Skip to main content

Thank you for visiting nature.com. 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.

  • Original Article
  • Published:

A genome-wide association study identifies new loci for ACE activity: potential implications for response to ACE inhibitor

Abstract

Because angiotensin-converting enzyme (ACE) activity is implicated widely in biological systems, we aimed to identify its novel quantitative trait loci for the purposes of understanding ACE activity regulation and pharmacogenetics relating to ACE inhibitor (ACEI). We performed a two-stage genome-wide association study: (1) from 400 young-onset hypertension (YOH) subjects and (2) a confirmation study with an additional 623 YOH subjects. In the first stage, eight single nucleotide polymorphisms (SNPs) of the ACE structural gene and one SNP of ABO genes were significantly associated with ACE activity. SNP rs4343 in exon17 near the well-known insertion/deletion polymorphism had the strongest association. We confirmed in the second stage that three SNPs: rs4343 in ACE gene (P=3.0 × 10−25), rs495828 (P=3.5 × 10−8) and rs8176746 (P=9.3 × 10−5) in ABO gene were significantly associated with ACE activity. We further replicated the association between ABO genotype/blood types and ACE activity in an independent YOH family study (428 hypertension pedigrees), and showed a potential differential blood pressure response to ACEI in subjects with varied numbers of ACE-activity-raising alleles. These findings may broaden our understanding of the mechanisms controlling ACE activity and advance our pharmacogenetic knowledge on ACEI.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1
Figure 2

Similar content being viewed by others

References

  1. The Wellcome Trust Case Control Consortium. Genome-wide association study of 14 000 cases of seven common diseases and 3000 shared controls. Nature 2007; 447: 661–678.

    Article  PubMed Central  Google Scholar 

  2. Wang TH, Wang HS . A genome-wide association study primer for clinicians. Taiwan J Obstet Gynecol 2009; 48: 89–95.

    Article  PubMed  Google Scholar 

  3. Samani NJ, Erdmann J, Hall AS, Hengstenberg C, Mangino M, Mayer B et al. Genomewide association analysis of coronary artery disease. N Engl J Med 2007; 357: 443–453.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Ikram MA, Seshadri S, Bis JC, Fornage M, DeStefano AL, Aulchenko YS et al. Genomewide association studies of stroke. N Engl J Med 2009; 360: 1718–1728, NEJMoa0900094.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Gottesman II, Gould TD . The endophenotype concept in psychiatry: etymology and strategic intentions. Am J Psychiatry 2003; 160: 636–645.

    Article  PubMed  Google Scholar 

  6. Pan WH, Lynn KS, Chen CH, Wu YL, Lin CY, Chang HY . Using endophenotypes for pathway clusters to map complex disease genes. Genet Epidemiol 2006; 30: 143–154.

    Article  PubMed  Google Scholar 

  7. Castellon R, Hamdi HK . Demystifying the ACE polymorphism: from genetics to biology. Curr Pharm Des 2007; 13: 1191–1198.

    Article  CAS  PubMed  Google Scholar 

  8. Turner AJ, Hooper NM . The angiotensin-converting enzyme gene family: genomics and pharmacology. Trends Pharmacol Sci 2002; 23: 177–183.

    Article  CAS  PubMed  Google Scholar 

  9. Ehlers MR, Riordan JF . Angiotensin-converting enzyme: new concepts concerning its biological role. Biochemistry 1989; 28: 5311–5318.

    Article  CAS  PubMed  Google Scholar 

  10. Sayed-Tabatabaei FA, Oostra BA, Isaacs A, van Duijn CM, Witteman JC . ACE polymorphisms. Circ Res 2006; 98: 1123–1133.

    Article  CAS  PubMed  Google Scholar 

  11. Rudnicki M, Mayer G . Significance of genetic polymorphisms of the renin–angiotensin–aldosterone system in cardiovascular and renal disease. Pharmacogenomics 2009; 10: 463–476.

    Article  CAS  Google Scholar 

  12. Rigat B, Hubert C, Alhenc-Gelas F, Cambien F, Corvol P, Soubrier F . An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels. J Clin Invest 1990; 86: 1343–1346.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Zhu X, Bouzekri N, Southam L, Cooper RS, Adeyemo A, McKenzie CA et al. Linkage and association analysis of angiotensin I-converting enzyme (ACE)-gene polymorphisms with ACE concentration and blood pressure. Am J Hum Genet 2001; 68: 1139–1148.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Alhenc-Gelas F, Richard J, Courbon D, Warnet JM, Corvol P . Distribution of plasma angiotensin I-converting enzyme levels in healthy men: relationship to environmental and hormonal parameters. J Lab Clin Med 1991; 117: 33–39.

    CAS  PubMed  Google Scholar 

  15. Pan WH, Hung YT, Shaw NS, Lin W, Lee SD, Chiu CF et al. Elderly Nutrition and Health Survey in Taiwan (1999–2000): research design, methodology and content. Asia Pac J Clin Nutr 2005; 14: 203–210.

    PubMed  Google Scholar 

  16. Kasahara Y, Ashihara Y . Colorimetry of angiotensin-I converting enzyme activity in serum. Clin Chem 1981; 27: 1922–1925.

    CAS  PubMed  Google Scholar 

  17. Wang RY, Chung CM, Fann CS, Yang HC, Chen JW, Jong YS et al. Genome-wide scan for quantitative ACE activity in Taiwan Young-Onset Hypertension study. Hum Hered 2008; 65: 85–90.

    Article  CAS  PubMed  Google Scholar 

  18. Blumenfeld OO, Patnaik SK . Allelic genes of blood group antigens: a source of human mutations and cSNPs documented in the Blood Group Antigen Gene Mutation Database. Hum Mutat 2004; 23: 8–16.

    Article  CAS  PubMed  Google Scholar 

  19. Zeger SL, Liang KY . Longitudinal data analysis for discrete and continuous outcomes. Biometrics 1986; 42: 121–130.

    Article  CAS  PubMed  Google Scholar 

  20. Cidl K, Strelcova L, Znojil V, Vachi J . Angiotensin I-converting enzyme (ACE) polymorphism and ABO blood groups as factors codetermining plasma ACE activity. Exp Hematol 1996; 24: 790–794.

    CAS  PubMed  Google Scholar 

  21. Takasaki S, Yamashita K, Kobata A . The sugar chain structures of ABO blood group active glycoproteins obtained from human erythrocyte membrane. J Biol Chem 1978; 253: 6086–6091.

    CAS  PubMed  Google Scholar 

  22. Borecki IB, Elston RC, Rosenbaum PA, Srinivasan SR, Berenson GS . ABO associations with blood pressure, serum lipids and lipoproteins, and anthropometric measures. Hum Hered 1985; 35: 161–170.

    Article  CAS  PubMed  Google Scholar 

  23. Bezemer ID, Rosendaal FR . Predictive genetic variants for venous thrombosis: what's new? Semin Hematol 2007; 44: 85–92.

    Article  CAS  PubMed  Google Scholar 

  24. Wu O, Bayoumi N, Vickers MA, Clark P . ABO(H) blood groups and vascular disease: a systematic review and meta-analysis. J Thromb Haemost 2008; 6: 62–69.

    Article  CAS  PubMed  Google Scholar 

  25. Jenkins PV, O’Donnell JS . ABO blood group determines plasma von Willebrand factor levels: a biologic function after all? Transfusion 2006; 46: 1836–1844.

    Article  CAS  PubMed  Google Scholar 

  26. Naim HY . Human small intestinal angiotensin-converting enzyme: intracellular transport, secretion and glycosylation. Biochem J 1993; 296 (Part 3): 607–615.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Veterans Administration Cooperative Study Group on Antihypertensive Agents. Comparison of propranolol and hydrochlorothiazide for the initial treatment of hypertension. II. Results of long-term therapy. JAMA 1982; 248: 2004–2011.

    Article  Google Scholar 

  28. Arnett DK, Davis BR, Ford CE, Boerwinkle E, Leiendecker-Foster C, Miller MB et al. Pharmacogenetic association of the angiotensin-converting enzyme insertion/deletion polymorphism on blood pressure and cardiovascular risk in relation to antihypertensive treatment: the Genetics of Hypertension-Associated Treatment (GenHAT) study. Circulation 2005; 111: 3374–3383.

    Article  CAS  Google Scholar 

  29. Belz GG, Breithaupt K, Erb K . Review of studies on the clinical pharmacodynamics of cilazapril. J Cardiovasc Pharmacol 1994; 24 (Suppl 2): S14–S19.

    Article  CAS  PubMed  Google Scholar 

  30. Lang RM, DiBianco R, Broderick GT, Gottlieb SS, Kostis J, Lyle PA et al. First-dose effects of enalapril 2.5 mg and captopril 6.25 mg in patients with heart failure: a double-blind, randomized, multicenter study. The Enalapril-Captopril Investigators. Am Heart J 1994; 128: 551–556.

    Article  CAS  PubMed  Google Scholar 

  31. Ehret GB, Morrison AC, O’Connor AA, Grove ML, Baird L, Schwander K et al. Replication of the Wellcome Trust genome-wide association study of essential hypertension: the Family Blood Pressure Program. Eur J Hum Genet 2008; 16: 1507–1511.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank John Yin for editing the paper and Academia Sinica National Genotyping Center (Taipei, Taiwan) for performing genotyping of the second-stage subjects. This research was supported by the Department of Health (DOH90-TD-1037), the National Science Council (NSC91-3112-P-001-025-YGPCP91-25), Academia Sinica (AS91IBMS2PP-A) and Academia Sinica Genomics and Proteinomics Program (2003–2006) in Taiwan.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to W-H Pan.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chung, CM., Wang, RY., Chen, JW. et al. A genome-wide association study identifies new loci for ACE activity: potential implications for response to ACE inhibitor. Pharmacogenomics J 10, 537–544 (2010). https://doi.org/10.1038/tpj.2009.70

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/tpj.2009.70

Keywords

This article is cited by

Search

Quick links