Abstract

We examined the association of common variants at the NPPA-NPPB locus with circulating concentrations of the natriuretic peptides, which have blood pressure–lowering properties. We genotyped SNPs at the NPPA-NPPB locus in 14,743 individuals of European ancestry, and identified associations of plasma atrial natriuretic peptide with rs5068 (P = 8 × 10−70), rs198358 (P = 8 × 10−30) and rs632793 (P = 2 × 10−10), and of plasma B-type natriuretic peptide with rs5068 (P = 3 × 10−12), rs198358 (P = 1 × 10−25) and rs632793 (P = 2 × 10−68). In 29,717 individuals, the alleles of rs5068 and rs198358 that showed association with increased circulating natriuretic peptide concentrations were also found to be associated with lower systolic (P = 2 × 10−6 and 6 × 10−5, respectively) and diastolic blood pressure (P = 1 × 10−6 and 5 × 10−5), as well as reduced odds of hypertension (OR = 0.85, 95% CI = 0.79–0.92, P = 4 × 10−5; OR = 0.90, 95% CI = 0.85–0.95, P = 2 × 10−4, respectively). Common genetic variants at the NPPA-NPPB locus found to be associated with circulating natriuretic peptide concentrations contribute to interindividual variation in blood pressure and hypertension.

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Acknowledgements

The Framingham Heart Study of the National Heart, Lung, and Blood Institute and Boston University School of Medicine was supported by contract no. N01-HC-25195 and the CardioGenomics Program for Genomic Applications (HL66582). The ANP measurements in Finrisk97 were performed by the MORGAM Biomarkers Study funded by the Medical Research Council, UK (G0601463: 80983). C.N.-C. was supported by NIH K23-HL-080025, a Doris Duke Charitable Foundation Clinical Scientist Development Award and a Burroughs Wellcome Fund Career Award for Medical Scientists. T.J.W. was supported by NIH K23-HL-074077, R01-HL-086875, R01-HL-083197, R01-DK-081572 and the American Heart Association. R.S.V. was supported by a research career award from the NIH (K24-HL-04334, R01 HL093328). K.D.B. was supported by R01-HL-070896. L.P. was supported by the Center of Excellence in Complex Disease Genetics of the Academy of Finland, Biocentrum Helsinki Foundation, Finland and the Nordic Center of Excellence. V.S. was supported by the Sigrid Juselius Foundation. P.N. was supported by the Ernhold Lundstrom Foundation and the Swedish Heart and Lung Foundation. O.M. was supported by the Swedish Medical Research Council, the Swedish Heart and Lung Foundation, the Medical Faculty of Lund University, Malmö University Hospital, the Albert Påhlsson Research Foundation, the Crafoord foundation, the Ernhold Lundströms Research Foundation, the Region Skane, the Hulda and Conrad Mossfelt Foundation, the King Gustaf V and Queen Victoria Foundation and the Lennart Hanssons Memorial Fund. The authors also wish to thank the following companies for their support of the natriuretic peptide assays: Shionogi, BRAHMS, and Siemens Healthcare Diagnostics. C.N.-C., O.M. and T.J.W. had full access to the study data and take responsibility for its content. The funding sources had no role in the design, analysis and interpretation, the writing of the manuscript or the decision to submit for publication.

Author information

Author notes

    • Ramachandran S Vasan
    •  & Daniel Levy

    These authors contributed equally to this work.

    • Olle Melander
    •  & Thomas J Wang

    These authors contributed equally to this work.

Affiliations

  1. Center for Human Genetic Research, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts 02114, USA.

    • Christopher Newton-Cheh
    •  & Sekar Kathiresan
  2. Cardiovascular Research Center, Cardiology Division, Massachusetts General Hospital, 185 Cambridge Street, Boston, Massachusetts 02114, USA.

    • Christopher Newton-Cheh
    • , Kenneth D Bloch
    • , Sekar Kathiresan
    •  & Thomas J Wang
  3. Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, Massachusetts, 02142, USA.

    • Christopher Newton-Cheh
    • , Aarti Surti
    • , Candace Guiducci
    • , Sekar Kathiresan
    •  & Joel N Hirschhorn
  4. National Heart, Lung, and Blood Institute's Framingham Heart Study, 73 Mt. Wayte Avenue #2, Framingham, Massachusetts 01702, USA.

    • Christopher Newton-Cheh
    • , Martin G Larson
    • , Ramachandran S Vasan
    • , Daniel Levy
    • , Sekar Kathiresan
    • , Emelia J Benjamin
    • , Xiaoyan Yin
    •  & Thomas J Wang
  5. Department of Mathematics, Boston University School of Medicine, 111 Cummington Street, Boston, Massachusetts, 02215, USA.

    • Martin G Larson
  6. Preventive Medicine and Cardiology Sections, Boston University School of Medicine, 715 Albany Street, Boston, Massachusetts, 02118, USA.

    • Ramachandran S Vasan
    •  & Emelia J Benjamin
  7. National Heart, Lung, and Blood Institute, Bethesda, Maryland 20892, USA.

    • Daniel Levy
  8. Department of Anesthesia, Massachusetts General Hospital, 32 Fruit Street, Boston, Massachuestts 02114, USA.

    • Kenneth D Bloch
  9. Research Department, BRAHMS AG, Neuendorfstrasse 25, D-16761 Hennigsdorf, Germany.

    • Joachim Struck
    • , Nils G Morgenthaler
    •  & Andreas Bergmann
  10. Department of Medicine II, Building 605, Johannes Gutenberg University Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany.

    • Stefan Blankenberg
  11. A UKCRC, Centre of Excellence for Public Health (NI), Mulhouse, Royal Victoria Hospital, Grosvenor Road, Belfast, BT12 6BJ, Northern Ireland, UK.

    • Frank Kee
  12. Clinical Research Center (CRC), Entrance 72, Bldg. 91, Floor 12, Malmö University Hospital, SE 205 02 Malmö, Sweden.

    • Peter Nilsson
    •  & Olle Melander
  13. KTL National Public Health Institute, Department of Health Promotion and Chronic Disease Prevention, Mannerheimintie 166, FI-00300 Helsinki, Finland.

    • Leena Peltonen
    • , Erkki Vartiainen
    •  & Veikko Salomaa
  14. Human Genetics, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA, UK.

    • Leena Peltonen
  15. Institute of Molecular Medicine Finland FIMM, Biomedicum Helsinki, 2U, Tukholmankatu 8, FI-00290 Helsinki, Finland.

    • Leena Peltonen
  16. Program in Genomics and Division in Endocrinology, Children's Hospital, 300 Longwood Avenue, Boston, Massachusetts 02115, USA.

    • Joel N Hirschhorn
  17. Department of Genetics, Harvard Medical School, 300 Longwood Avenue, Boston, Massachusetts 02115, USA.

    • Joel N Hirschhorn

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Contributions

C.N.-C., M.G.L., O.M. and T.J.W. designed the study. C.N.-C., K.D.B., A.S., C.G., J.S., N.G.M., A.B., S.B., F.K. and O.M. generated the data. C.N.-C., M.G.L., X.Y. and O.M. were responsible for the analyses. C.N.-C. and T.J.W. drafted the manuscript. All authors contributed to interpretation of the data and critical review of the manuscript and approved the final version.

Competing interests

Dr. Bloch has sponsored research agreements with and serves on the scientific advisory board of IKARIA/INOTherapeutics. Dr. Bloch reports no conflicts of interest related to this manuscript. Drs. Struck, Morgenthaler, and Bergmann are employees of and Dr. Bergmann holds stock in BRAHMS, AG. BRAHMS, AG holds patent rights on the midregional pro-ANP assay. Dr. Hirschhorn has an equity interest in and receives consulting fees for Correlagen Diagnostics. No other potential conflict of interest relevant to this article was reported.

Corresponding authors

Correspondence to Christopher Newton-Cheh or Thomas J Wang.

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DOI

https://doi.org/10.1038/ng.328

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