Genetic variants in CETP increase risk of intracerebral hemorrhage.
Genetic variants in CETP increase risk of intracerebral hemorrhage.
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DOI：
10.1002/ana.24780
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发表时间：
2016-11
影响因子：
11.2
通讯作者：
Rosand, Jonathan
中科院分区：
文献类型：
--
作者：
Anderson, Christopher D.;Falcone, Guido J.;Phuah, Chia-Ling;Radmanesh, Farid;Brouwers, H. Bart;Battey, Thomas W. K.;Biffi, Alessandro;Peloso, Gina M.;Liu, Dajiang J.;Ayres, Alison M.;Goldstein, Joshua N.;Viswanathan, Anand;Greenberg, Steven M.;Selim, Magdy;Meschia, James F.;Brown, Devin L.;Worrall, Bradford B.;Silliman, Scott L.;Tirschwell, David L.;Flaherty, Matthew L.;Kraft, Peter;Jagiella, Jeremiasz M.;Schmidt, Helena;Hansen, Bjorn M.;Jimenez-Conde, Jordi;Giralt-Steinhauer, Eva;Elosua, Roberto;Cuadrado-Godia, Elisa;Soriano, Carolina;van Nieuwenhuizen, Koen M.;Klijn, Catharina J. M.;Rannikmae, Kristiina;Samarasekera, Neshika;Salman, Rustam Al-Shahi;Sudlow, Catherine L.;Deary, Ian J.;Morotti, Andrea;Pezzini, Alessandro;Pera, Joanna;Urbanik, Andrzej;Pichler, Alexander;Enzinger, Christian;Norrving, Bo;Montaner, Joan;Fernandez-Cadenas, Israel;Delgado, Pilar;Roquer, Jaume;Lindgren, Arne;Slowik, Agnieszka;Schmidt, Reinhold;Kidwell, Chelsea S.;Kittner, Steven J.;Waddy, Salina P.;Langefeld, Carl D.;Abecasis, Goncalo;Willer, Cristen J.;Kathiresan, Sekar;Woo, Daniel;Rosand, Jonathan
在观察性流行病学研究中，较高的血浆高密度脂蛋白胆固醇(HDLC)与脑出血(ICH)的风险增加相关。降低胆固醇酯转移蛋白(CETP)基因活性的DNA序列变体会增加血浆高密度脂蛋白；因此，抑制CETP并提高高密度脂蛋白的药物正在临床开发中。在这里，我们测试了CETP DNA序列变异与较高的高密度脂蛋白胆固醇相关的假设，也增加了脑出血的风险。我们对CETP进行了两次候选基因分析。首先，我们在3项研究的1,149例脑出血患者和1,238名对照中测试了个别CETP变异，随后在5项研究的1,625例和1,845名对照中进行了重复试验。其次，我们构建了一个由CETP基因座上7个独立变异组成的遗传风险评分，并测试了该评分与高密度脂蛋白胆固醇和脑出血风险的相关性。CETP中有12个变异与脑出血有名义上的关联，其中rs173539基因座的关联最强(优势比[OR] = 1.25，标准误[SE] = 0.06，p = 6.0 × 10−4)，在研究中没有异质性(I 2 = 0%)。这种关联在欧洲血统的患者中也得到了复制(p = 0.03)。在全球脂质遗传学联合会中发现CETP变异体使高密度脂蛋白-C升高2.85 mg/dl的遗传得分与脑出血风险密切相关(OR∼1.86，SE = 0.13，p = 1.39 × 10−6)。CETP基因变异与高密度脂蛋白胆固醇升高相关，增加了脑出血的风险。鉴于CETP抑制和其他高密度脂蛋白升高策略的持续治疗进展，可能有必要进一步探索潜在的不利脑血管后果。Ann Neurol 2016；80：730-740
In observational epidemiologic studies, higher plasma high‐density lipoprotein cholesterol (HDL‐C) has been associated with increased risk of intracerebral hemorrhage (ICH). DNA sequence variants that decrease cholesteryl ester transfer protein (CETP) gene activity increase plasma HDL‐C; as such, medicines that inhibit CETP and raise HDL‐C are in clinical development. Here, we test the hypothesis that CETP DNA sequence variants associated with higher HDL‐C also increase risk for ICH. We performed 2 candidate‐gene analyses of CETP. First, we tested individual CETP variants in a discovery cohort of 1,149 ICH cases and 1,238 controls from 3 studies, followed by replication in 1,625 cases and 1,845 controls from 5 studies. Second, we constructed a genetic risk score comprised of 7 independent variants at the CETP locus and tested this score for association with HDL‐C as well as ICH risk. Twelve variants within CETP demonstrated nominal association with ICH, with the strongest association at the rs173539 locus (odds ratio [OR] = 1.25, standard error [SE] = 0.06, p = 6.0 × 10−4) with no heterogeneity across studies (I 2 = 0%). This association was replicated in patients of European ancestry (p = 0.03). A genetic score of CETP variants found to increase HDL‐C by ∼2.85mg/dl in the Global Lipids Genetics Consortium was strongly associated with ICH risk (OR = 1.86, SE = 0.13, p = 1.39 × 10−6). Genetic variants in CETP associated with increased HDL‐C raise the risk of ICH. Given ongoing therapeutic development in CETP inhibition and other HDL‐raising strategies, further exploration of potential adverse cerebrovascular outcomes may be warranted. Ann Neurol 2016;80:730–740
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