The Association of the Vanin-1 N131S Variant with Blood Pressure Is Mediated by Endoplasmic Reticulum-Associated Degradation and Loss of Function


Hypertension (HTN) or high blood pressure (BP) is common worldwide and a major risk factor for cardiovascular disease and all-cause mortality. Identification of genetic variants of consequence for HTN serves as the molecular basis for its treatment. Using admixture mapping analysis of the Family Blood Pressure Program data, we recently identified that the VNN1 gene (encoding the protein vanin-1), in particular SNP rs2272996 (N131S), was associated with BP in both African Americans and Mexican Americans. Vanin-1 was reported to act as an oxidative stress sensor using its pantetheinase enzyme activity. Because a linkage between oxidative stress and HTN has been hypothesized for many years, vanin-1's pantetheinase activity offers a physiologic rationale for BP regulation. Here, 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. We further demonstrated that the N131S mutation in vanin-1 leads to its rapid degradation in cells, resulting in loss of function on the plasma membrane. The loss of function of vanin-1 is associated with reduced BP. Therefore, our results indicate that vanin-1 is a new candidate to be manipulated to ameliorate HTN.


Vyšlo v časopise: The Association of the Vanin-1 N131S Variant with Blood Pressure Is Mediated by Endoplasmic Reticulum-Associated Degradation and Loss of Function. PLoS Genet 10(9): e32767. doi:10.1371/journal.pgen.1004641
Kategorie: Research Article
prolekare.web.journal.doi_sk: 10.1371/journal.pgen.1004641

Souhrn

Hypertension (HTN) or high blood pressure (BP) is common worldwide and a major risk factor for cardiovascular disease and all-cause mortality. Identification of genetic variants of consequence for HTN serves as the molecular basis for its treatment. Using admixture mapping analysis of the Family Blood Pressure Program data, we recently identified that the VNN1 gene (encoding the protein vanin-1), in particular SNP rs2272996 (N131S), was associated with BP in both African Americans and Mexican Americans. Vanin-1 was reported to act as an oxidative stress sensor using its pantetheinase enzyme activity. Because a linkage between oxidative stress and HTN has been hypothesized for many years, vanin-1's pantetheinase activity offers a physiologic rationale for BP regulation. Here, 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. We further demonstrated that the N131S mutation in vanin-1 leads to its rapid degradation in cells, resulting in loss of function on the plasma membrane. The loss of function of vanin-1 is associated with reduced BP. Therefore, our results indicate that vanin-1 is a new candidate to be manipulated to ameliorate HTN.


Zdroje

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