The association of the vanin-1 N131S variant with blood pressure is mediated by endoplasmic reticulum-associated degradation and loss of function Journal Article


Authors: Wang, Y. J.; Tayo, B. O.; Bandyopadhyay, A.; Wang, H; Feng, T.; Franceschini, N; Tang, H; Gao, J; Sung, Y. J.; COGENT BP Consortium; Elston, R. C.; Williams, S. M.; Cooper, R. S.; Mu, T. W.; Zhu, X
Article 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.
Journal Title: PLoS genetics
Volume: 10
Issue: 9
ISSN: 1553-7404; 1553-7390
Publisher: Unknown  
Journal Place: United States
Date Published: 2014
Start Page: e1004641
Language: eng
DOI/URL:
Notes: GR: HG003054/HG/NHGRI NIH HHS/United States; GR: HL007567-29/HL/NHLBI NIH HHS/United States; GR: HL053353/HL/NHLBI NIH HHS/United States; GR: HL086718/HL/NHLBI NIH HHS/United States; JID: 101239074; OID: NLM: PMC4169380; 2014/09 [ecollection]; 2014/06/12 [received]; 2014/07/30 [accepted]; 2014/09/18 [epublish]; epublish