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Rare, Damaging DNA Variants in CORIN and Risk of Coronary Artery Disease : Insights From Functional Genomics and Large-Scale Sequencing Analyses

Wang, Minxian ; Lee-Kim, Vivian S. ; Atri, Deepak S. ; Elowe, Nadine H. ; Yu, John ; Garvie, Colin W. ; Won, Hong Hee ; Hadaya, Joseph E. ; MacDonald, Bryan T. and Trindade, Kevin , et al. (2021) In Circulation. Genomic and precision medicine 14(5).
Abstract

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... (More)

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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organization
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type
Contribution to journal
publication status
published
subject
keywords
coronary artery disease, homeostasis, mutation, natriuretic peptides, odds ratio
in
Circulation. Genomic and precision medicine
volume
14
issue
5
article number
e003399
publisher
Lippincott Williams & Wilkins
external identifiers
  • scopus:85119458017
  • pmid:34592835
ISSN
2574-8300
DOI
10.1161/CIRCGEN.121.003399
language
English
LU publication?
yes
id
b6dc3a42-4a46-4a80-90cd-228c4b0861bc
date added to LUP
2021-12-03 11:08:21
date last changed
2024-04-06 14:38:07
@article{b6dc3a42-4a46-4a80-90cd-228c4b0861bc,
  abstract     = {{<p>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 &lt;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.</p>}},
  author       = {{Wang, Minxian and Lee-Kim, Vivian S. and Atri, Deepak S. and Elowe, Nadine H. and Yu, John and Garvie, Colin W. and Won, Hong Hee and Hadaya, Joseph E. and MacDonald, Bryan T. and Trindade, Kevin and Melander, Olle and Rader, Daniel J. and Natarajan, Pradeep and Kathiresan, Sekar and Kaushik, Virendar K. and Khera, Amit V. and Gupta, Rajat M.}},
  issn         = {{2574-8300}},
  keywords     = {{coronary artery disease; homeostasis; mutation; natriuretic peptides; odds ratio}},
  language     = {{eng}},
  number       = {{5}},
  publisher    = {{Lippincott Williams & Wilkins}},
  series       = {{Circulation. Genomic and precision medicine}},
  title        = {{Rare, Damaging DNA Variants in CORIN and Risk of Coronary Artery Disease : Insights From Functional Genomics and Large-Scale Sequencing Analyses}},
  url          = {{http://dx.doi.org/10.1161/CIRCGEN.121.003399}},
  doi          = {{10.1161/CIRCGEN.121.003399}},
  volume       = {{14}},
  year         = {{2021}},
}