Clinical and Population Studies 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. (Arterioscler Thromb Vasc Biol. 2010;30:327-332.)