Tuteja Sony, Wang Lu, Dunbar Richard L, Chen Jinbo, DerOhannessian Stephanie, Marcovina Santica M, Elam Marshall, Lader Ellis, Rader Daniel J
Departments of aMedicine bBiostatistics and Epidemiology cGenetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania dDepartment of Medicine, Northwest Lipid Metabolism and Diabetes Research Laboratories, University of Washington, Seattle, Washington eDepartment of Pharmacology and Medicine, University of Tennessee, Knoxville, Tennessee fSt Peter's Health Partners, Kingston, New York, USA.
Pharmacogenet Genomics. 2017 Aug;27(8):285-293. doi: 10.1097/FPC.0000000000000289.
Niacin has been used for seven decades to modulate plasma lipids, but its mechanism of action is still unclear. We sought to determine whether variants in the niacin receptor gene, hydroxyl-carboxylic receptor 2 (HCAR2), are associated with lipid response to treatment.
Coding variants, rs7314976 (p.R311C) and rs2454727 (p.M317I), were genotyped in 2067 participants from the Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides and Impact on Global Health Outcomes (AIM-HIGH) trial. AIM-HIGH was a randomized, placebo-controlled trial that was conducted to assess the effect of extended-release niacin in patients with cardiovascular disease aggressively treated with low-density lipoprotein cholesterol-lowering therapy.
There was no association of p.R311C or p.M317I with changes in low-density lipoprotein cholesterol, triglycerides, or high-density lipoprotein cholesterol at 1 year in groups receiving placebo or extended-release niacin. In White patients, the reduction in lipoprotein (a) [Lp(a)] in response to niacin was greater in homozygous carriers of the major 317M allele (-22.7%; P=0.005) compared with minor allele carriers (-15.3%). This was directionally consistent in the Black participants. Upon combining both groups, the reduction in Lp(a) in response to niacin was significantly greater in the homozygous major allele carriers (-23.0%; P=0.003) compared with minor allele carriers (-15.2%).
Understanding the genetic contribution toward variation in response to niacin therapy, including Lp(a) reduction, could uncover mechanisms by which niacin decreases Lp(a), an important independent risk factor for cardiovascular disease.
烟酸已被用于调节血脂七十年，但其作用机制仍不清楚。我们试图确定烟酸受体基因——羟基羧酸受体2（HCAR2）的变异是否与治疗的血脂反应相关。
对动脉粥样硬化血栓形成干预代谢综合征伴低高密度脂蛋白/高甘油三酯及对全球健康结局影响（AIM-HIGH）试验的2067名参与者进行编码变异rs7314976（p.R311C）和rs2454727（p.M317I）的基因分型。AIM-HIGH是一项随机、安慰剂对照试验，旨在评估缓释烟酸对接受积极低密度脂蛋白胆固醇降低治疗的心血管疾病患者的影响。
在接受安慰剂或缓释烟酸治疗的组中，p.R311C或p.M317I与1年时低密度脂蛋白胆固醇、甘油三酯或高密度脂蛋白胆固醇的变化无关联。在白人患者中，与次要等位基因携带者（-15.3%）相比，主要317M等位基因纯合携带者对烟酸反应时脂蛋白（a）[Lp（a）]的降低幅度更大（-22.7%；P=0.005）。在黑人参与者中这一趋势一致。将两组合并后，与次要等位基因携带者（-15.2%）相比，主要等位基因纯合携带者对烟酸反应时Lp（a）的降低幅度显著更大（-23.0%；P=0.003）。
了解对烟酸治疗反应变异的遗传贡献，包括Lp（a）降低，可能揭示烟酸降低Lp（a）的机制，Lp（a）是心血管疾病的一个重要独立危险因素。
