Genome-wide association study of cardiac troponin I in the general population

Abstract

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 is 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 and HF development in the general population. Using genetically informed methods for causal inference helps inform the role and value of measuring cTnI in the general population.

Cardiac Troponin I and Risk of Stroke: A Mendelian Randomization Study

“… 38 , 39 Hence, to explore the causal effects of circulating cTnI on HF and AMI, Marta R. Moksnes et al performed a two-sample MR analysis, but no causal association was found. 16 This conclusion corroborated with the findings in the present study. Consistently, another MR study suggested that GDF-15, a stress responsive cytokine, was not causally associated with stroke risk, except a suggested relationship with CES.…”

“…15 Genetic variants associated with circulating cTnI levels were derived from the hitherto largest GWAS meta-analysis of 48,115 individuals. 16 Twelve single-nucleotide polymorphisms (SNPs) with genome-wide significance (P < 5 × 10 −8 ) were collected. The F-statistics were estimated to identify any weak instrument bias using the formula F ¼ R 2 NÀ 2 1À R 2 , where R 2 indicates the proportion of the variance of circulating cTnI explained by the genetic instruments and N refers to the sample size.…”

Genetically Predicted Cardiac Troponin I Concentrations and Risk of Stroke and Atrial Fibrillation

“…Instrumental variables for circulating cTnI concentrations were selected from a GWAS meta-analysis of the Trøndelag Health Study ((HUNT, n = 29,839) and the Generation Scotland Scottish Family Health Study (GS:SFHS, n = 18,276) with 48,115 European individuals. [17] This GWAS identi ed 12 genome-wide signi cant (P < 5×10 − 8 ) SNPs independently associated with cTnI concentrations (Supplementary Table 1). These 12 SNPs explained 1.2% phenotypic variation of circulating cTnI concentrations.…”

“…[7,22] Because genetic variants are randomly allocated at conception and unlikely to be affected by disease in later life, MR can avoid the confounding and reverse causality in observational studies. Recently, a genome-wide association study (GWAS) has identi ed several single nucleotide polymorphisms (SNPs) that are independently associated with circulating cTnI concentrations in the general population, [17] providing potential tools for MR. In this study, we aimed to use a two-sample MR to evaluate whether genetically predicted circulating cTnI concentrations are causally associated with the risk of stroke, IS, IS subtypes (large artery stroke [LAS], small vessel stroke [SVS] and cardioembolic stroke [CES]), intracerebral hemorrhage (ICH).…”

Roles of Cullin-RING Ubiquitin Ligases in Cardiovascular Diseases

“…Unlike CAND1 that is ubiquitously expressed in all types of human cells, CAND2 protein is only detected in striated muscles (skeletal and cardiac) and testis [36,37,222]. While the role of CAND2 in regulating CRLs has not been well elucidated yet, population genetics and genome-wide association studies have identified CAND2 as a risk factor for multiple types of cardiovascular diseases (especially atrial fibrillation) [223][224][225][226][227][228][229]. A recent study aiming to determine the mechanism by which mTOR promotes pathological cardiac remodeling identified CAND2 as a gene significantly upregulated by mTOR in mouse cardiomyocytes, and CAND2 depletion led to decreased protein level of Grk5 and disassembly, and substrate receptor modules in CRL1 complexes are changed [201,219].…”