T2D and obesity in a population-based sample of 7710 American Indians. METHODS: Tag SNPs in/near FOXO1A (minor allele frequency≥0.05) were analyzed for association with T2D at early-onset (n=1060) and all ages (n=7710), and with insulin secretion (n=298). SNPs were also analyzed for association with maximum body mass index (BMI) in adulthood (n=5918), maximum BMI z-score in childhood (n=5350) and % body fat (n=555). RESULTS: An intronic SNP rs2297627 associated with early-onset T2D [OR=1.34(1.13-1.58), p=8.7×10(−4)] and T2D onset at any age [OR=1.19 (1.09-1.30), p=1×10(−4)]. The T2D risk allele also associated with lower acute insulin secretion (β=0.88, as a multiplier, p=0.02). Another intronic SNP (rs1334241, D’=0.99, r(2)=0.49 with rs2297627) associated with maximum adulthood BMI (β=1.02, as a multiplier, p=3×10(−5)), maximum childhood BMI z-score (β=0.08, p=3 × 10(−4)) and % body fat (β=0.83%, p=0.04). CONCLUSIONS: Common variation in FOXO1A may modestly affect risk for T2D and obesity in American Indians.