Mapping renal impairment and cardiac structure and function: a comprehensive analysis of prospective cohort study, Mendelian randomization and shared genetic etiology

Abstract

BackgroundThe elevated risk of heart failure in kidney dysfunction is well-identified. However, the influence of early alteration of renal impairment on cardiac structure and function, as well as their shared genetic susceptibility associations have not been well reported. AimTo investigate the associations between renal function and cardiac parameters using cardiac magnetic resonance images (CMR). MethodsOf 29,546 European subjects underwent CMR test were recruited from UK Biobank study. Multivariable generalized linear regression was used to analyze the association of different kidney function indexes with CMR-traits. Genetic correlation between early renal impairment and CMR-traits were evaluated by linkage disequilibrium score regression and Mendelian randomization. DesignA comprehensive analysis of prospective cohort study, Mendelian randomization and shared genetic etiology. ResultsObservational and genetic correlation analyses consistently reveal that a mild reduction in estimated glomerular filtration rate (eGFR) is independently associated with lower biventricular volume parameters and left ventricular cardiac output (LVCO), respectively. Through a rigorous application of Heritability Estimation from and Summary Statistics ({rho}-HESS) and cross-trait meta-analysis, we identified 20 novel shared loci (e.g. rs2472297, located at CYP1A1) between eGFR based on cystatin C decline and reduced right ventricular end systolic volume (RVESV), and 2 loci (rs4371638, located at SHROOM3; rs34591452, located at STRA6) showed strong evidence of colocalization (probability for H4>0.95). Pathway enrichment analysis revealed that pathways of eGFR decline and reduced RVESV associated with enzyme inhibitor activity, endopeptidase regulator activity, and cysteine-type endopeptidase inhibitor activity. ConclusionsOur study indicates significant observational and genetic correlations between early renal impairment and lower biventricular volume parameters and LVCO.