Smith J Gustav, Luk Kevin, Schulz Christina-Alexandra, Engert James C, Do Ron, Hindy George, Rukh Gull, Dufresne Line, Almgren Peter, Owens David S, Harris Tamara B, Peloso Gina M, Kerr Kathleen F, Wong Quenna, Smith Albert V, Budoff Matthew J, Rotter Jerome I, Cupples L Adrienne, Rich Stephen, Kathiresan Sekar, Orho-Melander Marju, Gudnason Vilmundur, O'Donnell Christopher J, Post Wendy S, Thanassoulis George
Department of Cardiology, Clinical Sciences, Lund University, Lund, Sweden2Department of Heart Failure and Valvular Disease, Skåne University Hospital, Lund, Sweden3Department of Clinical Sciences, Lund University, Malmö, Sweden4Program in Medical and Pop.
McGill University Health Center, Preventive and Genomic Cardiology, Montreal, Quebec, Canada.
JAMA. 2014 Nov 5;312(17):1764-71. doi: 10.1001/jama.2014.13959.
Plasma low-density lipoprotein cholesterol (LDL-C) has been associated with aortic stenosis in observational studies; however, randomized trials with cholesterol-lowering therapies in individuals with established valve disease have failed to demonstrate reduced disease progression.
To evaluate whether genetic data are consistent with an association between LDL-C, high-density lipoprotein cholesterol (HDL-C), or triglycerides (TG) and aortic valve disease.
DESIGN, SETTING, AND PARTICIPANTS: Using a Mendelian randomization study design, we evaluated whether weighted genetic risk scores (GRSs), a measure of the genetic predisposition to elevations in plasma lipids, constructed using single-nucleotide polymorphisms identified in genome-wide association studies for plasma lipids, were associated with aortic valve disease. We included community-based cohorts participating in the CHARGE consortium (n = 6942), including the Framingham Heart Study (cohort inception to last follow-up: 1971-2013; n = 1295), Multi-Ethnic Study of Atherosclerosis (2000-2012; n = 2527), Age Gene/Environment Study-Reykjavik (2000-2012; n = 3120), and the Malmö Diet and Cancer Study (MDCS, 1991-2010; n = 28,461).
Aortic valve calcium quantified by computed tomography in CHARGE and incident aortic stenosis in the MDCS.
The prevalence of aortic valve calcium across the 3 CHARGE cohorts was 32% (n = 2245). In the MDCS, over a median follow-up time of 16.1 years, aortic stenosis developed in 17 per 1000 participants (n = 473) and aortic valve replacement for aortic stenosis occurred in 7 per 1000 (n = 205). Plasma LDL-C, but not HDL-C or TG, was significantly associated with incident aortic stenosis (hazard ratio [HR] per mmol/L, 1.28; 95% CI, 1.04-1.57; P = .02; aortic stenosis incidence: 1.3% and 2.4% in lowest and highest LDL-C quartiles, respectively). The LDL-C GRS, but not HDL-C or TG GRS, was significantly associated with presence of aortic valve calcium in CHARGE (odds ratio [OR] per GRS increment, 1.38; 95% CI, 1.09-1.74; P = .007) and with incident aortic stenosis in MDCS (HR per GRS increment, 2.78; 95% CI, 1.22-6.37; P = .02; aortic stenosis incidence: 1.9% and 2.6% in lowest and highest GRS quartiles, respectively). In sensitivity analyses excluding variants weakly associated with HDL-C or TG, the LDL-C GRS remained associated with aortic valve calcium (P = .03) and aortic stenosis (P = .009). In instrumental variable analysis, LDL-C was associated with an increase in the risk of incident aortic stenosis (HR per mmol/L, 1.51; 95% CI, 1.07-2.14; P = .02).
Genetic predisposition to elevated LDL-C was associated with presence of aortic valve calcium and incidence of aortic stenosis, providing evidence supportive of a causal association between LDL-C and aortic valve disease. Whether earlier intervention to reduce LDL-C could prevent aortic valve disease merits further investigation.
在观察性研究中，血浆低密度脂蛋白胆固醇（LDL-C）与主动脉瓣狭窄有关；然而，在患有已确诊瓣膜疾病的个体中进行的降胆固醇治疗随机试验未能证明疾病进展有所减缓。
评估遗传数据是否与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关联一致。
设计、设置和参与者：采用孟德尔随机化研究设计，我们评估了加权遗传风险评分（GRS），即一种使用在全基因组关联研究中确定的单核苷酸多态性构建的、衡量血浆脂质升高遗传易感性的指标，是否与主动脉瓣疾病相关。我们纳入了参与CHARGE联盟的社区队列（n = 6942），包括弗雷明汉心脏研究（队列起始至最后随访：1971 - 2013年；n = 1295）、动脉粥样硬化多民族研究（2000 - 2012年；n = 2527）、雷克雅未克年龄基因/环境研究（2000 - 2012年；n = 3120）以及马尔默饮食与癌症研究（MDCS，1991 - 2010年；n = 28461）。
通过CHARGE中的计算机断层扫描量化主动脉瓣钙化以及MDCS中的新发主动脉瓣狭窄。
3个CHARGE队列中主动脉瓣钙化的患病率为32%（n = 2245）。在MDCS中，中位随访时间为16.1年，每1000名参与者中有17人发生主动脉瓣狭窄（n = 473），每1000人中有7人因主动脉瓣狭窄进行了主动脉瓣置换（n = 205）。血浆LDL-C而非HDL-C或TG与新发主动脉瓣狭窄显著相关（每mmol/L的风险比[HR]为1.28；95%置信区间[CI]为1.04 - 1.57；P = 0.02；最低和最高LDL-C四分位数组中主动脉瓣狭窄的发生率分别为1.3%和2.4%）。LDL-C的GRS而非HDL-C或TG的GRS与CHARGE中主动脉瓣钙化的存在显著相关（每GRS增加的优势比[OR]为1.38；95% CI为1.09 - 1.74；P = 0.007），并且与MDCS中的新发主动脉瓣狭窄相关（每GRS增加的HR为2.78；95% CI为1.22 - 6.37；P = 0.02；最低和最高GRS四分位数组中主动脉瓣狭窄的发生率分别为1.9%和2.6%）。在排除与HDL-C或TG弱相关的变异的敏感性分析中，LDL-C的GRS仍与主动脉瓣钙化（P = 0.03）和主动脉瓣狭窄（P = 0.009）相关。在工具变量分析中，LDL-C与新发主动脉瓣狭窄风险的增加相关（每mmol/L的HR为1.51；95% CI为1.07 - 2.14；P = 0.02）。
LDL-C升高的遗传易感性与主动脉瓣钙化的存在和主动脉瓣狭窄的发生率相关，为LDL-C与主动脉瓣疾病之间的因果关联提供了支持证据。早期干预降低LDL-C是否能预防主动脉瓣疾病值得进一步研究。
