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Association of common variants in NPPA and NPPB with circulating natriuretic peptides and blood pressure

Nature Genetics volume 41, pages 348–353 (2009)Cite this article

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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Figure 1: Linkage disequilibrium map across NPPA-NPPB locus in CEPH reference sample.
Figure 2: N-terminal proANP and BNP concentration in 7,091 individuals from Finrisk97 by genotype and by hypertension status.

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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

  1. Ramachandran S Vasan and Daniel Levy: These authors contributed equally to this work.

  2. Olle Melander and Thomas J Wang: These authors contributed equally to this work.

Authors and Affiliations

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

    Christopher Newton-Cheh & Sekar Kathiresan

  2. Cardiology Division, Cardiovascular Research Center, Massachusetts General Hospital, 185 Cambridge Street, Boston, 02114, Massachusetts, 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, 02142, Massachusetts, 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, 01702, Massachusetts, 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, 02215, Massachusetts, USA

    Martin G Larson

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

    Ramachandran S Vasan & Emelia J Benjamin

  7. National Heart, Lung, and Blood Institute, Bethesda, 20892, Maryland, USA

    Daniel Levy

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

    Kenneth D Bloch

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

    Joachim Struck, Nils G Morgenthaler & Andreas Bergmann

  10. Department of Medicine II, Building 605, Johannes Gutenberg University Mainz, Langenbeckstrasse 1, Mainz, 55131, 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, Malmö, SE 205 02, Sweden

    Peter Nilsson & Olle Melander

  13. Department of Health Promotion and Chronic Disease Prevention, KTL National Public Health Institute, Mannerheimintie 166, Helsinki, FI-00300, 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, Helsinki, FI-00290, Finland

    Leena Peltonen

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

    Joel N Hirschhorn

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

    Joel N Hirschhorn

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  1. Christopher Newton-Cheh
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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.

Corresponding authors

Correspondence to Christopher Newton-Cheh or Thomas J Wang.

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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.

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Newton-Cheh, C., Larson, M., Vasan, R. et al. Association of common variants in NPPA and NPPB with circulating natriuretic peptides and blood pressure. Nat Genet 41, 348–353 (2009). https://doi.org/10.1038/ng.328

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