title: Liver X receptor α gene polymorphisms and variable cardiovascular outcomes in patients treated with antihypertensive therapy: results from the INVEST-GENES study.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics, University of Florida College of Medicine, Gainesville, FL, USA.
authors.forename: Elvin Tyrone
authors.initials: ET
authors.lastname: Price
authors.forename: Michael A
authors.initials: MA
authors.lastname: Pacanowski
authors.forename: Michael A
authors.initials: MA
authors.lastname: Martin
authors.forename: Rhonda M
authors.initials: RM
authors.lastname: Cooper-DeHoff
authors.forename: Carl J
authors.initials: CJ
authors.lastname: Pepine
authors.forename: Issam
authors.initials: I
authors.lastname: Zineh
authors.forename: Julie A
authors.initials: JA
authors.lastname: Johnson
mesh_terms: D000368:Aged; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D001262:Atenolol / Q000627:therapeutic use; D015992:Body Mass Index; D002121:Calcium Channel Blockers / Q000627:therapeutic use; D016022:Case-Control Studies; D003324:Coronary Artery Disease / Q000150:complications*; D004247:DNA / Q000235:genetics; D005260:Female; D005838:Genotype; D006801:Humans; D006973:Hypertension / Q000188:drug therapy* / Q000209:etiology*; D000071518:Liver X Receptors; D008297:Male; D057093:Orphan Nuclear Receptors / Q000235:genetics*; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011446:Prospective Studies; D016896:Treatment Outcome; D014700:Verapamil / Q000627:therapeutic use
chemical_list: D000959:Antihypertensive Agents; D002121:Calcium Channel Blockers; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; D057093:Orphan Nuclear Receptors; D001262:Atenolol; D004247:DNA; D014700:Verapamil