title: The Coronary Artery Disease-associated Coding Variant in Zinc Finger C3HC-type Containing 1 (ZC3HC1) Affects Cell Cycle Regulation.
abstract: Genome-wide association studies have to date identified multiple coronary artery disease (CAD)-associated loci; however, for most of these loci the mechanism by which they affect CAD risk is unclear. The CAD-associated locus 7q32.2 is unusual in that the lead variant, rs11556924, is not in strong linkage disequilibrium with any other variant and introduces a coding change in ZC3HC1, which encodes NIPA. In this study, we show that rs11556924 polymorphism is associated with lower regulatory phosphorylation of NIPA in the risk variant, resulting in NIPA with higher activity. Using a genome-editing approach we show that this causes an effective decrease in cyclin-B1 stability in the nucleus, thereby slowing its nuclear accumulation. By perturbing the rate of nuclear cyclin-B1 accumulation, rs11556924 alters the regulation of mitotic progression resulting in an extended mitosis. This study shows that the CAD-associated coding polymorphism in ZC3HC1 alters the dynamics of cell-cycle regulation by NIPA.
authors.affiliation: From the Department of Cardiovascular Sciences and NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, University of Leicester, Leicester, LE3 9QP and.
authors.forename: Peter D
authors.identifier: 0000-0002-6667-7562
authors.initials: PD
authors.lastname: Jones
authors.affiliation: From the Department of Cardiovascular Sciences and NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, University of Leicester, Leicester, LE3 9QP and.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Kaiser
authors.affiliation: From the Department of Cardiovascular Sciences and NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, University of Leicester, Leicester, LE3 9QP and.
authors.forename: Maryam
authors.initials: M
authors.lastname: Ghaderi Najafabadi
authors.affiliation: From the Department of Cardiovascular Sciences and NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, University of Leicester, Leicester, LE3 9QP and.
authors.forename: David G
authors.initials: DG
authors.lastname: McVey
authors.affiliation: From the Department of Cardiovascular Sciences and NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, University of Leicester, Leicester, LE3 9QP and.
authors.forename: Allan J
authors.initials: AJ
authors.lastname: Beveridge
authors.affiliation: Horizon Discovery Limited, 7100 Cambridge Research Park, Waterbeach, Cambridge CB25 9TL, United Kingdom.
authors.forename: Christine L
authors.initials: CL
authors.lastname: Schofield
authors.affiliation: From the Department of Cardiovascular Sciences and NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, University of Leicester, Leicester, LE3 9QP and.
authors.forename: Nilesh J
authors.initials: NJ
authors.lastname: Samani
authors.affiliation: From the Department of Cardiovascular Sciences and NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, University of Leicester, Leicester, LE3 9QP and tw126@le.ac.uk.
authors.forename: Tom R
authors.initials: TR
authors.lastname: Webb
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D003324:Coronary Artery Disease / Q000235:genetics / Q000378:metabolism; D056744:Cyclin B1 / Q000235:genetics / Q000378:metabolism; D056426:Genetic Loci; D006801:Humans; D015810:Linkage Disequilibrium; D008938:Mitosis / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D011110:Polymorphism, Genetic; D016335:Zinc Fingers / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C534699:CCNB1 protein, human; D018797:Cell Cycle Proteins; D056744:Cyclin B1; D009687:Nuclear Proteins; C477288:ZC3HC1 protein, human
keywords: CAD; cell cycle; coronary artery disease; cyclin; cyclin-dependent kinase (CDK); genome editing; phosphorylation; protein structure; rAAV; single-nucleotide polymorphism (SNP)