Liver X receptor-α (LXRA) is a nuclear receptor that regulates genes important in cholesterol homeostasis and inflammation. Several single nucleotide polymorphisms (SNPs) in the LXRA gene (NR1H3) have been earlier associated with metabolic phenotypes (dyslipidemia and elevated body mass index). Metabolic dysregulation is a major contributor to coronary disease; therefore, we assessed LXRA in International Verapamil Sustained Release SR Trandolapril Study Genetic Substudy (INVEST-GENES), a genetic-substudy of a large clinical trial in patients with hypertension and coronary artery disease.
Seven tag SNPs in the LXRA gene region (NR1H3) were selected for study: rs11039149, rs12221497, rs2279238, rs7120118, rs326213, rs11039159, and rs10501321. One thousand fifty-nine patients were genotyped from the INVEST-GENES case–control set (verapamil-sustained release-based or atenolol-based treatment strategies) that comprised of 297 cases frequency matched (approximately 2.5:1) with that of event-free controls by sex and race. The primary outcome was defined as first occurrence of all-cause death, nonfatal myocardial infarction, or nonfatal stroke. Adjusted odds ratios (ORs) were calculated using logistic regression.
Three of the seven SNPs were associated with significant effects on the primary outcome in nonBlacks. The variant G allele of rs11039149 and the variant A allele of rs12221497 were associated with reduced risk of experiencing the primary outcome [OR: 0.62, confidence interval (CI): 0.45–0.85, P=0.003 and OR: 0.60, CI: 0.39–0.91, P=0.016, respectively]. The rs2279238 genotype was associated with a significant increase in risk for the primary outcome (OR: 1.42, CI: 1.03–1.95, P=0.03). Furthermore, there was a significant genotype–treatment strategy interaction for carriers of the variant T allele of rs2279238 (OR for verapamil-sustained release strategy compared with atenolol strategy: 2.86, CI: 1.50–5.46, P=0.0015). Diplotype analyses showed that the SNPs are rarely coinherited and support the directionally opposite effects of the SNPs on the primary outcome.
LXRA genotypes were associated with variable risk for cardiovascular outcomes and pharmacogenetic effect in INVEST-GENES. These novel findings suggest that LXRA is a genetic/pharmacogenetic target that should be further explored.
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aDepartment of Pharmacotherapy and Translational Research and Center for Pharmacogenomics
bDivision of Cardiovascular Medicine, University of Florida College of Medicine, Gainesville, Florida, USA
Correspondence to Dr Julie A. Johnson, PharmD, Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics, University of Florida College of Pharmacy, PO Box 100486, Gainesville, FL 32610, USA Tel: +1 352 273 6007; fax: +1 352 273 6121; e-mail: email@example.com
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Drs Issam Zineh and Michael A. Pacanowski are currently US FDA employees, this work was conducted when they were employed by the University of Florida. The content of this manuscript represents the view of the authors. No official US FDA endorsement is intended nor should be inferred.
Received November 10, 2010
Accepted January 31, 2011