Association of Genetic Variation in \(FTO\) with Risk of Obesity and Type 2 Diabetes with Data from 96,551 East and South Asians

Abstract

Aims/hypothesis: (FTO) harbours the strongest known obesity-susceptibility locus in Europeans. While there is growing evidence for a role for (FTO) in obesity risk in Asians, its association with type 2 diabetes, independently of BMI, remains inconsistent. To test whether there is an association of the (FTO) locus with obesity and type 2 diabetes, we conducted a meta-analysis of 32 populations including 96,551 East and South Asians. Methods: All studies published on the association between (FTO)-rs9939609 (or proxy [r(^2) > 0.98]) and BMI, obesity or type 2 diabetes in East or South Asians were invited. Each study group analysed their data according to a standardised analysis plan. Association with type 2 diabetes was also adjusted for BMI. Random-effects meta-analyses were performed to pool all effect sizes. Results: The (FTO)-rs9939609 minor allele increased risk of obesity by 1.25-fold/allele (p = 9.0 × 10(^{−19})), overweight by 1.13-fold/allele (p = 1.0 × 10(^{−11})) and type 2 diabetes by 1.15-fold/allele (p = 5.5 × 10(^{−8})). The association with type 2 diabetes was attenuated after adjustment for BMI (OR 1.10-fold/allele, p = 6.6 × 10(^{−5})). The (FTO)-rs9939609 minor allele increased BMI by 0.26 kg/m2 per allele (p = 2.8 × 10(^{−17})), WHR by 0.003/allele (p = 1.2 × 10(^{−6})), and body fat percentage by 0.31%/allele (p = 0.0005). Associations were similar using dominant models. While the minor allele is less common in East Asians (12–20%) than South Asians (30–33%), the effect of (FTO) variation on obesity-related traits and type 2 diabetes was similar in the two populations. Conclusions/interpretation: (FTO) is associated with increased risk of obesity and type 2 diabetes, with effect sizes similar in East and South Asians and similar to those observed in Europeans. Furthermore, (FTO) is also associated with type 2 diabetes independently of BMI. Electronic supplementary material The online version of this article (doi:10.1007/s00125-011-2370-7) contains peer-reviewed but unedited supplementary material, which is available to authorised users.