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.

Rare independent mutations in renal salt handling genes contribute to blood pressure variation

This article has been updated


The effects of alleles in many genes are believed to contribute to common complex diseases such as hypertension. Whether risk alleles comprise a small number of common variants or many rare independent mutations at trait loci is largely unknown. We screened members of the Framingham Heart Study (FHS) for variation in three genes—SLC12A3 (NCCT), SLC12A1 (NKCC2) and KCNJ1 (ROMK)—causing rare recessive diseases featuring large reductions in blood pressure. Using comparative genomics, genetics and biochemistry, we identified subjects with mutations proven or inferred to be functional. These mutations, all heterozygous and rare, produce clinically significant blood pressure reduction and protect from development of hypertension. Our findings implicate many rare alleles that alter renal salt handling in blood pressure variation in the general population, and identify alleles with health benefit that are nonetheless under purifying selection. These findings have implications for the genetic architecture of hypertension and other common complex traits.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type



Prices may be subject to local taxes which are calculated during checkout

Figure 1: Proven and inferred mutations in SLC12A3, SLC12A1 and KCNJ1 in the Framingham Heart Study offspring cohort.
Figure 2: Heterozygous mutations in SLC12A3, SLC12A1 and KCNJ1 lower blood pressure.
Figure 3: Correlation of blood pressures among sibling pairs in Framingham Heart Study.
Figure 4: Reduced prevalence of hypertension among mutation carriers.

Accession codes



Change history

  • 13 April 2008

    In the version of this article initially published online, an equal contribution statement was missing for the first two authors Weizhen Ji and Jia Nee Foo. These authors should be identified as equal contributors to the manuscript. The error has been corrected for all versions of the article


  1. 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).

    Article  CAS  Google Scholar 

  2. Saxena, R. et al. Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science 316, 1331–1336 (2007).

    Article  CAS  Google Scholar 

  3. Scott, L.J. et al. A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants. Science 316, 1341–1345 (2007).

    Article  CAS  Google Scholar 

  4. Zeggini, E. et al. Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes. Science 316, 1336–1341 (2007).

    Article  CAS  Google Scholar 

  5. Helgadottir, A. et al. A common variant on chromosome 9p21 affects the risk of myocardial infarction. Science 316, 1491–1493 (2007).

    Article  CAS  Google Scholar 

  6. McPherson, R. et al. A common allele on chromosome 9 associated with coronary heart disease. Science 316, 1488–1491 (2007).

    Article  CAS  Google Scholar 

  7. Frayling, T.M. et al. A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science 316, 889–894 (2007).

    Article  CAS  Google Scholar 

  8. 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).

  9. Pritchard, J.K. Are rare variants responsible for susceptibility to complex diseases? Am. J. Hum. Genet. 69, 124–137 (2001).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  11. Lifton, R.P. Genetic dissection of human blood pressure variation: common pathways from rare phenotypes. Harvey Lect. 100, 71–101 (2004–2005).

    PubMed  Google Scholar 

  12. Birkenhäger, R. et al. Mutation of BSND causes Bartter syndrome with sensorineural deafness and kidney failure. Nat. Genet. 29, 310–314 (2001).

    Article  Google Scholar 

  13. Simon, D.B. et al. Mutations in the chloride channel gene, CLCNKB, cause Bartter's syndrome type III. Nat. Genet. 17, 171–178 (1997).

    Article  CAS  Google Scholar 

  14. Simon, D.B. et al. Bartter's syndrome, hypokalaemic alkalosis with hypercalciuria, is caused by mutations in the Na-K-2Cl cotransporter NKCC2. Nat. Genet. 13, 183–188 (1996).

    Article  CAS  Google Scholar 

  15. Simon, D.B. et al. Genetic heterogeneity of Bartter's syndrome revealed by mutations in the K+ channel, ROMK. Nat. Genet. 14, 152–156 (1996).

    Article  CAS  Google Scholar 

  16. Simon, D.B. et al. Gitelman's variant of Bartter's syndrome, inherited hypokalaemic alkalosis, is caused by mutations in the thiazide-sensitive Na-Cl cotransporter. Nat. Genet. 12, 24–30 (1996).

