Obesity-related genetic determinants of stroke

As obesity, circulating lipids and other vascular/metabolic factors influence the risk of stroke, we examined if genetic variants associated with these conditions are related to risk of stroke using a case-control study in Galicia, Spain. A selection of 200 single-nucleotide polymorphisms previously found to be related to obesity, body mass index, circulating lipids, type 2 diabetes, heart failure, obesity-related cancer and cerebral infarction were genotyped in 465 patients diagnosed with stroke and 480 population-based controls. An unsupervised Lasso regression procedure was carried out for single-nucleotide polymorphism selection based on their potential effect on stroke according to obesity. Selected genotypes were further analysed through multivariate logistic regression to study their association with risk of stroke. Using unsupervised selection procedures, nine single-nucleotide polymorphisms were found to be related to risk of stroke overall and after stratification by obesity. From these, rs10761731, rs2479409 and rs6511720 in obese subjects [odds ratio (95% confidence interval) = 0.61 (0.39-0.95) (P = 0.027); 0.54 (0.35-0.84) (P = 0.006) and 0.42 (0.22-0.80) (P = 0.0075), respectively], and rs865686 in non-obese subjects [odds ratio (95% confidence interval) = 0.67 (0.48-0.94) (P = 0.019)], were independently associated with risk of stroke after multivariate logistic regression procedures. The associations between the three single-nucleotide polymorphisms found to be associated with stroke risk in obese subjects were more pronounced among females; for rs10761731, odds ratios among obese males and females were 1.07 (0.58-1.97) (P = 0.84), and 0.31 (0.14-0.69) (P = 0.0018), respectively; for rs2479409, odd ratios were 0.66 (0.34-1.27) (P = 0.21), and 0.49 (0.24-0.99) (P = 0.04), for obese males and females, respectively; the stroke-rs6511720 association was also slightly more pronounced among obese females, odds ratios were 0.33 (0.13-0.87) (P = 0.022), and 0.28 (0.09-0.85) (P = 0.02) for obese males and females, respectively. The rs865686-stroke association was more pronounced among non-obese males [odds ratios = 0.61 (0.39-0.96) (P = 0.029) and 0.72 (0.42-1.22) (P = 0.21), for non-obese males and females, respectively]. A combined genetic score of variants rs10761731, rs2479409 and rs6511720 was highly predictive of stroke risk among obese subjects (P = 2.04 × 10-5), particularly among females (P = 4.28 × 10-6). In summary, single-nucleotide polymorphisms rs1076173, rs2479409 and rs6511720 were found to independently increase the risk of stroke in obese subjects after adjustment for established risk factors. A combined score with the three genomic variants was an independent predictor of risk of stroke among obese subjects in our population.