Associations of Variants in FTO and Near MC4R With Obesity Traits in South Asian Indians

Abstract

Recent genome‐wide association studies show that loci in FTO and melanocortin 4 receptor (MC4R) associate with obesity‐related traits. Outside Western populations the associations between these variants have not always been consistent and in Indians it has been suggested that FTO relates to diabetes without an obvious intermediary obesity phenotype. We investigated the association between genetic variants in FTO (rs9939609) and near MC4R (rs17782313) with obesity‐ and type 2 diabetes (T2DM)‐related traits in a longitudinal birth cohort of 2,151 healthy individuals from the Vellore birth cohort in South India. The FTO locus displayed significant associations with several conventional obesity‐related anthropometric traits. The per allele increase is about 1% for BMI, waist circumference (WC), hip circumference (HC), and waist—hip ratio. Consistent associations were observed for adipose tissue‐specific measurements such as skinfold thickness reinforcing the association with obesity‐related traits. Obesity associations for the MC4R locus were weak or nonsignificant but a signal for height (P < 0.001) was observed. The effect on obesity‐related traits for FTO was seen in adulthood, but not at younger ages. The loci also showed nominal associations with increased blood glucose but these associations were lost on BMI adjustment. The effect of FTO on obesity‐related traits was driven by an urban environmental influence. We conclude that rs9939609 variant in the FTO locus is associated with measures of adiposity and metabolic consequences in South Indians with an enhanced effect associated with urban living. The detection of these associations in Indians is challenging because conventional anthropometric obesity measures work poorly in the Indian “thin‐fat” phenotype.

The importance of gene–environment interactions in human obesity

“…This trend is supported by a recent analysis of the Framingham Heart Study (FHS), which demonstrated that risk allele carriage in FTO rs9939609 was associated with a greater increase in BMI among individuals born after 1942 compared with those who were born before 1942 [96]. The FTO intron 1 variant is weakly associated with BMI in South Asian Indian populations, but its effect on weight is stronger in urban compared with rural dwellers [97,98]. A lack of association of FTO with obesityrelated traits was also observed in a Gambian rural population [99].…”

Common FTO rs9939609 variant and risk of type 2 diabetes in Palestine

“…Although FTO -T2DM association was found, the lack of association between FTO rs9939609 and obesity is most probably due to the small sample size -and thereby decreased statistical power- which was the most important limitation in this study and thus larger sample size is required to verify these results. However, weight, skinfold thicknesses, body fat percentage and waist circumference are reported to be more reliable markers of obesity than BMI [38]. We believe that obesity-related genetic variants also modulate glucose–insulin secretion.…”

Genetics of Obesity

“…FTO rs9939609 variant has been shown to be associated with measures of adiposity and metabolic consequences in South Indians with an enhanced effect associated with urban living [84,85].…”