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

Abstract

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(2)≥0.97) associated with 91% increased transcriptional activity.

CONCLUSIONS:

This study suggests that functional genetic variation in LXRα predicts risk of ischemic vascular disease in the general population.

• Authors: Stefan Stender, Ruth Frikke-Schmidt, Aristomenis Anestis, Dimitris Kardassis, Amar A Sethi, Børge G Nordestgaard, Anne Tybjærg-Hansen
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 31 Issue 12 Pg. 2990-6 (Dec 2011) ISSN: 1524-4636 [Electronic] United States
• PMID: 21903943 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Liver X Receptors
• NR1H3 protein, human
• Orphan Nuclear Receptors

Topics

• Adult
• Aged
• Cerebrovascular Disorders (epidemiology, genetics)
• Cross-Sectional Studies
• Denmark (epidemiology)
• Female
• Follow-Up Studies
• Genetic Predisposition to Disease (genetics)
• Genetic Variation (genetics)
• Genotype
• Homozygote
• Humans
• Liver X Receptors
• Male
• Middle Aged
• Myocardial Ischemia (epidemiology, genetics)
• Orphan Nuclear Receptors (genetics)
• Predictive Value of Tests
• Retrospective Studies
• Risk Factors