Abstract 12381: Cardiac Injury Measured by High-Sensitive Cardiac Troponin T Linked to Novel Genetic Loci: Multi-Ethnic Study of Atherosclerosis (MESA).

Introduction: High-sensitivity cardiac troponin T (hs-cTnT) plasma levels are associated with cardiac injury and incident heart failure. The mechanisms for biomarker release leading to cardiac injury are unclear, and the sole previous genome-wide association study (GWAS; Yu, 2013) suggested genetic variants near NCOA2 and TNNT2 are associated with hs-cTnT. Hypothesis: The Multi-Ethnic Study of Atherosclerosis (MESA), by incorporating multi-omics data, will validate previous findings, refine loci mapping, provide mechanistic insights, and identify novel loci of cardiac injury. Methods: Baseline plasma hs-cTnT levels were measured in 6,131 MESA participants free of clinical cardiovascular disease (mean age 62.2±10.2 yrs; 47.6% men, 39% White, 26% African-American, 23% Hispanic, 12% Chinese). We conducted a GWAS of the log hs-cTnT level (>11M post-QC single nucleotide polymorphisms (SNPs)) and specific candidate SNPs for hs-cTnT dichotomized at the upper percentile of risk. We meta-analyzed the four ethnic groups under fixed effects and ancestry-adjusted meta-regression models. Results: We validated the NCOA2 locus with a different index SNP (rs10091864) 44kb upstream of NCOA2 (p=3x10-9), consistent in all ethnic groups. In Genotype-Tissue Expression analysis, rs10091864 is an expression quantitative trait locus (eQTL) for XKR9 and is co-localized with eQTLs for an intergenic non-coding RNA (LOC101926892). We identified a novel association with a missense coding SNP (rs79412473) in TBCK (imputed well only in whites, p=4x10-8). A gene with strong physiological impact and gene expression evidence (BCL2) had an associated intronic SNP (rs899967) that was consistent in effect, directionally and size, with the Yu report, but did not reach GWAS significance (joint p=1.5x10-7). The dichotomous trait (TNNT2) association was replicated only in African-Americans (p=0.03). Conclusions: In summary, we have evidence for additional novel genetic loci associated with cardiac injury as measured by hs-cTnT and replicated the NCOA2 association in MESA. Use of these genetic findings may provide better mechanistic insights into the pathophysiology of cardiac injury and incident heart failure. [ABSTRACT FROM AUTHOR]