An FTO variant is associated with Type 2 diabetes in South Asian populations after accounting for body mass index and waist circumference

Abstract

Aims: A common variant, rs9939609, in the FTO (fat mass and obesity) gene is associated with adiposity in Europeans, explaining its relationship with diabetes. However, data are inconsistent in South Asians. Our aim was to investigate the association of the FTO rs9939609 variant with obesity, obesity-related traits and Type 2 diabetes in South Asian individuals, and to use meta-analyses to attempt to clarify to what extent BMI influences the association of FTO variants with diabetes in South Asians.

Methods: We analysed rs9939609 in two studies of Pakistani individuals: 1666 adults aged ≥40 years from the Karachi population-based Control of Blood Pressure and Risk Attenuation (COBRA) study and 2745 individuals of Punjabi ancestry who were part of a Type 2 diabetes case-control study (UK Asian Diabetes Study/Diabetes Genetics in Pakistan; UKADS/DGP). The main outcomes were BMI, waist circumference and diabetes. Regression analyses were performed to determine associations between FTO alleles and outcomes. Summary estimates were combined in a meta-analysis of 8091 South Asian individuals (3919 patients with Type 2 diabetes and 4172 control subjects), including those from two previous studies.

Results: In the 4411 Pakistani individuals from this study, the age-, sex- and diabetes-adjusted association of FTO variant rs9939609 with BMI was 0.45 (95%CI 0.24-0.67) kg/m(2) per A-allele (P=3.0 × 10(-5) ) and with waist circumference was 0.88 (95% CI 0.36-1.41) cm per A-allele (P=0.001). The A-allele (30% frequency) was also significantly associated with Type 2 diabetes [per A-allele odds ratio (95%CI) 1.18 (1.07-1.30); P=0.0009]. A meta-analysis of four South Asian studies with 8091 subjects showed that the FTO A-allele predisposes to Type 2 diabetes [1.22 (95%CI 1.14-1.31); P=1.07 × 10(-8) ] even after adjusting for BMI [1.18 (95%CI 1.10-1.27); P=1.02 × 10(-5) ] or waist circumference [1.18 (95%CI 1.10-1.27); P=3.97 × 10(-5) ].

Conclusions: The strong association between FTO genotype and BMI and waist circumference in South Asians is similar to that observed in Europeans. In contrast, the strong association of FTO genotype with diabetes is only partly accounted for by BMI.

Figure 1

Meta-analysis plots for the association between the FTO rs9939609 single nucleotide polymorphism and Type 2 diabetes before (a) and after (b) adjustment for BMI. In the pooled South Asian populations, rs9939609 was significantly associated with diabetes before (P = 1.07× 10⁻⁸) and after (P = 1.02× 10⁻⁵) BMI adjustment. Significant heterogeneity was detected between the South Asian studies and the European studies after BMI adjustment (P = 0.009). The single nucleotide polymorphisms included in the meta-analysis from Renstrom et al. (7) and Thorleiffsson et al. (8) were rs1121980 and rs8050136, respectively, both of which are good proxies for rs9939609 [D’/r² values of 1/1 and 0.96/0.85, respectively, estimated using the CEPH (CEU) HapMap samples]. Data from Sanghera et al [17] (using subjects from the Sikh Diabetes Study) were reanalysed to give allelic odds ratios before inclusion in the meta-analysis. COBRA, Control of Blood Pressure and Risk Attenuation; DGP, Diabetes Genetics in Pakistan; UKADS, UK Asian Diabetes Study.