Department of Public Health and Nursing, K.G. Jebsen Center for Genetic Epidemiology, NTNU - Norwegian University of Science and Technology, 7491 Trondheim, Norway.
Division of Research and Innovation, Akershus University Hospital, 1478 Lørenskog, Norway.
Hum Mol Genet. 2021 Oct 13;30(21):2027-2039. doi: 10.1093/hmg/ddab124.
Circulating cardiac troponin proteins are associated with structural heart disease and predict incident cardiovascular disease in the general population. However, the genetic contribution to cardiac troponin I (cTnI) concentrations and its causal effect on cardiovascular phenotypes are unclear. We combine data from two large population-based studies, the Trøndelag Health Study and the Generation Scotland Scottish Family Health Study, and perform a genome-wide association study of high-sensitivity cTnI concentrations with 48 115 individuals. We further use two-sample Mendelian randomization to investigate the causal effects of circulating cTnI on acute myocardial infarction (AMI) and heart failure (HF). We identified 12 genetic loci (8 novel) associated with cTnI concentrations. Associated protein-altering variants highlighted putative functional genes: CAND2, HABP2, ANO5, APOH, FHOD3, TNFAIP2, KLKB1 and LMAN1. Phenome-wide association tests in 1688 phecodes and 83 continuous traits in UK Biobank showed associations between a genetic risk score for cTnI and cardiac arrhythmias, metabolic and anthropometric measures. Using two-sample Mendelian randomization, we confirmed the non-causal role of cTnI in AMI (5948 cases, 355 246 controls). We found indications for a causal role of cTnI in HF (47 309 cases and 930 014 controls), but this was not supported by secondary analyses using left ventricular mass as outcome (18 257 individuals). Our findings clarify the biology underlying the heritable contribution to circulating cTnI and support cTnI as a non-causal biomarker for AMI in the general population. Using genetically informed methods for causal inference helps inform the role and value of measuring cTnI in the general population.
循环心肌肌钙蛋白蛋白与结构性心脏病相关，并可预测普通人群中的心血管疾病事件。然而，心肌肌钙蛋白 I（cTnI）浓度的遗传贡献及其对心血管表型的因果效应尚不清楚。我们结合了两项大型基于人群的研究，即特隆德拉格健康研究和苏格兰基因研究苏格兰家庭健康研究的数据，并对 48115 个人进行了高敏肌钙蛋白 I 浓度的全基因组关联研究。我们进一步使用两样本孟德尔随机化来研究循环 cTnI 对急性心肌梗死（AMI）和心力衰竭（HF）的因果影响。我们确定了 12 个与 cTnI 浓度相关的遗传位点（8 个为新发现）。相关的蛋白改变变体突出了可能的功能基因：CAND2、HABP2、ANO5、APOH、FHOD3、TNFAIP2、KLKB1 和 LMAN1。在 UK Biobank 中的 1688 个 phecode 和 83 个连续特征的全表型关联测试显示，cTnI 的遗传风险评分与心律失常、代谢和人体测量特征之间存在关联。使用两样本孟德尔随机化，我们证实了 cTnI 在 AMI 中的非因果作用（5948 例病例，355246 例对照）。我们发现 cTnI 在 HF 中的因果作用的迹象（47309 例病例和 930014 例对照），但使用左心室质量作为结局的二次分析并不支持这一结果（18257 例个体）。我们的研究结果阐明了循环 cTnI 遗传贡献的生物学基础，并支持 cTnI 作为普通人群中 AMI 的非因果生物标志物。使用基于遗传的因果推理方法有助于了解在普通人群中测量 cTnI 的作用和价值。
