The association of the vanin-1 N131S variant with blood pressure is mediated by endoplasmic reticulum-associated degradation and loss of function.
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)-an...
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2014-09-01
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doaj-6279526100634962b83c7a9c242dbdcc2020-11-24T21:32:48ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042014-09-01109e100464110.1371/journal.pgen.1004641The association of the vanin-1 N131S variant with blood pressure is mediated by endoplasmic reticulum-associated degradation and loss of function.Ya-Juan WangBamidele O TayoAnupam BandyopadhyayHeming WangTao FengNora FranceschiniHua TangJianmin GaoYun Ju SungCOGENT BP consortiumRobert C ElstonScott M WilliamsRichard S CooperTing-Wei MuXiaofeng ZhuHigh 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.http://europepmc.org/articles/PMC4169380?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Ya-Juan Wang Bamidele O Tayo Anupam Bandyopadhyay Heming Wang Tao Feng Nora Franceschini Hua Tang Jianmin Gao Yun Ju Sung COGENT BP consortium Robert C Elston Scott M Williams Richard S Cooper Ting-Wei Mu Xiaofeng Zhu |
spellingShingle |
Ya-Juan Wang Bamidele O Tayo Anupam Bandyopadhyay Heming Wang Tao Feng Nora Franceschini Hua Tang Jianmin Gao Yun Ju Sung COGENT BP consortium Robert C Elston Scott M Williams Richard S Cooper Ting-Wei Mu Xiaofeng Zhu The association of the vanin-1 N131S variant with blood pressure is mediated by endoplasmic reticulum-associated degradation and loss of function. PLoS Genetics |
author_facet |
Ya-Juan Wang Bamidele O Tayo Anupam Bandyopadhyay Heming Wang Tao Feng Nora Franceschini Hua Tang Jianmin Gao Yun Ju Sung COGENT BP consortium Robert C Elston Scott M Williams Richard S Cooper Ting-Wei Mu Xiaofeng Zhu |
author_sort |
Ya-Juan Wang |
title |
The association of the vanin-1 N131S variant with blood pressure is mediated by endoplasmic reticulum-associated degradation and loss of function. |
title_short |
The association of the vanin-1 N131S variant with blood pressure is mediated by endoplasmic reticulum-associated degradation and loss of function. |
title_full |
The association of the vanin-1 N131S variant with blood pressure is mediated by endoplasmic reticulum-associated degradation and loss of function. |
title_fullStr |
The association of the vanin-1 N131S variant with blood pressure is mediated by endoplasmic reticulum-associated degradation and loss of function. |
title_full_unstemmed |
The association of the vanin-1 N131S variant with blood pressure is mediated by endoplasmic reticulum-associated degradation and loss of function. |
title_sort |
association of the vanin-1 n131s variant with blood pressure is mediated by endoplasmic reticulum-associated degradation and loss of function. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS Genetics |
issn |
1553-7390 1553-7404 |
publishDate |
2014-09-01 |
description |
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. |
url |
http://europepmc.org/articles/PMC4169380?pdf=render |
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