Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Copenhagen, Denmark; The Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, Copenhagen, Denmark; Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Copenhagen, Denmark; The Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, Copenhagen, Denmark; Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; The Copenhagen City Heart Study, Frederiksberg Hospital, Copenhagen University Hospital, Copenhagen, Denmark.
JACC Heart Fail. 2016 Jan;4(1):78-87. doi: 10.1016/j.jchf.2015.08.006. Epub 2015 Dec 2.
OBJECTIVES: This study sough to test whether elevated lipoprotein(a) levels and corresponding LPA risk genotypes (low number of kringle IV type 2 repeats, rs3798220 and rs10455872, minor allele carriers) are associated with an increased risk of heart failure (HF). BACKGROUND: Elevated lipoprotein(a) levels represent a genetically determined risk factor for myocardial infarction (MI) and aortic valve stenosis (AVS). It is presently unknown whether elevated lipoprotein(a) levels also cause heart failure (HF). METHODS: We combined 2 general population studies, the Copenhagen City Heart Study (n = 10,855) and the Copenhagen General Population Study (n = 87,242), which totaled 98,097 Danish participants, of whom 4,122 were diagnosed with HF (1976 to 2013). We conducted observational and genetic instrumental variable analyses in a Mendelian randomization study design, assessing evidence of causality, and we performed mediation analyses. RESULTS: Elevated lipoprotein(a) levels were associated with multivariable adjusted hazard ratios for HF of 1.10 (95% CI: 0.97 to 1.25) for the 34th to 66th percentiles (8 to 19 mg/dl), 1.24 (95% CI: 1.08 to 1.42) for the 67th to 90th percentiles (20 to 67 mg/dl), 1.57 (95% CI: 1.32 to 1.87) for the 91st to 99th percentiles (68 to 153 mg/dl), and 1.79 (95% CI: 1.18 to 2.73) for levels >99th percentile (>153 mg/dl) versus levels <34th percentile (<8 mg/dl) (trend, p < 0.001), corresponding to a population-attributable risk of 9%. By combining all LPA risk genotypes, instrumental variable analysis yielded a genetic relative risk for HF of 1.18 (95% CI: 1.04 to 1.34) per 10-fold higher lipoprotein(a) levels, which was comparable to the corresponding observational hazard ratio of 1.22 (95% CI: 1.11 to 1.35). Upon exclusion of participants diagnosed with MI or AVS, risk estimates were attenuated. Accordingly, 63% (95% CI: 45% to 99%) of HF risk was mediated via MI and AVS combined. CONCLUSIONS: Elevated lipoprotein(a) levels and corresponding LPA risk genotypes were associated with an increased risk of HF consistent with a causal association. The association appeared to be partly mediated by MI and AVS.
目的：本研究旨在检验脂蛋白(a)水平升高及其相应的 LPA 风险基因型（kringle IV 型 2 重复次数较少、rs3798220 和 rs10455872 、次要等位基因携带者）是否与心力衰竭（HF）风险增加相关。
背景：脂蛋白(a)水平升高是心肌梗死（MI）和主动脉瓣狭窄（AVS）的遗传决定因素。目前尚不清楚脂蛋白(a)水平升高是否也会导致心力衰竭（HF）。
方法：我们结合了两项一般人群研究，哥本哈根城市心脏研究（n=10855）和哥本哈根一般人群研究（n=87242），共有 98097 名丹麦参与者，其中 4122 人被诊断为 HF（1976 年至 2013 年）。我们在孟德尔随机化研究设计中进行了观察性和遗传工具变量分析，评估因果关系的证据，并进行了中介分析。
结果：脂蛋白(a)水平升高与多变量调整后的 HF 风险比相关，第 34 至 66 百分位（8 至 19mg/dl）为 1.10（95%CI：0.97 至 1.25），第 67 至 90 百分位（20 至 67mg/dl）为 1.24（95%CI：1.08 至 1.42），第 91 至 99 百分位（68 至 153mg/dl）为 1.57（95%CI：1.32 至 1.87），第 99 百分位以上（153mg/dl 以上）与第 34 百分位以下（8mg/dl 以下）相比，风险比为 1.79（95%CI：1.18 至 2.73）（趋势，p<0.001），对应 9%的人群归因风险。通过结合所有 LPA 风险基因型，工具变量分析得出 HF 的遗传相对风险为脂蛋白(a)水平每升高 10 倍增加 1.18（95%CI：1.04 至 1.34），与相应的观察性危险比 1.22（95%CI：1.11 至 1.35）相当。排除 MI 或 AVS 诊断的参与者后，风险估计值减弱。因此，HF 风险的 63%（95%CI：45%至 99%）通过 MI 和 AVS 联合介导。
结论：脂蛋白(a)水平升高及其相应的 LPA 风险基因型与 HF 风险增加相关，与因果关系一致。这种关联似乎部分是通过 MI 和 AVS 介导的。
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