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

• Published in: PLoS genetics 2014-09, Vol.10 (9), p.e1004641-e1004641
• Main Authors: Wang, Ya-Juan, Tayo, Bamidele O, Bandyopadhyay, Anupam, Wang, Heming, Feng, Tao, Franceschini, Nora, Tang, Hua, Gao, Jianmin, Sung, Yun Ju, Elston, Robert C, Williams, Scott M, Cooper, Richard S, Mu, Ting-Wei, Zhu, Xiaofeng
• Format: Article
• Language: English
• Subjects: African Americans; Alleles; Amidohydrolases - blood; Amidohydrolases - genetics; Amidohydrolases - metabolism; Analysis; Antihypertensive Agents - pharmacology; Antihypertensive Agents - therapeutic use; Biology and Life Sciences; Blood pressure; Blood Pressure - drug effects; Blood Pressure - genetics; Cardiovascular disease; Chromosomes; Cohort Studies; Endoplasmic reticulum; Endoplasmic Reticulum-Associated Degradation - genetics; Enzyme Activation; Epidemiology; Genealogy; Genetic aspects; Genetic Association Studies; Genetic engineering; Genetic Variation; Genotype; GPI-Linked Proteins - blood; GPI-Linked Proteins - genetics; GPI-Linked Proteins - metabolism; Health aspects; Heart; Hispanic Americans; Humans; Hypertension; Hypertension - drug therapy; Hypertension - epidemiology; Hypertension - genetics; Medicine and Health Sciences; Mortality; Mutation; Oxidative stress; Phenotype; Physiological aspects; Plasma; Polymorphism, Single Nucleotide; Proteins; Research and Analysis Methods; Risk factors; Single nucleotide polymorphisms
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1004641

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.