Our results demonstrate that in Asian Indians, variants in the FTO gene predispose to type 2 diabetes; however, unlike in Europeans, they do not appear to do this entirely through their influence on BMI, central obesity and adiposity [1, 2]. Sanghera et al.  recently reported a significant association of FTO gene variants with type 2 diabetes in North Indian Sikhs that was unaffected by controlling for BMI. They suggested that ethnic differences were responsible for the variable results. A recent study in East Asians also found borderline evidence that the association of the FTO gene with BMI was weaker compared with that in studies of Europeans, but the association with type 2 diabetes was similar . The finding that the FTO variants are associated with type 2 diabetes argues against a difference in linkage disequilibrium with a putative functional variant in these two populations. Although population stratification may be a possible explanation that may confound the results, recent evidence suggests that despite the geographic and linguistic diversity, Indians as a whole display a low level of genetic heterogeneity . Recent studies in Chinese and Japanese populations did not find an association of FTO variants with type 2 diabetes, but a weak association with BMI was found in Japanese [4, 5]. Another study reported that FTO variants might influence the risk of severe obesity in the Japanese . The frequencies of the A allele at the rs9939609 variant were lower in Chinese (0.12) and Japanese (0.18) populations compared with those in Europeans (0.45) and Indians (0.30), meaning that the studies in East Asians have less power [4–6]. It is well known that Indians (and Asians in general) have a lower BMI than Europeans, and the relationship between obesity measures and risk of type 2 diabetes is steeper . This has been ascribed to relatively higher central obesity (WHR) and higher adiposity (body fat percentage) in Asians for a given BMI compared with that in Europeans . The association between FTO variants and type 2 diabetes in this study, independent of measures of obesity, could indicate that BMI is a poor measure of adiposity in South Asian Indians. However, the possibility remains that there could be underlying differences in the way the FTO gene works to influence the risk of type 2 diabetes in Asian Indians and in Europeans.
The functional role of the FTO gene is not yet understood, nor is it clear how the variants affect body size and predict the risk of type 2 diabetes. Based on sequence homology, the FTO gene is predicted to code for a 2-oxoglutarate-dependent demethylase enzyme , which influences nucleic acid demethylation and so may be important in epigenetic regulation. It is intriguing that maternal vitamin B12 and folate nutrition influenced adiposity and insulin resistance in Indian children , suggesting that 1-carbon (methyl) metabolism may have an important role in predicting risk for type 2 diabetes. It would be interesting to see if the micronutrients mentioned above influence the effect of the FTO gene on adiposity.
In conclusion, our results demonstrate that in Indians, variants of the FTO gene predispose to type 2 diabetes, but not entirely through their effect on BMI. Our results are consistent with those recorded in North Indian Sikhs but an independent replication of the weaker effect of FTO variants on BMI is required . These results suggest a difference in the possible mechanism of the association from that in Europeans and reinforce our previous suggestion that the relationship between BMI and type 2 diabetes may be different in Indians. Comparative studies of FTO in South Asians and Europeans, including functional genomic and epigenetic analyses, may help to understand critical mechanisms in the pathogenesis of obesity and type 2 diabetes.