Novel abdominal adiposity genes and the risk of type 2 diabetes: findings from two prospective cohorts.

Three loci were recently identified for central adiposity from a genome wide association study (MSRA [rs545854; G/C], LYPLAL1 [rs2605100; G/A], TFAP2B [rs987237; A/G]). Central obesity is a strong risk factor for type 2 diabetes (T2D). Therefore, we hypothesized that these single nucleotide polymorphisms (SNPs) would be associated with increased risk of T2D and may influence circulating adipokine concentrations. Participants from two large case control studies nested in the Nurses' Health Study (3394 women, 1245 cases) and the Health Professionals Follow-up Study (2154 men, 862 cases) were genotyped for these SNPs. The association of these SNPs with plasma adipokine concentrations was determined among a subgroup of women without diabetes (n=987). After adjustment for age and other risk factors of diabetes, the MSRA variant was associated with an increased T2D risk in men only, with an adjusted OR of 1.30 (95% CI: 1.09-1.56) associated with each copy of the variant allele. In pooled analyses of men and women, each additional copy of the LYPLAL1 allele (G) was associated with 9% increased T2D risk (adjusted OR 1.09; 95%CI: 0.99-1.19). No significant associations were seen with the TFAP2B SNP with a pooled adjusted OR of 1.05 (95% CI: 0.95-1.17) per allele copy. In addition, carriers of the MSRA risk variant had lower percent high molecular weight adiponectin (-2.1%, p=0.04). Carriers of the TFAP2B risk variant, however, had lower leptin levels (-2.7 ng/ml, p=0.005). These findings suggest potential associations of novel central obesity genes with T2D risk and adipokine regulation.