1. ¹Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
2. ²Department of Epidemiology, University of California at Los Angeles, School of Public Health, Los Angeles, California, USA
3. ³Molecular and Integrative Physiological Science Program, Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts, USA
4. ⁴Department of Field Studies, MedStar Research Institute, Washington, District of Columbia, USA
5. ⁵Geisinger Center for Health Research, Danville, Pennsylvania, USA
6. ⁶Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA
7. ⁷Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California, USA
8. ⁸Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
9. ⁹Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California, USA

Correspondence: Simin Liu (siminliu@ucla.edu)

Received 12 March 2008; Accepted 15 May 2008; Published online 11 September 2008.

Abstract

The FTO gene was recently identified as a susceptibility locus for both obesity and type 2 diabetes by whole-genome association analyses of several European populations. We tested for an association between FTO risk alleles and obesity and diabetes in a well-characterized multiethnic cohort of postmenopausal women in the United States. We genotyped two most significantly associated single-nucleotide polymorphisms (SNPs) (rs9939609 and rs8050136) in intron 1 of FTO gene in a nested case–control study of 1,517 diabetes cases and 2,123 controls from the Women's Health Initiative–Observational Study (WHI-OS). The allelic frequencies of either rs9939609 or rs8050136 differed widely across four ethnic groups. The frequency of the rare allele A of rs9939609 among controls was much lower in Asians/Pacific Islanders (17%) than in blacks (45%), whites (40%), and Hispanics (31%). We found significant associations of rs9939609 with BMI and waist circumference in white and Hispanic women, but not among black and Asian/Pacific Islander women. On average, each copy of the risk-allele A at rs9939609 was significantly associated with 0.45 kg/m² increase in BMI (95% confidence interval (CI): 0.16–0.74; P = 0.004) and 0.97 cm increase in waist circumference (95% CI: 0.21–0.65; P = 0.0002). Similar results were observed for rs8050136. However, we found no significant genetic associations with diabetes risk, either within the full study sample or in any ethnic group. In conclusion, common genetic variants in the intron 1 of FTO gene may confer a modest susceptibility to obesity in an ethnicity-specific manner, but may be unlikely to contribute to a clinically significant diabetes risk.