Elevated Lipoprotein(a) Levels, LPA Risk Genotypes, and Increased Risk of Heart Failure in the General Population

详细信息    查看全文

• 作者：Pia R. Kamstrup ; MD ; PhD^&lowast ; ; ^&dagger ; ; ^&Dagger ; ; ^{pia.roerbaek.kamstrup@regionh.dk" class="auth_mail" title="E-mail the corresponding author} ; Bø ; rge G. Nordestgaard ; MD ; DMSc^&lowast ; ; ^&dagger ; ; ^&Dagger ; ; ^§ ;
• 关键词：genetics ; heart failure ; lipoproteins
• 刊名：JACC: Heart Failure
• 出版年：2016
• 出版时间：January 2016
• 年：2016
• 卷：4
• 期：1
• 页码：78-87
• 全文大小：840 K

文摘

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).

bsSec_2">Background

bspara0015">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).

bsSec_3">Methods

bspara0020">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.

bsSec_4">Results

bspara0025">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.

bsSec_5">Conclusions

bspara0030">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.