    Article  CAS  Google Scholar 

  17. Rudin, A. Bartter's syndrome. A review of 28 patients followed for 10 years. Acta Med. Scand. 224, 165–171 (1988).

    Article  CAS  Google Scholar 

  18. Chanchevalap, S. et al. Involvement of histidine residues in proton sensing of ROMK1 channel. J. Biol. Chem. 275, 7811–7817 (2000).

    Article  CAS  Google Scholar 

  19. Riveira-Munoz, E. et al. Transcriptional and functional analyses of SLC12A3 mutations: new clues for the pathogenesis of Gitelman syndrome. J. Am. Soc. Nephrol. 18, 1271–1283 (2007).

    Article  CAS  Google Scholar 

  20. De Jong, J.C. et al. Functional expression of mutations in the human NaCl cotransporter: evidence for impaired routing mechanisms in Gitelman's syndrome. J. Am. Soc. Nephrol. 13, 1442–1448 (2002).

    Article  CAS  Google Scholar 

  21. Schwalbe, R.A., Bianchi, L., Accili, E.A. & Brown, A.M. Functional consequences of ROMK mutants linked to antenatal Bartter's syndrome and implications for treatment. Hum. Mol. Genet. 7, 975–980 (1998).

    Article  CAS  Google Scholar 

  22. Sabath, E. et al. Pathophysiology of functional mutations of the thiazide-sensitive Na-Cl cotransporter in Gitelman disease. Am. J. Physiol. Renal Physiol. 287, F195–F203 (2004).

    Article  CAS  Google Scholar 

  23. Syrén, M.-L. et al. Identification of fifteen novel mutations in the SLC12A3 gene encoding the Na-Cl co-transporter in Italian patients with Gitelman syndrome. Hum. Mutat. 20, 78 (2002).

    Article  Google Scholar 

  24. Lemmink, H.H. et al. Novel mutations in the thiazide-sensitive NaCl cotransporter gene in patients with Gitelman syndrome with predominant localization to the C-terminal domain. Kidney Int. 54, 720–730 (1998).

    Article  CAS  Google Scholar 

  25. Ramensky, V., Bork, P. & Sunyaev, S. Human non-synonymous SNPs: server and survey. Nucleic Acids Res. 30, 3894–3900 (2002).

    Article  CAS  Google Scholar 

  26. Ng, P.C. & Henikoff, S. SIFT: Predicting amino acid changes that affect protein function. Nucleic Acids Res. 31, 3812–3814 (2003).

    Article  CAS  Google Scholar 

  27. Thomas, P.D. et al. Applications for protein sequence–function evolution data: mRNA/protein expression analysis and coding SNP scoring tools. Nucleic Acids Res. 34, W645–W650 (2006).

    Article  Google Scholar 

  28. Van Gestel, S., Houwing-Duistermaat, J.J., Adolfsson, R., van Duijn, C.M. & Van Broeckhoven, C. Power of selective genotyping in genetic association analyses of quantitative traits. Behav. Genet. 30, 141–146 (2000).

    Article  CAS  Google Scholar 

  29. Cruz, D.N. et al. Mutations in the Na-Cl cotransporter reduce blood pressure in humans. Hypertension 37, 1458–1464 (2001).

    Article  CAS  Google Scholar 

  30. Cooper, D.N., Krawczak, M. & Antonorakis, S.E. The nature and mechanisms of human gene mutation. In The Metabolic and Molecular Bases of Inherited Disease (eds. Scriver, C., Beaudet, A.L., Sly, W.S. & Valle, D.) 259–291 (McGraw-Hill, New York, 1995).

    Google Scholar 

  31. The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). J. Am. Med. Assoc. 288, 2981–2997 (2002).

  32. Kannel, W.B., Wolf, P.A., Verter, J. & McNamara, P.M. Epidemiologic assessment of the role of blood pressure in stroke. The Framingham Study. J. Am. Med. Assoc. 214, 301–310 (1970).

