Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

Common variation in KLKB1 and essential hypertension risk: tagging-SNP haplotype analysis in a case-control study

  • 242 Accesses

  • 13 Citations


The human plasma kallikrein gene (KLKB1) encodes plasma kallikrein, a serine protease that catalyzes the release of kinins and other vasoactive peptides and may be involved in the pathogenesis of hypertension. In this study, we performed a haplotype-based study to assess the effect of common genetic variation in the KLKB1 gene on the risk of essential hypertension. Eight common single nucleotide polymorphisms (SNPs) were selected from the HapMap database and used to determine the pattern of linkage disequilibrium (LD) and haplotype structure within the KLKB1 gene. Four tag SNPs were then identified with over 85% power to predict both common haplotypes and remaining common SNPs, and genotyped in 1,317 cases with essential hypertension and 1,269 healthy controls. Single SNP analyses indicated that SNPs rs2304595 and rs4253325 were significantly associated with hypertension, adjusted for covariates. Compared with the most common Hap2 CAGC, Hap1 AGAC and Hap3 CGAC, which carry the susceptible rs2304595 G allele and rs4253325 A allele, were found to significantly increase the risk of essential hypertension with adjusted odds ratios equal to 1.37 and 1.17, respectively (P < 0.0001 and 0.028). A strongly significant interaction with gene-drinking was also observed. Among drinkers, the adjusted OR for Hap1 relative to Hap2 was increased to 2.50 (95% CI, 2.40 to 2.61; P < 0.0001). This was the first study to perform association analysis of the KLKB1 gene with essential hypertension. Our findings suggested that common genetic variation in the KLKB1 gene might contribute to the risk of hypertension in the northern Han Chinese population.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2
Fig. 3


  1. Ahmadi KR, Weale ME, Xue ZY, Soranzo N, Yarnall DP, Briley JD, Maruyama Y, Kobayashi M, Wood NW, Spurr NK, Burns DK, Roses AD, Saunders AM, Goldstein DB (2005) A single-nucleotide polymorphism tagging set for human drug metabolism and transport. Nat Genet 37:84–89

  2. Beaubien G, Rosinski-Chupin I, Mattei MG, Mbikay M, Chretien M, Seidah NG (1991) Gene structure and chromosomal localization of plasma kallikrein. Biochemistry 30:1628–1635

  3. Carlson CS, Eberle MA, Rieder MJ, Yi Q, Kruglyak L, Nickerson DA (2004) Selecting a maximally informative set of single-nucleotide polymorphisms for association analyses using linkage disequilibrium. Am J Hum Genet 74:106–120

  4. Chapman JM, Cooper JD, Todd JA, Clayton DG (2003) Detecting disease associations due to linkage disequilibrium using haplotype tags: a class of tests and the determinants of statistical power. Hum Hered 56:18–31

  5. Chung DW, Fujikawa K, McMullen BA, Davie EW (1986) Human plasma prekallikrein, a zymogen to a serine protease that contains four tandem repeats. Biochemistry 25:2410–2417

  6. Daly MJ, Rioux JD, Schaffner SF, Hudson TJ, Lander ES (2001) High-resolution haplotype structure in the human genome. Nat Genet 29:229–232

  7. Dielis AW, Smid M, Spronk HM, Hamulyak K, Kroon AA, ten Cate H, de Leeuw PW (2005) The prothrombotic paradox of hypertension: role of the renin-angiotensin and kallikrein-kinin systems. Hypertension 46:1236–1242

  8. Gabriel SB, Schaffner SF, Nguyen H, Moore JM, Roy J, Blumenstiel B, Higgins J, DeFelice M, Lochner A, Faggart M, Liu-Cordero SN, Rotimi C, Adeyemo A, Cooper R, Ward R, Lander ES, Daly MJ, Altshuler D (2002) The structure of haplotype blocks in the human genome. Science 296:2225–2229

  9. Gu D, Reynolds K, Wu X, Chen J, Duan X, Muntner P, Huang G, Reynolds RF, Su S, Whelton PK, He J (2002) Prevalence, awareness, treatment, and control of hypertension in china. Hypertension 40:920–927

  10. Gu D, Reynolds K, Wu X, Chen J, Duan X, Reynolds RF, Whelton PK, He J (2005) Prevalence of the metabolic syndrome and overweight among adults in China. Lancet 365:1398–1405

  11. Johnson GC, Esposito L, Barratt BJ, Smith AN, Heward J, Di Genova G, Ueda H, Cordell HJ, Eaves IA, Dudbridge F, Twells RC, Payne F, Hughes W, Nutland S, Stevens H, Carr P, Tuomilehto-Wolf E, Tuomilehto J, Gough SC, Clayton DG, Todd JA (2001) Haplotype tagging for the identification of common disease genes. Nat Genet 29:233–237

  12. Lake SL, Lyon H, Tantisira K, Silverman EK, Weiss ST, Laird NM, Schaid DJ (2003) Estimation and tests of haplotype-environment interaction when linkage phase is ambiguous. Hum Hered 55:56–65

  13. Marcondes S, Antunes E (2005) The plasma and tissue kininogen-kallikrein-kinin system: role in the cardiovascular system. Curr Med Chem Cardiovasc Hematol Agents 3:33–44

  14. Nunes VA, Gozzo AJ, Sampaio MU, Juliano MA, Sampaio CA, Araujo MS (2003) Mapping of human plasma kallikrein active site by design of peptides based on modifications of a Kazal-type inhibitor reactive site. J Protein Chem 22:533–541

  15. Patil N, Berno AJ, Hinds DA, Barrett WA, Doshi JM, Hacker CR, Kautzer CR, Lee DH, Marjoribanks C, McDonough DP, Nguyen BT, Norris MC, Sheehan JB, Shen N, Stern D, Stokowski RP, Thomas DJ, Trulson MO, Vyas KR, Frazer KA, Fodor SP, Cox DR (2001) Blocks of limited haplotype diversity revealed by high-resolution scanning of human chromosome 21. Science 294:1719–1723

  16. Perloff D, Grim C, Flack J, Frohlich ED, Hill M, McDonald M, Morgenstern BZ (1993) Human blood pressure determination by sphygmomanometry. Circulation 88:2460–2470

  17. Qin ZS, Niu T, Liu JS (2002) Partition-ligation-expectation-maximization algorithm for haplotype inference with single-nucleotide polymorphisms. Am J Hum Genet 71:1242–1247

  18. Schaid DJ, Rowland CM, Tines DE, Jacobson RM, Poland GA (2002) Score tests for association between traits and haplotypes when linkage phase is ambiguous. Am J Hum Genet 70:425–434

  19. Schmaier AH (2003) The kallikrein-kinin and the renin-angiotensin systems have a multilayered interaction. Am J Physiol Regul Integr Comp Physiol 285:R1–13

  20. Stram DO, Haiman CA, Hirschhorn JN, Altshuler D, Kolonel LN, Henderson BE, Pike MC (2003) Choosing haplotype-tagging SNPS based on unphased genotype data using a preliminary sample of unrelated subjects with an example from the Multiethnic Cohort Study. Hum Hered 55:27–36

  21. Tanaka Y, Yamashita Y (2002) Effects of ethanol administration at a high-dose level on the stimulatory action by bradykinin in vascular permeability. J Nutr Sci Vitaminol (Tokyo) 48:270–277

  22. Tang J, Yu CL, Williams SR, Springman E, Jeffery D, Sprengeler PA, Estevez A, Sampang J, Shrader W, Spencer J, Young W, McGrath M, Katz BA (2005) Expression, crystallization, and three-dimensional structure of the catalytic domain of human plasma kallikrein. J Biol Chem 280:41077–41089

  23. The International HapMap Project (2003) Nature 426:789–796

  24. Thompson EA, Deeb S, Walker D, Motulsky AG (1988) The detection of linkage disequilibrium between closely linked markers: RFLPs at the AI-CIII apolipoprotein genes. Am J Hum Genet 42:113–124

  25. Ward R (1990) Familial aggregation and genetic epidemiology of blood pressure. In: Laragh JH, Brenner BM (eds) Hypertension: pathophysiology, diagnosis, and management. Raven Press, New York, pp 81–100

  26. Weale ME, Depondt C, Macdonald SJ, Smith A, Lai PS, Shorvon SD, Wood NW, Goldstein DB (2003) Selection and evaluation of tagging SNPs in the neuronal-sodium-channel gene SCN1A: implications for linkage-disequilibrium gene mapping. Am J Hum Genet 73:551–565

  27. Wildman RP, Gu D, Muntner P, Huang G, Chen J, Duan X, He J (2005) Alcohol intake and hypertension subtypes in Chinese men. J Hypertens 23:737–743

  28. Yu H, Anderson PJ, Freedman BI, Rich SS, Bowden DW (2000) Genomic structure of the human plasma prekallikrein gene, identification of allelic variants, and analysis in end-stage renal disease. Genomics 69:225–234

  29. Yu H, Bowden DW, Spray BJ, Rich SS, Freedman BI (1998) Identification of human plasma kallikrein gene polymorphisms and evaluation of their role in end-stage renal disease. Hypertension 31:906–911

Download references


This work was supported by National Basic Research Program of China (Grant No. 2006CB503805), the Ministry of Science and Technology of The People’s Republic of China (Grant No. 2006AA02Z170) and Beijing Natural Science Foundation (Grant No. 7061006).

Author information

Correspondence to Dongfeng Gu.

Additional information

Conflict of interests: None.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material (DOC 83.0 KB)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Lu, X., Zhao, W., Huang, J. et al. Common variation in KLKB1 and essential hypertension risk: tagging-SNP haplotype analysis in a case-control study. Hum Genet 121, 327–335 (2007). https://doi.org/10.1007/s00439-007-0340-4

Download citation


  • Association study
  • Haplotype
  • HapMap
  • Human plasma kallikrein
  • Hypertension
  • Tag SNP