Vanin-1 T26I polymorphism, hypertension and cardiovascular events in two large urban-based prospective studies in Swedes

Abstract

Vanin-1 T26I polymorphism, hypertension and cardiovascular events in two large urban-based prospective studies in Swedes.Fava, Cristiano; Montagnana, Martina; Danese, E; Sjögren, Marketa; Almgren, Peter; Engström, Gunnar; Hedblad, Bo; Guidi, G C; Minuz, P; Melander, Olle Link to publication Citation for published version (APA): Fava, C., Montagnana, M., Danese, E., Sjögren, M., Almgren, P., Engström, G., ... Melander, O. (2011). Vanin-1 T26I polymorphism, hypertension and cardiovascular events in two large urban-based prospective studies in Swedes. Nutrition Metabolism and Cardiovascular Diseases. DOI: 10.1016DOI: 10. /j.numecd.2011 General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights.• Users may download and print one copy of any publication from the public portal for the purpose of private study or research.• You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal ABSTRACT Background: Vanin-1 (gene name VNN1) is an enzyme with pantetheinase activity generating the amino-thiol cysteamine which is implicated in the regulation of redox status through its effect on glutathione. We tested the hypothesis that the rs2294757 VNN1 T26I polymorphism could affect blood pressure (BP) levels, hypertension prevalence, and risk of incident cardiovascular events. Methods:The VNN1 T26I polymorphism was genotyped in 5664 participants of the cardiovascular cohort of the "Malmö Diet and Cancer" (MDC-CVA) study and successively in 17874 participants of the "Malmö Preventive project"(MPP). The incidence of cardiovascular events was monitored for an average of nearly 12 years of follow-up in the MDC-CVA and for 25 years in the MPP.Results: Both before and after adjustment for sex, age and BMI in the MDC-CVA the polymorphism had a mild lowering effect on diastolic BP and hypertension, especially in females.However in MPP no effect on BP phenotypes was detectable. Before and after adjustment for major cardiovascular risk factors, the hazard ratio for incident ischemic stroke and coronary events in MDC-CVA was not significantly different in carriers of different genotypes. Conclusions:Our data do not support a major role for the VNN1 T26I variant in determining BP level and incident ischemic events.

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

“…We tested two variants, N131S and T26I, as regards how they influence the total vanin-1 protein levels because other investigators have suggested that T26I may be a candidate variant for BP variation as well [13]. We utilized the human embryonic kidney 293 (HEK293) cells stably expressing these vanin-1 variants because HEK293 cells have high transfection efficiency and physiologically-relevant cell environment for vanin-1 protein expression [23].…”

“…Our group reported that the missense variant rs2272996 (N131S) in VNN1 was associated with BP through admixture mapping, and we conducted a follow-up association analysis in African and Mexican American samples [11], [12]. The association evidence in European-ancestry population is however less convincing [12], [13] In the current study, we performed meta-analysis using the COGENT consortium consisting of 19 studies with a total sample size of nearly 30,000 African ancestry subjects and confirmed the association evidence between rs2272996 and SBP (P = 0.01, Table 1 ). …”

“…By further genotyping the functional variants in the region of interest on chromosome 6, the VNN1 gene, in particular SNP rs2272996 (N131S) was found to account for the association with BP in both African Americans and Mexican Americans, but this association was not observed in European Americans [12]. Fava et al [13] recently argued that rs2294757 (T26I), rather than N131S, was a more likely functional variant accounting for the effect on BP because it is located in a splicing regulation site in VNN1 , but these investigators only found a weak association between T26I and both DBP and HTN in one of the two studies that they carried out. The results of this study are consistent with the lack of evidence for association observed in European Americans in the Dallas Heart Study [12].…”

Investigation of Candidate Genes and Mechanisms Underlying Obesity Associated Type 2 Diabetes Mellitus Using Bioinformatics Analysis and Screening of Small Drug Molecules 

“…Hirai et al [100], Vuori et al [101], Porta et al [102], Nomoto et al [103] and Blindbaek et al [104] demonstrates that VAMP2, CACNB2, SLC19A3, PFKFB3 and MFAP4 are essential for progression of type 1 diabetes, but these genes might be key for advancement of obesity associated type 2 diabetes mellitus. CACNA1A [105], ALK (ALK receptor tyrosine kinase) [106], SLC4A4 [107], STOX1 [108], COL3A1 [109], VNN1 [110], SLC4A7 [111], BDKRB2 [112], DRD1 [113] and LPAR1 [114] have reported signi cantly linked with hypertension, but these genes might be crucial for progression of obesity associated type 2 diabetes mellitus. KCNE2 [115], DLL1 [116], ACVR1C [117], RGS3 [118], MLXIPL (MLX interacting protein like) [119], PAG1 [120], SLC2A10 [121] and GRB14 [122] play important role in type 2 diabetes mellitus progression.…”

Identification of novel prognostic targets in coronary artery disease and related complications using bioinformatics and next generation sequencing data analysis

“…CD274 [175] [190], PDGFC (platelet derived growth factor C) [191], TLR2 [192], PRKAB2 [193], HDAC9 [194], NCOA4 [195], LATS2 [196], DICER1 [197], IL1RN [198], GCH1 [148], EGR1 [199] IQGAP2 [351], GCLC (glutamate-cysteine ligase catalytic subunit) [352], VEGFA (vascular endothelial growth factor A) [353], ITGB1 [354], LDLR (low density lipoprotein receptor) [355], TLR6 [316], SIRT1 [356], FGL2 [357], TET2 [358], PHF2 [328], VEGFB (vascular endothelial growth factor B) [359], SELENOM (selenoprotein M) [360], TRPM4 [361], OLFM2 [362] and ATAD3A [363] are thought to be involved in non-alcoholic fatty liver disease. Altered expression of ATOH8 [364], STAT1 [365], ARG1 [366], TLR4 [367], VNN1 [368], ABCA1 [369], IFIH1 [370], PTGS2 [371], F2RL1 [289], CYP2D6 [372], PDK4 [373], RNF213 [374], JAK2 [375], NOTCH2 [376], PDGFC (platelet derived growth factor C) [377], TLR2 [378], CYP1B1 [379], IL1RN [380], GCH1…”