Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics, University of Florida College of Medicine, Gainesville, FL, USA.
Pharmacogenet Genomics. 2011 Jun;21(6):333-40. doi: 10.1097/FPC.0b013e3283452fec.
BACKGROUND/AIMS: 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.
背景/目的：肝 X 受体-α（LXRA）是一种核受体，可调节胆固醇稳态和炎症过程中的重要基因。此前，LXRA 基因（NR1H3）中的几个单核苷酸多态性（SNP）与代谢表型（血脂异常和体重指数升高）有关。代谢失调是导致冠心病的主要原因；因此，我们在国际维拉帕米持续释放 SR 阿替洛尔研究遗传亚研究（INVEST-GENES）中评估了 LXRA，这是一项大型高血压和冠心病临床试验的遗传亚研究。
选择 LXRA 基因（NR1H3）区域的 7 个标签 SNP 进行研究：rs11039149、rs12221497、rs2279238、rs7120118、rs326213、rs11039159 和 rs10501321。从 INVEST-GENES 病例对照集中对 1059 例患者进行基因分型（基于维拉帕米持续释放或阿替洛尔的治疗策略），该病例对照集由 297 例病例组成，通过性别和种族与无事件对照者的频率相匹配（大约 2.5:1）。主要结局定义为全因死亡、非致死性心肌梗死或非致死性卒中的首次发生。使用逻辑回归计算调整后的比值比（OR）。
在非黑人中，7 个 SNP 中有 3 个与主要结局有显著关联。rs11039149 的 G 变体等位基因和 rs12221497 的 A 变体等位基因与降低发生主要结局的风险相关[OR：0.62，置信区间（CI）：0.45-0.85，P=0.003 和 OR：0.60，CI：0.39-0.91，P=0.016]。rs2279238 基因型与主要结局的风险显著增加相关（OR：1.42，CI：1.03-1.95，P=0.03）。此外，携带 rs2279238 变体 T 等位基因的患者存在显著的基因型-治疗策略相互作用（与阿替洛尔策略相比，维拉帕米持续释放策略的 OR：2.86，CI：1.50-5.46，P=0.0015）。双等位基因分析表明，这些 SNP 很少同时遗传，并且支持 SNP 对主要结局的方向性相反影响。
LXRA 基因型与 INVEST-GENES 中的心血管结局和药物遗传学效应的可变风险相关。这些新发现表明 LXRA 是一个遗传/药物遗传学靶点，应进一步探索。
