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 < 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.
Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes Of Health, Phoenix, Arizona, USA.
Yunhua L
YL
Muller
Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes Of Health, Phoenix, Arizona, USA.
Robert L
RL
Hanson
Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes Of Health, Phoenix, Arizona, USA.
Gregory
G
Wiessner
Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes Of Health, Phoenix, Arizona, USA.
Lori
L
Nieboer
Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes Of Health, Phoenix, Arizona, USA.
Sayuko
S
Kobes
Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes Of Health, Phoenix, Arizona, USA.
Paolo
P
Piaggi
Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes Of Health, Phoenix, Arizona, USA.
Mahdi
M
Abdussamad
Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes Of Health, Phoenix, Arizona, USA.
Chidinma
C
Okani
Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes Of Health, Phoenix, Arizona, USA.
William C
WC
Knowler
Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes Of Health, Phoenix, Arizona, USA.
Clifton
C
Bogardus
Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes Of Health, Phoenix, Arizona, USA.
Leslie J
LJ
Baier
D015992:Body Mass Index; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005260:Female; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D007198:Indians, North American / Q000235:genetics*; D008297:Male; D009765:Obesity / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D055815:Young Adult
C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors