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Abstract

Blood pressure is a major cardiovascular disease risk factor. To date, few variants associated with interindividual blood pressure variation have been identified and replicated. Here we report results of a genome-wide association study of systolic (SBP) and diastolic (DBP) blood pressure and hypertension in the CHARGE Consortium (n = 29,136), identifying 13 SNPs for SBP, 20 for DBP and 10 for hypertension at P < 4 × 10−7. The top ten loci for SBP and DBP were incorporated into a risk score; mean BP and prevalence of hypertension increased in relation to the number of risk alleles carried. When ten CHARGE SNPs for each trait were included in a joint meta-analysis with the Global BPgen Consortium (n = 34,433), four CHARGE loci attained genome-wide significance (P < 5 × 10−8) for SBP (ATP2B1, CYP17A1, PLEKHA7, SH2B3), six for DBP (ATP2B1, CACNB2, CSK-ULK3, SH2B3, TBX3-TBX5, ULK4) and one for hypertension (ATP2B1). Identifying genes associated with blood pressure advances our understanding of blood pressure regulation and highlights potential drug targets for the prevention or treatment of hypertension.

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Change history

  • 17 May 2009

    NOTE: In the version of this article initially published online, the respective exponents of the P values for association of rs8096897 and rs880315 with SBP were transposed. The error has been corrected for the print, PDF and HTML versions of this article.

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Acknowledgements

The authors acknowledge the essential role of the Cohorts for Heart and Aging Research in Genome Epidemiology (CHARGE) Consortium in development and support of this manuscript. CHARGE members include The Netherland's Rotterdam Study (RS), Framingham Heart Study (FHS), Cardiovascular Health Study (CHS), the NHLBI's Atherosclerosis Risk in Communities (ARIC) Study, and the NIA's Iceland Age, Gene/Environment Susceptibility (AGES) Study.

AGES: The Age, Gene/Environment Susceptibility Reykjavik Study is funded by NIH contract N01-AG-12100, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association) and the Althingi (the Icelandic Parliament).

ARIC: The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021 and N01-HC-55022, and grants R01HL087641, R01HL59367, R37HL051021, R01HL086694 and U10HL054512; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. A.K. is supported by a German Research Foundation Fellowship.

CHS: The Cardiovascular Health Study was supported by contract numbers N01-HC-85079 through N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, grant numbers U01 HL080295 and R01 HL087652 from the National Heart, Lung, and Blood Institute. A full list of principal CHS investigators and institutions can be found at http://www.chs-nhlbi.org/pi.htm.

FHS: The National Heart, Lung, and Blood Institute's Framingham Heart Study is a joint project of the National Institutes of Health and Boston University School of Medicine and was supported by the National Heart, Lung, and Blood Institute's Framingham Heart Study (contract No. N01-HC-25195) and its contract with Affymetrix, Inc. for genotyping services (contract No. N02-HL-6-4278). Analyses reflect the efforts and resource development from the Framingham Heart Study investigators participating in the SNP Health Association Resource (SHARe) project. A portion of this research was conducted using the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center.

RS: The Rotterdam Study is supported by the Erasmus Medical Center and Erasmus University Rotterdam; the Netherlands Organization for Scientific Research; the Netherlands Organization for Health Research and Development (ZonMw); the Research Institute for Diseases in the Elderly (RIDE); The Netherlands Heart Foundation; the Ministry of Education, Culture and Science; the Ministry of Health Welfare and Sports; the European Commission (DG XII); the Municipality of Rotterdam and the ErasmusMC translational research fund (2004-44). Support for genotyping was provided by the Netherlands Organization for Scientific Research (NWO Groot, 175.010.2005.011, 911.03.012) and Research Institute for Diseases in the Elderly (014.93.015; RIDE2). This study was supported by the Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) project nr. 050-060-810. We thank P. Arp, M. Jhamai, M. Moorhouse, M. Verkerk and S. Bervoets for their help in creating the database and M. Struchalin for his contributions to the imputations of the data. The authors are grateful to the study participants, the staff from the Rotterdam Study and the participating general practioners and pharmacists.

Author information

Author notes

    • Daniel Levy
    • , Georg B Ehret
    • , Kenneth Rice
    • , Germaine C Verwoert
    • , Lenore J Launer
    • , Vilmundur Gudnason
    • , Martin G Larson
    • , Aravinda Chakravarti
    • , Bruce M Psaty
    •  & Cornelia M van Duijn

    These authors contributed equally to this work.

Affiliations

  1. National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts, USA.

    • Daniel Levy
    • , Andrew D Johnson
    • , Ramachandran S Vasan
    • , Shih-Jen Hwang
    • , Christopher J O'Donnell
    • , Emelia J Benjamin
    • , Caroline S Fox
    • , Thomas J Wang
    •  & Martin G Larson
  2. Center for Population Studies, NHLBI, Bethesda, Maryland, USA.

    • Daniel Levy
    • , Andrew D Johnson
    • , Shih-Jen Hwang
    • , Christopher J O'Donnell
    •  & Caroline S Fox
  3. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, Maryland, USA.

    • Georg B Ehret
    • , Dan E Arking
    • , Santhi K Ganesh
    •  & Aravinda Chakravarti
  4. Division of Cardiology, Geneva University Hospital, Geneva, Switzerland.

    • Georg B Ehret
  5. Department of Biostatistics, University of Washington, Seattle, Washington, USA.

    • Kenneth Rice
    •  & Thomas Lumley
  6. Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.

    • Germaine C Verwoert
    • , Abbas Dehghan
    • , Yurii Aulchenko
    • , Fernando Rivadeneira
    • , Francesco U S Mattace-Raso
    • , Albert Hofman
    • , André G Uitterlinden
    • , Jacqueline C M Witteman
    •  & Cornelia M van Duijn
  7. Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.

    • Germaine C Verwoert
    • , Fernando Rivadeneira
    • , Eric J G Sijbrands
    •  & André G Uitterlinden
  8. National Institute of Aging's Laboratory for Epidemiology, Demography, and Biometry, Bethesda, Maryland, USA.

    • Lenore J Launer
    •  & Tamara B Harris
  9. Cardiovascular Health Research Unit and Department of Medicine, University of Washington, Seattle, Washington, USA.

    • Nicole L Glazer
    •  & Joshua Bis
  10. Human Genetics Center, University of Texas Health Science Center, Houston, Texas, USA.

    • Alanna C Morrison
    •  & Eric Boerwinkle
  11. Icelandic Heart Association, Kopavogur, Iceland.

    • Thor Aspelund
    • , Gudny Eiriksdottir
    • , Albert V Smith
    •  & Vilmundur Gudnason
  12. University of Iceland, Reykjavik, Iceland.

    • Thor Aspelund
    •  & Vilmundur Gudnason
  13. Department of Epidemiology and Medicine, Johns Hopkins University, Baltimore, Maryland, USA.

    • Anna Köttgen
    • , Josef Coresh
    •  & Aravinda Chakravarti
  14. Department of Cardiology, Boston University School of Medicine, Boston, Massachusetts, USA.

    • Ramachandran S Vasan
    •  & Emelia J Benjamin
  15. Department of Preventive Medicine, Boston University School of Medicine, Boston, Massachusetts, USA.

    • Ramachandran S Vasan
    •  & Emelia J Benjamin
  16. Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts, USA.

    • Ramachandran S Vasan
    •  & Emelia J Benjamin
  17. Epidemiology Section, Boston University School of Public Health, Boston, Massachusetts, USA.

    • Ramachandran S Vasan
    •  & Emelia J Benjamin
  18. Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.

    • Xiuqing Guo
    • , Kent Taylor
    •  & Jerome I Rotter
  19. Cardiovascular Engineering, Inc., Norwood, Massachusetts, USA.

    • Gary F Mitchell
  20. Department of Internal Medicine, Section of Geriatric Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.

    • Francesco U S Mattace-Raso
  21. Department of Biostatistics, Johns Hopkins University, Baltimore, Maryland, USA.

    • Robert B Scharpf
  22. National Human Genome Research Institute, Vascular Biology Section, Bethesda, Maryland, USA.

    • Santhi K Ganesh
  23. Carolina Cardiovascular Biology Center, Chapel Hill, North Carolina, USA.

    • Gerardo Heiss
  24. Division of Cardiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.

    • Thomas J Wang
  25. Department of Mathematics and Statistics, Boston University, Boston, Massachusetts, USA.

    • Martin G Larson
  26. Departments of Epidemiology, Medicine, and Health Services, University of Washington, Seattle, Washington, USA.

    • Bruce M Psaty
  27. Center for Health Studies, Group Health, Seattle, Washington, USA.

    • Bruce M Psaty
  28. Member of the Netherlands Consortium on Healthy Aging (NCHA), The Netherlands.

    • Germaine C Verwoert
    •  & Jacqueline C M Witteman

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Contributions

ARIC: Study design and phenotype collection, E.B., J.C.; data analysis, G.E., A.K., D.E.A., S.K.G., A.C.M., R.B.S. A.C.; manuscript preparation, A.C.; manuscript revisions, G.E., E.B., A.C.

AGES–Reykjavik Study: Study design, V.G., T.A., A.V.S., G.E., T.B.H. L.J.L.; statistical analysis, V.G., T.A., A.V.S.; manuscript revisions, V.G., T.A., A.V.S., G.E., T.B.H., L.J.L.

CHS: Phenotype collection, B.M.P.; genotyping, J.R., K.T.; data analysis, K.R., N.L.G., J.B., J.I.R., K.T., T.L., B.M.P.; manuscript preparation, B.M.P.; manuscript revisions, K.R., N.L.G., L.B., J.R., K.T., X.G., B.M.P.

Rotterdam: Genotyping, F.R., A.G.U.; phenotype collection and definition, A.H., E.J.G.S., J.C.M.W.; data analysis, G.C.V., A.D., Y.A., C.M.van.D.; manuscript preparation, C.M.van.D.; manuscript revisions, G.C.V., J.C.M.W., C.M.van.D.

FHS: Phenotype collection, C.S.F., E.J.B., C.J.O., T.J.W., D.L., V.G.R.; phenotype data preparation, M.G.L., S.-J.H.; data analysis, M.G.L., S.-J.H., A.D.J.; data interpretation, A.D.J., G.F.M., T.J.W., V.R., C.S.F., D.L.; manuscript preparation, D.L.; manuscript revisions, M.G.L., A.D.J., G.M., E.B., V.R., C.J.O.

Competing interests

Aravinda Chakravarti is a paid consultant with Affymetrix in accordance with the policies of Johns Hopkins. Gary Mitchell is CEO of Cardiovascular Engineering, Inc., which makes devices for measuring arterial waveforms.

Corresponding authors

Correspondence to Daniel Levy or Cornelia M van Duijn.

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https://doi.org/10.1038/ng.384

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