title: The association of the vanin-1 N131S variant with blood pressure is mediated by endoplasmic reticulum-associated degradation and loss of function.
abstract: High blood pressure (BP) is the most common cardiovascular risk factor worldwide and a major contributor to heart disease and stroke. We previously discovered a BP-associated missense SNP (single nucleotide polymorphism)-rs2272996-in the gene encoding vanin-1, a glycosylphosphatidylinositol (GPI)-anchored membrane pantetheinase. In the present study, we first replicated the association of rs2272996 and BP traits with a total sample size of nearly 30,000 individuals from the Continental Origins and Genetic Epidemiology Network (COGENT) of African Americans (P=0.01). This association was further validated using patient plasma samples; we observed that the N131S mutation is associated with significantly lower plasma vanin-1 protein levels. We observed that the N131S vanin-1 is subjected to rapid endoplasmic reticulum-associated degradation (ERAD) as the underlying mechanism for its reduction. Using HEK293 cells stably expressing vanin-1 variants, we showed that N131S vanin-1 was degraded significantly faster than wild type (WT) vanin-1. Consequently, there were only minimal quantities of variant vanin-1 present on the plasma membrane and greatly reduced pantetheinase activity. Application of MG-132, a proteasome inhibitor, resulted in accumulation of ubiquitinated variant protein. A further experiment demonstrated that atenolol and diltiazem, two current drugs for treating hypertension, reduce the vanin-1 protein level. Our study provides strong biological evidence for the association of the identified SNP with BP and suggests that vanin-1 misfolding and degradation are the underlying molecular mechanism.
authors.affiliation: Department of Epidemiology and Biostatistics, School of Medicine, Case Western Reserve University, Cleveland, Ohio, United States of America; Center for Proteomics and Bioinformatics, School of Medicine, Case Western Reserve University, Cleveland, Ohio, United States of America.
authors.forename: Ya-Juan
authors.initials: YJ
authors.lastname: Wang
authors.affiliation: Department of Public Health Sciences, Loyola University Chicago, Stritch School of Medicine, Maywood, Illinois, United States of America.
authors.forename: Bamidele O
authors.initials: BO
authors.lastname: Tayo
authors.affiliation: Department of Chemistry, Boston College, Chestnut Hill, Massachusetts, United States of America.
authors.forename: Anupam
authors.initials: A
authors.lastname: Bandyopadhyay
authors.affiliation: Department of Epidemiology and Biostatistics, School of Medicine, Case Western Reserve University, Cleveland, Ohio, United States of America.
authors.forename: Heming
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Epidemiology and Biostatistics, School of Medicine, Case Western Reserve University, Cleveland, Ohio, United States of America.
authors.forename: Tao
authors.initials: T
authors.lastname: Feng
authors.affiliation: Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Nora
authors.initials: N
authors.lastname: Franceschini
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, California, United States of America.
authors.forename: Hua
authors.initials: H
authors.lastname: Tang
authors.affiliation: Department of Chemistry, Boston College, Chestnut Hill, Massachusetts, United States of America.
authors.forename: Jianmin
authors.initials: J
authors.lastname: Gao
authors.affiliation: Division of Biostatistics, Washington University School of Medicine, St Louis, Missouri, United States of America.
authors.forename: Yun Ju
authors.initials: YJ
authors.lastname: Sung
authors.affiliation: Department of Epidemiology and Biostatistics, School of Medicine, Case Western Reserve University, Cleveland, Ohio, United States of America.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Elston
authors.affiliation: Department of Genetics, Geisel School of Medicine, Dartmouth College, Hanover, New Hampshire, United States of America.
authors.forename: Scott M
authors.initials: SM
authors.lastname: Williams
authors.affiliation: Department of Public Health Sciences, Loyola University Chicago, Stritch School of Medicine, Maywood, Illinois, United States of America.
authors.forename: Richard S
authors.initials: RS
authors.lastname: Cooper
authors.affiliation: Department of Physiology and Biophysics, School of Medicine, Case Western Reserve University, Cleveland, Ohio, United States of America.
authors.forename: Ting-Wei
authors.initials: TW
authors.lastname: Mu
authors.affiliation: Department of Epidemiology and Biostatistics, School of Medicine, Case Western Reserve University, Cleveland, Ohio, United States of America.
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Zhu
mesh_terms: D000483:Alleles; D000581:Amidohydrolases / Q000097:blood / Q000235:genetics* / Q000378:metabolism*; D000959:Antihypertensive Agents / Q000494:pharmacology / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects / Q000235:genetics*; D015331:Cohort Studies; D060746:Endoplasmic Reticulum-Associated Degradation / Q000235:genetics*; D004789:Enzyme Activation; D058851:GPI-Linked Proteins / Q000097:blood / Q000235:genetics / Q000378:metabolism; D056726:Genetic Association Studies; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D006973:Hypertension / Q000188:drug therapy / Q000453:epidemiology / Q000235:genetics; D009154:Mutation; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide
chemical_list: D000959:Antihypertensive Agents; D058851:GPI-Linked Proteins; D000581:Amidohydrolases; C022314:pantetheinase