Genetic Variation in Liver X Receptor Alpha and Risk of Ischemic Vascular Disease in the General Population

OBJECTIVE—Although animal studies indicate that liver X receptor alpha (LXRα) might influence risk of atherosclerosis, data in humans remain scarce. We tested the hypothesis that genetic variation in LXRα associates with risk of ischemic vascular disease and/or plasma lipid and lipoprotein levels in the general population. METHODS AND RESULTS—We studied 10,281 white persons of Danish ancestry from a general population cohort, including 1,986 in whom ischemic heart disease (IHD) developed, and 989 in whom ischemic cerebrovascular disease developed. We examined another 51,429 white persons of Danish ancestry from a general population study, including 3,789 with IHD. We genotyped 10 genetic variants identified by resequencing LXRα. Homozygosity for −840AA/−115AA(=2.7%) predicted hazard ratios of 1.3 (95% confidence interval, 1.0–1.7) for IHD, 1.6 (1.2–2.2) for myocardial infarction, and 1.7 (1.3–2.4) for ischemic cerebrovascular disease. The corresponding odds ratios in the second cohort were 1.1 (0.9–1.4) for IHD and 1.5 (1.1–2.0) for myocardial infarction. In the combined studies, odds ratios were 1.2 (1.0–1.4) for IHD and 1.5 (1.2–1.9) for myocardial infarction. Homozygosity for −840AA/−115AA did not associate with lipid or lipoprotein levels. LXRα −1830T>C (tagging the haplotype −1830C/−840A/−115A, all r≥0.97) associated with 91% increased transcriptional activity. CONCLUSION—This study suggests that functional genetic variation in LXRα predicts risk of ischemic vascular disease in the general population.