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)-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. © 2014 wang et al.