    Article  CAS  Google Scholar 

  33. He, J. & Whelton, P.K. Elevated systolic blood pressure and risk of cardiovascular and renal disease: overview of evidence from observational epidemiologic studies and randomized controlled trials. Am. Heart J. 138, 211–219 (1999).

    Article  CAS  Google Scholar 

  34. Kannel, W.B., Schwartz, M.J. & McNamara, P.M. Blood pressure and risk of coronary heart disease: the Framingham study. Dis. Chest 56, 43–52 (1969).

    Article  CAS  Google Scholar 

  35. Franklin, S.S. et al. Does the relation of blood pressure to coronary heart disease risk change with aging? The Framingham Heart Study. Circulation 103, 1245–1249 (2001).

    Article  CAS  Google Scholar 

  36. Sieck, U.V. & Ohlsson, A. Fetal polyuria and hydramnios associated with Bartter's syndrome. Obstet. Gynecol. 63, 22S–24S (1984).

    CAS  PubMed  Google Scholar 

  37. Ohlsson, A., Sieck, U., Cumming, W., Akhtar, M. & Serenius, F. A variant of Bartter's syndrome. Bartter's syndrome associated with hydramnios, prematurity, hypercalciuria and nephrocalcinosis. Acta Paediatr. Scand. 73, 868–874 (1984).

    Article  CAS  Google Scholar 

  38. Shaer, A.J. Inherited primary renal tubular hypokalemic alkalosis: a review of Gitelman and Bartter syndromes. Am. J. Med. Sci. 322, 316–332 (2001).

    Article  CAS  Google Scholar 

  39. Cohen, J.C. et al. Multiple rare alleles contribute to low plasma levels of HDL cholesterol. Science 305, 869–872 (2004).

    Article  CAS  Google Scholar 

  40. Romeo, S. et al. Population-based resequencing of ANGPTL4 uncovers variations that reduce triglycerides and increase HDL. Nat. Genet. 39, 513–516 (2007).

    Article  CAS  Google Scholar 

  41. Veterans Administration Cooperative Study Group on Antihypertensive Agents. Effects of treatment on morbidity in hypertension. Results in patients with diastolic blood pressures averaging 115 through 129 mm Hg. J. Am. Med. Assoc. 202, 1028–1034 (1967).

  42. Tchernitchko, D., Goossens, M. & Wajcman, H. In silico prediction of the deleterious effect of a mutation: proceed with caution in clinical genetics. Clin. Chem. 50, 1974–1978 (2004).

    Article  CAS  Google Scholar 

  43. Takahashi, N. et al. Posttranscriptional compensation for heterozygous disruption of the kidney-specific NaK2Cl cotransporter gene. J. Am. Soc. Nephrol. 13, 604–610 (2002).

    CAS  PubMed  Google Scholar 

  44. Murphy, K.M. & Berg, K.D. Mutation and single nucleotide polymorphism detection using temperature gradient capillary electrophoresis. Expert Rev. Mol. Diagn. 3, 811–818 (2003).

    Article  CAS  Google Scholar 

  45. Franklin, S.S. et al. Hemodynamic patterns of age-related changes in blood pressure. The Framingham Heart Study. Circulation 96, 308–315 (1997).

    Article  CAS  Google Scholar 

  46. Cruz, D.N. The renal tubular Na-Cl co-transporter (NCCT): a potential genetic link between blood pressure and bone density? Nephrol. Dial. Transplant. 16, 691–694 (2001).

    Article  CAS  Google Scholar 

Download references


We thank C. Nelson-Williams for management of the DNA database. J.N.F. is supported by the Agency for Science, Technology and Research, Singapore. This work was supported in part by a US National Institutes of Health Specialized Center of Research in Hypertension grant (to R.P.L.) and the US National Heart, Lung and Blood Institute's Framingham Heart Study contract NO1-HC-25195.

Author information

Authors and Affiliations


Corresponding author

Correspondence to Richard P Lifton.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–2, Supplementary Tables 1–5, Supplementary Note (PDF 128 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


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