低密度脂蛋白胆固醇相关遗传变异体与主动脉瓣钙化及偶发主动脉瓣狭窄的相关性

2014-12-15 J.古斯塔夫.史密斯等 瑞典隆德大学临床科学心脏病学系等 张 中国医学论坛报

意义观察性研究显示,血浆低密度脂蛋白胆固醇(LDL-C)与主动脉瓣狭窄相关;然而,在有明确瓣膜疾病患者中,应用降胆固醇治疗的随机试验,未能证实该疗法可以减缓疾病进展。 目的评估遗传学数据是否支持LDL-C、高密度脂蛋白胆固醇(HDL-C)或甘油三酯(TG)与主动脉瓣疾病之间的相关性。 设计、场所和参与者我们应用孟德尔随机化研究设计,评估遗传学危险加权评分(GRS)是否与主动脉瓣疾病

意义观察性研究显示,血浆低密度脂蛋白胆固醇(LDL-C)与主动脉瓣狭窄相关;然而,在有明确瓣膜疾病患者中,应用降胆固醇治疗的随机试验,未能证实该疗法可以减缓疾病进展。

目的评估遗传学数据是否支持LDL-C、高密度脂蛋白胆固醇(HDL-C)或甘油三酯(TG)与主动脉瓣疾病之间的相关性

设计、场所和参与者我们应用孟德尔随机化研究设计,评估遗传学危险加权评分(GRS)是否与主动脉瓣疾病相关。GRS是血脂升高遗传易感性的一个检测指标,通过应用血脂全基因组关联研究辨别出的单核苷酸多态性进行构建。我们纳入了参与CHARGE联盟的基于社区的队列(n=6942),包括弗雷明汉心脏研究(从队列组建至最后随访:1971-2013年,n=1295)、动脉粥样硬化的多种族研究(2000-2012年,n=2527)、雷克雅未克年龄基因/环境研究(2000-2012年,n=3120),以及马尔默饮食和癌症研究(MDCS,1991-2010年,n=28461)。

主要转归和检测指标在CHARGE中由计算机化体层摄影(CT)定量的主动脉瓣钙化,以及在MDCS中的偶发主动脉瓣狭窄

结果3个CHARGE队列中主动脉瓣钙化的患病率为32%(n=2245)。在MDCS中,中位随访16.1年期间,每1000名参与者中有17名发生主动脉瓣狭窄(n=473),每1000名参与者中有7名因主动脉瓣狭窄而接受主动脉瓣置换术(n=205)。血浆LDL-C(而非HDL-C或TG)与偶发主动脉瓣狭窄显著相关[每mmol/L的风险比(HR)为1.28,95%可信区间(CI)为1.04~1.57,P=0.02;LDL-C处于最低和最高四分位者的主动脉瓣狭窄发生率分别为1.3%和2.4%]。LDL-C GRS(而非HDL-C或TGGRS)在CHARGE中与存在主动脉瓣钙化显著相关[GRS每增加1单位的比值比(OR)为1.38,95%CI为1.09~1.74,P=0.007],并且与MDCS中的偶发主动脉瓣狭窄显著相关(GRS每增加1单位的HR为2.78,95%CI为1.22~6.37,P=0.02;GRS处于最低和最高四分位者的主动脉瓣狭窄发生率分别为1.9%和2.6%)。排除与HDL-C或TG弱相关变异体的敏感性分析中,LDL-CGRS仍与主动脉瓣钙化(P=0.03)及主动脉瓣狭窄(P=0.009)相关。在辅助变量分析中,LDL-C与偶发主动脉瓣狭窄的危险增加相关(每mmol/L的HR为1.51,95%CI为1.07~2.14,P=0.02)。

结论和相关性导致LDL-C升高的遗传易感性,与存在主动脉瓣钙化及偶发主动脉瓣狭窄相关,为LDL-C和主动脉瓣疾病之间存在因果联系提供了支持性证据。更早采取干预措施以降低LDL-C,是否可以预防主动脉瓣疾病,值得进一步研究。

原始出处:

Smith JG1, Luk K2, Schulz CA3, Engert JC4, Do R5, Hindy G3, Rukh G3, Dufresne L2, Almgren P3, Owens DS6, Harris TB7, Peloso GM8, Kerr KF9, Wong Q9, Smith AV10, Budoff MJ11, Rotter JI11, Cupples LA12, Rich S13, Kathiresan S14, Orho-Melander M3, Gudnason V10, O'Donnell CJ15, Post WS16, Thanassoulis G4; Cohorts for Heart and Aging Research in Genetic Epidemiology (CHARGE) Extracoronary Calcium Working Group.Association of low-density lipoprotein cholesterol-related genetic variants with aortic valve calcium and incident aortic stenosis.JAMA. 2014 Nov 5;312(17):1764-71. doi: 10.1001/jama.2014.13959.


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