A Common Missense Variant in OMA1 Associated with the Prognosis of Heart Failure

Abstract

Purpose: Mitochondrial dysfunction plays a vital role in the pathophysiologic process of heart failure (HF). As a quality control system, mitochondrial fusion and fission are under control of mitochondrial fusion and fission-related proteins. The objective of this study was to investigate the effects of common variants in mitochondrial fusion and fission-related genes on the prognosis of HF. Methods: We performed whole exome sequencing (WES) with 1000 HF patients; the statistically significant variant was further genotyped in the replicated population with 2324 HF patients. A series of function analysis including western blot, cell proliferation assay, and in vitro OMA1 activity assay were conducted to illuminate the underlying mechanism. Results: We identified a missense variant rs17117699 associated with the prognosis of HF in group without β-blocker use rather than with β-blocker use in two-stage population: adjusted P = 0.79, HR = 0.88 (0.36–2.13) in group with β-blocker use and adjusted P = 0.016, HR = 1.43 (1.07–1.91) in group without β-blocker in first-stage population; adjusted P = 0.42, HR = 0.85 (0.56–1.28) in group with β-blocker use and adjusted P = 0.015, HR = 1.39 (1.06–1.82) in group without β-blocker in replicated stage. Functional analysis indicated that rs17117699-G allele increased the activity of OMA1 assessed by the ratio of S-OPA1 to L-OPA1 and suppressed cells proliferation under ISO treatment when compared with rs17117699-T allele. Furthermore, OMA1 functioned downstream of β-adrenergic receptor signaling and ISO-induced OPA1 cleavage is dependent on OMA1. Conclusions: Our findings demonstrate that rs17117699T>G in OMA1 increases the risk of HF mortality via enhancing its OPA1 cleavage activity. It is a promising potential treatment target for HF. Clinical Trial Registration: NCT03461107. https://www.clinicaltrials.gov/ct2/show/NCT03461107?term=03461107&cond=Heart+Failure&cntry=CN&rank=1