Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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


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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

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.


  1. 1

    Chobanian, A.V. et al. The seventh report of the joint national committee on prevention, detection, evaluation, and treatment of high blood pressure: the JNC 7 report. J. Am. Med. Assoc. 289, 2560–2572 (2003).

    CAS  Article  Google Scholar 

  2. 2

    Lewington, S. et al. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet 360, 1903–1913 (2002).

    Article  Google Scholar 

  3. 3

    Vasan, R.S. et al. Impact of high-normal blood pressure on the risk of cardiovascular disease. N. Engl. J. Med. 345, 1291–1297 (2001).

    CAS  Article  Google Scholar 

  4. 4

    Levy, D. et al. Evidence for a gene influencing blood pressure on chromosome 17. Genome scan linkage results for longitudinal blood pressure phenotypes in subjects from the framingham heart study. Hypertension 36, 477–483 (2000).

    CAS  Article  Google Scholar 

  5. 5

    Lifton, R.P., Gharavi, A.G. & Geller, D.S. Molecular mechanisms of human hypertension. Cell 104, 545–556 (2001).

    CAS  Article  Google Scholar 

  6. 6

    Ji, W. et al. Rare independent mutations in renal salt handling genes contribute to blood pressure variation. Nat. Genet. 40, 592–599 (2008).

    CAS  Article  Google Scholar 

  7. 7

    de Bold, A.J., Borenstein, H.B., Veress, A.T. & Sonnenberg, H. A rapid and potent natriuretic response to intravenous injection of atrial myocardial extract in rats. Life Sci. 28, 89–94 (1981).

    CAS  Article  Google Scholar 

  8. 8

    John, S.W. et al. Genetic decreases in atrial natriuretic peptide and salt-sensitive hypertension. Science 267, 679–681 (1995).

    CAS  Article  Google Scholar 

  9. 9

    Schillinger, K.J. et al. Regulatable atrial natriuretic peptide gene therapy for hypertension. Proc. Natl. Acad. Sci. USA 102, 13789–13794 (2005).

    CAS  Article  Google Scholar 

  10. 10

    Numata, Y. et al. Immunoradiometric assay for the N-terminal fragment of proatrial natriuretic peptide in human plasma. Clin. Chem. 44, 1008–1013 (1998).

    CAS  PubMed  Google Scholar 

  11. 11

    Levy, D. et al. Framingham Heart Study 100K project: genome-wide associations for blood pressure and arterial stiffness. BMC Med. Genet. 8 (Suppl. 1), S3 (2007).

    Article  Google Scholar 

  12. 12

    The Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447, 661–678 (2007).

  13. 13

    Kato, N. et al. High-density association study and nomination of susceptibility genes for hypertension in the Japanese National Project. Hum. Mol. Genet. 17, 617–627 (2008).

    CAS  Article  Google Scholar 

  14. 14

    Wang, T.J. et al. Impact of age and sex on plasma natriuretic peptide levels in healthy adults. Am. J. Cardiol. 90, 254–258 (2002).

    CAS  Article  Google Scholar 

  15. 15

    Davey Smith, G. & Ebrahim, S. 'Mendelian randomization': can genetic epidemiology contribute to understanding environmental determinants of disease? Int. J. Epidemiol. 32, 1–22 (2003).

    Article  Google Scholar 

  16. 16

    Conen, D. et al. Natriuretic peptide precursor a gene polymorphisms and risk of blood pressure progression and incident hypertension. Hypertension 50, 1114–1119 (2007).

    CAS  Article  Google Scholar 

  17. 17

    Lynch, A.I. et al. Pharmacogenetic association of the NPPA T2238C genetic variant with cardiovascular disease outcomes in patients with hypertension. J. Am. Med. Assoc. 299, 296–307 (2008).

    CAS  Article  Google Scholar 

  18. 18

    Dries, D.L. et al. Corin gene minor allele defined by 2 missense mutations is common in blacks and associated with high blood pressure and hypertension. Circulation 112, 2403–2410 (2005).

    CAS  Article  Google Scholar 

  19. 19

    Kannel, W.B., Feinleib, M. & McNamara, P.M. An investigation of coronary heart disease in families: the Framingham Offspring Study. Am. J. Epidemiol. 110, 281–290 (1979).

    CAS  Article  Google Scholar 

  20. 20

    Wang, T.J. et al. Heritability and genetic linkage of plasma natriuretic peptide levels. Circulation 108, 13–16 (2003).

    Article  Google Scholar 

  21. 21

    Berglund, G., Elmstahl, S., Janzon, L. & Larsson, S.A. The Malmo Diet and Cancer Study. Design and feasibility. J. Intern. Med. 233, 45–51 (1993).

    CAS  Article  Google Scholar 

  22. 22

    Vartiainen, E. et al. Cardiovascular risk factor changes in Finland, 1972–1997. Int. J. Epidemiol. 29, 49–56 (2000).

    CAS  Article  Google Scholar 

  23. 23

    Berglund, G. et al. Long-term outcome of the Malmo preventive project: mortality and cardiovascular morbidity. J. Intern. Med. 247, 19–29 (2000).

    CAS  Article  Google Scholar 

  24. 24

    Cupples, L.A. & d'Agostino, R. Jr. Some Risk Factors Related to the Annual Incidence of Cardiovascular Disease and Death Using Pooled Repeated Biennial Measurements: Framingham Study: 30-year Follow-up (Government Printing Office, Washington, DC, 1987).

    Google Scholar 

  25. 25

    Nilsson, P.M., Engstrom, G. & Hedblad, B. The metabolic syndrome and incidence of cardiovascular disease in non-diabetic subjects–a population-based study comparing three different definitions. Diabet. Med. 24, 464–472 (2007).

    CAS  Article  Google Scholar 

  26. 26

    Kastarinen, M.J. et al. Trends in blood pressure levels and control of hypertension in Finland from 1982 to 1997. J. Hypertens. 16, 1379–1387 (1998).

    CAS  Article  Google Scholar 

  27. 27

    von Wowern, F. et al. Genetic variance of SGK-1 is associated with blood pressure, blood pressure change over time and strength of the insulin-diastolic blood pressure relationship. Kidney Int. 68, 2164–2172 (2005).

    CAS  Article  Google Scholar 

  28. 28

    Wang, T.J. et al. Impact of obesity on plasma natriuretic peptide levels. Circulation 109, 594–600 (2004).

    CAS  Article  Google Scholar 

  29. 29

    Wang, T.J. et al. Association of plasma natriuretic peptide levels with metabolic risk factors in ambulatory individuals. Circulation 115, 1345–1353 (2007).

    CAS  Article  Google Scholar 

  30. 30

    Skol, A.D., Scott, L.J., Abecasis, G.R. & Boehnke, M. Joint analysis is more efficient than replication-based analysis for two-stage genome-wide association studies. Nat. Genet. 38, 209–213 (2006).

    CAS  Article  Google Scholar 

Download references


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




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.

Ethics declarations

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.

Supplementary information

Supplementary Text and Figures

Supplementary Note, Supplementary Methods, Supplementary Tables 1–7 and Supplementary Figure 1 (PDF 278 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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).

Download citation

Further reading


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing