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.
Highlights
Hypertension (HTN) or high blood pressure (BP) is common in populations worldwide and a major risk factor for cardiovascular disease (CVD) and all-cause mortality [1]
Using admixture mapping analysis of the Family Blood Pressure Program data, we recently identified that the VNN1 gene, in particular SNP rs2272996 (N131S), was associated with BP in both African Americans and Mexican Americans
We first replicated the association of rs2272996 with BP in the Continental Origins and Genetic Epidemiology Network (COGENT), which included nearly 30,000 African Americans
Summary
Hypertension (HTN) or high blood pressure (BP) is common in populations worldwide and a major risk factor for cardiovascular disease (CVD) and all-cause mortality [1]. It is observed across ethnically diverse populations, the prevalence of HTN in the US varies from 27% in persons of European ancestry to 40% among those of African ancestry [2]. Increased rates of HTN among African Americans are the main factor contributing to their greater risk of CVD and end-stage renal disease compared to US whites [8,9]. Given the widespread occurrence of this condition, and our as yet limited ability to reduce the disease burden, identifying the genetic variants of BP phenotypes could elucidate the underlying biology of high BP and reduce the CVD prevalence
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