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VAV3 rs7528153 and VAV3-AS1 rs1185222 polymorphisms are associated with an increased risk of developing hypertension

  • Author Footnotes
    1 José Pablo Miramontes-González and Ricardo Usategui-Martín contributed equally to this work.
    José Pablo Miramontes-González
    Correspondence
    Corresponding authors.
    Footnotes
    1 José Pablo Miramontes-González and Ricardo Usategui-Martín contributed equally to this work.
    Affiliations
    Department of Internal Medicine, Hospital Universitario de Salamanca, Valladolid, Spain

    Molecular Medicine Unit, Department of Medicine, Universidad de Salamanca, Salamanca, Spain

    Institute of Biomedical Research of Salamanca (IBSAL), Hospital Universitario de Salamanca–USAL–CSIC and Institute of Molecular and Cellular Biology of Cancer (IBMCC), Universidad de Salamanca–CSIC, Salamanca, Spain

    Department of Medicine. University of California at San Diego, La Jolla, California-UCSD, United States
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  • Author Footnotes
    1 José Pablo Miramontes-González and Ricardo Usategui-Martín contributed equally to this work.
    Ricardo Usategui-Martín
    Footnotes
    1 José Pablo Miramontes-González and Ricardo Usategui-Martín contributed equally to this work.
    Affiliations
    Molecular Medicine Unit, Department of Medicine, Universidad de Salamanca, Salamanca, Spain

    Institute of Biomedical Research of Salamanca (IBSAL), Hospital Universitario de Salamanca–USAL–CSIC and Institute of Molecular and Cellular Biology of Cancer (IBMCC), Universidad de Salamanca–CSIC, Salamanca, Spain
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  • Javier Martín-Vallejo
    Affiliations
    Institute of Biomedical Research of Salamanca (IBSAL), Hospital Universitario de Salamanca–USAL–CSIC and Institute of Molecular and Cellular Biology of Cancer (IBMCC), Universidad de Salamanca–CSIC, Salamanca, Spain

    Department of Statistics, Universidad de Salamanca, Salamanca, Spain
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  • Michael Ziegler
    Affiliations
    Department of Medicine. University of California at San Diego, La Jolla, California-UCSD, United States
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  • Leopoldo López de Isla
    Affiliations
    Cardiac Image Unit. Hospital Clínico San Carlos. Madrid. Facultad de Medicina. Universidad Complutense de Madrid, Madrid, Spain
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  • Daniel O`Connor
    Affiliations
    Department of Medicine. University of California at San Diego, La Jolla, California-UCSD, United States
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  • Rogelio González-Sarmiento
    Correspondence
    Corresponding authors.
    Affiliations
    Molecular Medicine Unit, Department of Medicine, Universidad de Salamanca, Salamanca, Spain

    Institute of Biomedical Research of Salamanca (IBSAL), Hospital Universitario de Salamanca–USAL–CSIC and Institute of Molecular and Cellular Biology of Cancer (IBMCC), Universidad de Salamanca–CSIC, Salamanca, Spain
    Search for articles by this author
  • Author Footnotes
    1 José Pablo Miramontes-González and Ricardo Usategui-Martín contributed equally to this work.

      Highlights

      • Numerous vasoconstrictors stimulate RhoA in local populations of vascular SMCs.
      • The VAV3 gene encodes for VAV3 protein, a rho GEF factor.
      • VAV3-AS1 gene, a lncRNA, regulates VAV3 expression.
      • T allele of the VAV3 rs7528153 polymorphisms is associated with an increased risk of elevated BP values.
      • G allele of the VAV3-AS1 rs11185222 polymorphisms is associated with an increased risk of elevated BP values.

      Abstract

      The aetiology of essential hypertension is complex and involves both environmental and genetic factors. Approximately 30% of the inter-individual variability in blood pressure is genetically determined. It has been shown that numerous vasoconstrictors stimulate RhoA in local populations of vascular SMCs that, in turn, promote localised constriction of arterial blood vessels and elevations in blood pressure. The VAV3 gene encodes for VAV3 protein, a Rho GEF factor. VAV3-AS1 gene, a lncRNA, may regulate VAV3 expression. We performed an observational prospective case-control study, including patients attending in the Vascular Risk Unit from the University Hospital Salamanca for 6 months. A replication study was performed with data from The Kaiser Permanent database of the University of California. The results suggest that T allele of the VAV3 rs7528153 and G allele of the VAV3-AS1 rs11185222 polymorphisms are associated with an increased risk of developing hypertension. We hypothesise that these polymorphisms could modify blood pressure, likely through a modification in the Rho/Rac pathway. Our results suggest that those polymorphisms could be useful genetic markers of susceptibility to suffering hypertension.

