Assessing FOXO1A as a potential susceptibility locus for type 2 diabetes and obesity in American Indians - PubMed (original) (raw)

. 2015 Oct;23(10):1960-5.

doi: 10.1002/oby.21236. Epub 2015 Sep 4.

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Assessing FOXO1A as a potential susceptibility locus for type 2 diabetes and obesity in American Indians

Yunhua L Muller et al. Obesity (Silver Spring). 2015 Oct.

Abstract

Objective: A prior genome-wide association study (GWAS) in Pima Indians identified variation within FOXO1A that modestly associated with early-onset (onset age < 25 years) 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 7,710 American Indians.

Methods: Tag SNPs in/near FOXO1A (minor allele frequency ≥ 0.05) were analyzed for association with T2D at early onset (n = 1,060) and all ages (n = 7,710) and with insulin secretion (n = 298). SNPs were also analyzed for association with maximum body mass index (BMI) in adulthood (n = 5,918), maximum BMI z-score in childhood (n = 5,350), 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.

© 2015 The Obesity Society.

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Figures

Figure 1

Figure 1. Association data for rs2297627

Association with prevalence of T2D at any age (a); risk allele frequency distribution in early-onset T2D case and control groups (b); Kaplan-Meier survival curve for time to T2D onset (c) and plasma insulin concentrations in response to a 25-g intravenous glucose bolus (IVGTT) (d). The p value and OR for T2D at any age are adjusted for age, sex, birth year and heritage. The p value and OR for early-onset T2D (case-control analysis) are adjusted for sex and birth year and heritage. Cox proportional hazards model is used to determine the hazard rate ratio (HRR) for association with age of T2D onset including sex, birth-year, American/European ancestry and self-reported Pima heritage as covariates. Data for plasma insulin and glucose concentrations are given as adjusted mean±SE by genotypes. AIR (mean insulin increment from 3-5 min) is log10-transformed before analyses to approximate a normal distribution, and beta is exponentiated to obtain the effect per risk allele, expressed as a multiplier. The_p_ value and beta for AIR are adjusted for age, sex, % body fat and rate of glucose disappearance during insulin-stimulation. The p value and beta for plasma glucose concentrations are adjusted for age, sex and % body fat.

Figure 2

Figure 2. Association data for rs1334241

Maximum BMI in adulthood (a), maximum BMI z-score in childhood (b) and % body fat in adulthood (c). Adult BMI is the maximum BMI (kg/m2) from a non-diabetic examination recorded at age ≥15 years. Childhood BMI z-score is the maximum sex- and age-specific z-score identified between the ages of 5 and 20 years. Data are given as adjusted mean±SE by genotypes. Adult BMI is loge−transformed before analyses to approximate a normal distribution, and beta is exponentiated to obtain the effect estimate for each risk allele, expressed as a multiplier. Beta and_p_ values for adult BMI and childhood BMI z-score are adjusted for age, sex, birth year and heritage. Beta and p values for % body fat are adjusted for age, sex and heritage.

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