Genetic variation in liver x receptor alpha and risk of ischemic vascular disease in the general population

TY - JOUR

T1 - Genetic variation in liver x receptor alpha and risk of ischemic vascular disease in the general population

AU - Stender, Stefan

AU - Frikke-Schmidt, Ruth

AU - Anestis, Aristomenis

AU - Kardassis, Dimitris

AU - Sethi, Amar A.

AU - Nordestgaard, Børge G

AU - Tybjærg-Hansen, Anne

PY - 2011/12

Y1 - 2011/12

N2 - 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 r0.97) 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.

AB - 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 r0.97) 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.

U2 - 10.1161/atvbaha.111.223867

DO - 10.1161/atvbaha.111.223867

M3 - Journal article

SN - 1079-5642

VL - 31

SP - 2990

EP - 2996

JO - Arteriosclerosis, Thrombosis, and Vascular Biology

JF - Arteriosclerosis, Thrombosis, and Vascular Biology

IS - 12

ER -