      Keywords

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      References

        • Lim S.S.
        • Vos T.
        • Flaxman A.D.
        • Danaei G.
        • Shibuya K.
        • Adair-Rohani H.
        • et al.
        A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990-2010: a systematic analysis for the Global Burden of Disease Study.
        Lancet. 2010; 380 (2012): 2224-2260
        • Kearney P.M.
        • Whelton M.
        • Reynolds K.
        • Muntner P.
        • Whelton P.K.
        • He J
        Global burden of hypertension: analysis of worldwide data.
        Lancet. 2005; 365: 217-223
        • Menéndez E.
        • Delgado E.
        • Fernández-Vega F.
        • Prieto M.A.
        • Bordiú E.
        • Calle A.
        • et al.
        Prevalence, diagnosis, treatment, and control of hypertension in Spain. Results of the [email protected] study.
        Rev Esp Cardiol (Engl ed). 2016; 69: 572-578
        • Lifton R.P.
        • Gharavi A.G.
        • Geller D.S
        Molecular mechanisms of human hypertension.
        Cell. 2001; 104: 545-556
        • Sauzeau V.
        • Sevilla M.A.
        • Rivas-Elena J.V.
        • de Álava E.
        • Montero M.J.
        • López-Novoa J.M.
        • et al.
        VAV3 proto-oncogene deficiency leads to sympathetic hyperactivity and cardiovascular dysfunction.
        Nat Med. 2006; 12: 841-845
        • Perretta-Tejedor N.
        • Fernández-Mateos J.
        • García-Ortiz L.
        • Gómez-Marcos M.A.
        • Recio-Rodríguez J.I.
        • Agudo-Conde C.
        • et al.
        Association of VAV2 and VAV3 polymorphisms with cardiovascular risk factors.
        Sci Rep. 2017; ([cited 2017 Nov 13];7. Available from)
        • Gomez-Marcos M.A.
        • Gonzalez-Sarmiento R.
        • Recio-Rodríguez J.I.
        • Agudo-Conde C.
        • Gamella-Pozuelo L.
        • Perretta-Tejedor N.
        • et al.
        Relationship between target organ damage and blood pressure, retinal vessel calibre, oxidative stress and polymorphisms in VAV-2 and VAV-3 genes in patients with hypertension: a case-control study protocol (LOD-Hipertension).
        BMJ Open. 2014; 4e005112
        • Scheuermann J.C.
        • Boyer L.A.
        Getting to the heart of the matter: long non-coding RNAs in cardiac development and disease.
        EMBO J. 2013; 32: 1805-1816
        • Dechamethakun S.
        • Muramatsu M.
        Long noncoding RNA variations in cardiometabolic diseases.
        J Hum Genet. 2017; 62: 97-104https://doi.org/10.1038/jhg.2016.70
        • Lorenzen J.M.
        • Thum T.
        Long noncoding RNAs in kidney and cardiovascular diseases.
        Nat Rev Nephrol. 2016; 12: 360-373
        • Busch A.
        • Eken S.M.
        • Maegdefessel L
        Prospective and therapeutic screening value of non-coding RNA as biomarkers in cardiovascular disease.
        Ann Transl Med. 2016; 4: 236
        • Ishii N.
        • Ozaki K.
        • Sato H.
        • Mizuno H.
        • Saito S.
        • Takahashi A.
        • et al.
        Identification of a novel non-coding RNA, MIAT, that confers risk of myocardial infarction.
        J Hum Genet. 2006; 51: 1087-1099
        • Kumarswamy R.
        • Bauters C.
        • Volkmann I.
        • Maury F.
        • Fetisch J.
        • Holzmann A.
        • et al.
        Circulating long noncoding RNA, LIPCAR, predicts survival in patients with heart failure.
        Circ Res. 2014; 114: 1569-1575
        • Vausort M.
        • Wagner D.R.
        • Devaux Y
        Long noncoding RNAs in patients with acute myocardial infarctionnovelty and significance.
        Circ Res. 2014 12; 115: 668-677
        • Burd C.E.
        • Jeck W.R.
        • Liu Y.
        • Sanoff H.K.
        • Wang Z.
        • Sharpless N.E
        Expression of linear and novel circular forms of an INK4/ARF-associated non-coding RNA correlates with atherosclerosis risk.
        PLoS Genet. 2010; 6e1001233
        • Dechamethakun S.
        • Ikeda S.
        • Arai T.
        • Sato N.
        • Sawabe M.
        • Muramatsu M
        Associations between the CDKN2A/B, ADTRP and PDGFD polymorphisms and the development of coronary atherosclerosis in Japanese patients.
        J Atheroscler Thromb. 2014; 21: 680-690
        • Zhao Y.
        • Feng G.
        • Wang Y.
        • Yue Y.
        • Zhao W
        Regulation of apoptosis by long non-coding RNA HIF1A-AS1 in VSMCs: implications for TAA pathogenesis.
        Int J Clin Exp Pathol. 2014; 7: 7643-7652
        • Yang Y.
        • Cai Y.
        • Wu G.
        • Chen X.
        • Liu Y.
        • Wang X.
        • et al.
        Plasma long non-coding RNA, CoroMarker, a novel biomarker for diagnosis of coronary artery disease.
        Clin Sci. 2015; 129: 675-685
        • Waalen J.
        • Felitti V.
        • Gelbart T.
        • Ho N.J.
        • Beutler E
        Prevalence of coronary heart disease associated with HFE mutations in adults attending a health appraisal center.
        Am J Med. 2002; 113: 472-479
        • Schleinitz D.
        • Distefano J.K.
        • Kovacs P
        Targeted SNP genotyping using the TaqMan® assay.
        Methods Mol Biol. 2011; 700: 77-87
        • Breiman L.
        • Friedman J.
        • Olshen R.
        • Stone C
        Classification and regression trees.
        1st editor. Wadsworth International Group, Belmont, California1984
        • Bustelo X.R.
        Regulatory and signaling properties of the Vav family.
        Mol Cell Biol. 2000; 20: 1461-1477
        • Hornstein I.
        • Alcover A.
        • Katzav S
        Vav proteins, masters of the world of cytoskeleton organization.
        Cell Signal. 2004; 16: 1-11
        • Jaffe A.B.
        • Hall A.
        Rho GTPases: biochemistry and biology.
        Ann Rev Cell Dev Biol. 2005; 21: 247-269
        • Budzyn K.
        • Marley P.D.
        • Sobey C.G
        Targeting Rho and Rho-kinase in the treatment of cardiovascular disease.
        Trends Pharmacol Sci. 2006; 27: 97-104
        • Lee D.L.
        • Webb R.C.
        • Jin L
        Hypertension and RhoA/Rho-kinase signaling in the vasculature: highlights from the recent literature.
        Hypertension. 2004; 44: 796-799