Obesity Genotype Score and Cardiovascular Risk in Women With Type 2 Diabetes Mellitus

Objective— To investigate the associations between obesity-predisposing genetic variants, cardiovascular biomarkers, and cardiovascular disease (CVD) risk in women with preexisting type 2 diabetes mellitus. Methods and Results— We genotyped polymorphisms at nine established obesity loci in 1,395 women with diabetes from the Nurses’ Health Study: 449 women developed CVD, and 946 women did not develop CVD. A genetic risk score (GRS) was derived by summing risk alleles for each individual. Four polymorphisms (rs9939609 [ FTO ], rs11084753 [ KCTD15 ], rs10838738 [ MTCH2 ], and rs10938397 [ GNPDA2 ]) showed nominally significant associations with CVD. The GRS combining all obesity loci was linearly related to CVD risk ( P = 0.013 for trend). The odds ratio was 1.08 per risk allele (95% confidence interval, 1.02–1.15; P = 0.01) after adjustment for body mass index and other conventional risk factors. Women with the highest quartile of GRS had 53% (95% confidence interval, 6%–122%) increased CVD risk, compared with those in the lowest quartile of GRS ( P = 0.024). In addition, a higher GRS was associated with lower adiponectin levels ( P = 0.02). Further adjustment for body mass index and other covariates did not change the association ( P = 0.006). A higher GRS was also correlated with lower levels of high-density lipoprotein ( P = 0.01). Conclusion— Obesity-predisposing variants may jointly affect CVD risk among women with diabetes.