Key result
Rare CORIN loss-of-function variants show no link to CAD risk.
Why the study?
It was unknown whether Corin loss-of-function is causally associated with risk of coronary artery disease.
Does the presence of rare, damaging DNA variants in CORIN or circulating Corin concentrations affect the risk of coronary artery disease?
Case-Control (n=258,255)
Does the presence of rare, damaging DNA variants in CORIN or circulating Corin concentrations affect the risk of coronary artery disease?
Despite preliminary observations and biological plausibility, rare damaging variants in CORIN and circulating Corin concentrations are not associated with the risk of coronary artery disease.
Answers are grounded in this paper and cite their sources.
Rare CORIN variants do not increase CAD risk; leaves open therapeutic relevance in other phenotypes or populations.
Background: Corin is a protease expressed in cardiomyocytes that plays a key role in salt handling and intravascular volume homeostasis via activation of natriuretic peptides. It is unknown if Corin loss-of-function (LOF) is causally associated with risk of coronary artery disease (CAD). Methods: We analyzed all coding CORIN variants in an Italian case-control study of CAD. We functionally tested all 64 rare missense mutations in Western Blot and Mass Spectroscopy assays for proatrial natriuretic peptide cleavage. An expanded rare variant association analysis for Corin LOF mutations was conducted in whole exome sequencing data from 37 799 CAD cases and 212 184 controls. Results: We observed LOF variants in CORIN in 8 of 1803 (0.4%) CAD cases versus 0 of 1725 controls ( P , 0.007). Of 64 rare missense variants profiled, 21 (33%) demonstrated <30% of wild-type activity and were deemed damaging in the 2 functional assays for Corin activity. In a rare variant association study that aggregated rare LOF and functionally validated damaging missense variants from the Italian study, we observed no association with CAD—21 of 1803 CAD cases versus 12 of 1725 controls with adjusted odds ratio of 1.61 ([95% CI, 0.79–3.29]; P =0.17). In the expanded sequencing dataset, there was no relationship between rare LOF variants with CAD was also observed (odds ratio, 1.15 [95% CI, 0.89–1.49]; P =0.30). Consistent with the genetic analysis, we observed no relationship between circulating Corin concentrations with incident CAD events among 4744 participants of a prospective cohort study—sex-stratified hazard ratio per SD increment of 0.96 ([95% CI, 0.87–1.07], P =0.48). Conclusions: Functional testing of missense mutations improved the accuracy of rare variant association analysis. Despite compelling pathophysiology and a preliminary observation suggesting association, we observed no relationship between rare damaging variants in CORIN or circulating Corin concentrations with risk of CAD.
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Wang et al. (2021) conducted a case-control in Coronary artery disease (n=258,255). Rare loss-of-function variants in CORIN vs. Non-carriers was evaluated on Coronary artery disease (OR 1.15, 95% CI 0.89-1.49, p=0.30). Rare loss-of-function variants in CORIN were not associated with risk of coronary artery disease in a large-scale sequencing analysis (OR 1.15; 95% CI 0.89-1.49; P=0.30).
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