Human Genetics

, Volume 120, Issue 2, pp 201–210 | Cite as

An angiotensin converting enzyme haplotype predicts survival in patients with end stage renal disease

  • James B. Wetmore
  • Kirsten L. Johansen
  • Saunak Sen
  • Adriana M. Hung
  • David H. Lovett
Original Investigation


The renin-angiotensin system is implicated in the development of a variety of human diseases. Many studies have sought to characterize the clinical implications of polymorphisms in the angiotensin converting enzyme (ACE) gene. Given the high mortality rate of individuals on chronic hemodialysis (HD), we sought to investigate whether genetic diversity in the ACE gene correlates with mortality in this population. We assembled a racially diverse cohort of prevalent individuals on chronic outpatient HD, and followed it prospectively for a mean of 2.1 years. Subjects were genotyped for seven single nucleotide polymorphisms (SNPs) in the ACE gene. Haplotype probabilities were calculated using an expectation–maximization algorithm. Cox proportional hazards regression was used to determine associations between haplotype and time to mortality from initiation of HD. There was strong linkage disequilibrium (LD) across the ACE gene, with three tagging SNPs found to account for all seven-SNP haplotypes that had a frequency of greater than 4%. After adjustment for age, race, gender, and diabetes status, a three-locus haplotype was associated with a 72% risk reduction in mortality (P = 0.004). The majority of this association was captured by the TT genotype of A-239T promoter polymorphism. The TGG (non-wild-type) haplotype, consisting of three tagging SNPs in the ACE gene, is associated with significantly decreased risk of all-cause mortality in HD patients independent of age, race, gender, and diabetic status. This “protective” haplotype may encompass loci with functional significance in the ACE gene.


Linkage Disequilibrium Angiotensin Converting Enzyme Alzheimer Dementia High Linkage Disequilibrium Angiotensin Converting Enzyme Gene 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



This study was supported by NIH grants DK 39776 (DHL), DK 56182 (KLJ), DK 07219 (JBW), UCSF Foundation Greenberg Awards #80357 and #60519 (DHL, KLJ), Amgen Grant #20010180 (AMH, DHL, KLJ), and National Kidney Foundation Grants (AMH, JBW). We thank the UCSF Genomics Core Facility for their assistance in genotyping, and Satellite Dialysis for assistance in patient recruitment.

Supplementary material

439_2006_191_MOESM1_ESM.pdf (51 kb)
Supplementary material


  1. Agerholm-Larsen B, Nordestgaard BG, Tybjaerg-Hansen A (2000) ACE gene polymorphism in cardiovascular disease: meta-analyses of small and large studies in whites. Arterioscler Thromb Vasc Biol 20:484–492PubMedGoogle Scholar
  2. Akaike H (1973) Information theory and an extension of the maximum likelihood principle. In: Csaki F (ed) Proceedings of the second international symposium on information theory, Akademiai Kiado, Budapest, pp 267–281Google Scholar
  3. Bakris GL (2001) Angiotensin-converting enzyme inhibition to enhance vascular health-clinical and research models. Am J Hypertens 14:264S–269SPubMedCrossRefGoogle Scholar
  4. Bouzekri N, Zhu X, Jiang Y, McKenzie CA, Luke A, Forrester T, Adeyemo A, Kan D, Farrall M, Anderson S, Cooper RS, Ward R (2004) Angiotensin I-converting enzyme polymorphisms, ACE level and blood pressure among Nigerians, Jamaicans and African-Americans. Eur J Hum Genet 12:460–468PubMedCrossRefGoogle Scholar
  5. Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, Remuzzi G, Snapinn SM, Zhang Z, Shahinfar S (2001) Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 345:861–869PubMedCrossRefGoogle Scholar
  6. Cambien F, Costerousse O, Tiret L, Poirier O, Lecerf L, Gonzales MF, Evans A, Arveiler D, Cambou JP, Luc G, et al (1994) Plasma level and gene polymorphism of angiotensin-converting enzyme in relation to myocardial infarction. Circulation 90:669–676PubMedGoogle Scholar
  7. Chiano MN, Clayton DG (1998) Fine genetic mapping using haplotype analysis and the missing data problem. Ann Hum Genet 62(Pt 1):55–60PubMedCrossRefGoogle Scholar
  8. Cooper ME (2004) The role of the renin-angiotensin-aldosterone system in diabetes and its vascular complications. Am J Hypertens 17:16S–20S; quiz A2–A4Google Scholar
  9. Cox DR, Hinkley DV (1974) Theoretical statistics. Chapman and Hall, New YorkGoogle Scholar
  10. Cox R, Bouzekri N, Martin S, Southam L, Hugill A, Golamaully M, Cooper R, Adeyemo A, Soubrier F, Ward R, Lathrop GM, Matsuda F, Farrall M (2002) Angiotensin-1-converting enzyme (ACE) plasma concentration is influenced by multiple ACE-linked quantitative trait nucleotides. Hum Mol Genet 11:2969–2977PubMedCrossRefGoogle Scholar
  11. Dzau VJ (1993) Tissue renin-angiotensin system in myocardial hypertrophy and failure. Arch Intern Med 153:937–942PubMedCrossRefGoogle Scholar
  12. Dzau VJ, Bernstein K, Celermajer D, Cohen J, Dahlof B, Deanfield J, Diez J, Drexler H, Ferrari R, Van Gilst W, Hansson L, Hornig B, Husain A, Johnston C, Lazar H, Lonn E, Luscher T, Mancini J, Mimran A, Pepine C, Rabelink T, Remme W, Ruilope L, Ruzicka M, Schunkert H, Swedberg K, Unger T, Vaughan D, Weber M (2002) Pathophysiologic and therapeutic importance of tissue ACE: a consensus report. Cardiovasc Drugs Ther 16:149–160PubMedCrossRefGoogle Scholar
  13. Emigh TH (1980) Comparison of tests for Hardy–Weinberg equilibrium. Biometrics 36:627–642CrossRefGoogle Scholar
  14. Erdos EG, Skidgel RA (1987) The angiotensin I-converting enzyme. Lab Invest 56:345–348PubMedGoogle Scholar
  15. Excoffier L, Slatkin M (1995) Maximum-likelihood estimation of molecular haplotype frequencies in a diploid population. Mol Biol Evol 12:921–927PubMedGoogle Scholar
  16. Foy CA, Rice GI, Ossei-Gerning N, Mansfield MW, Grant PJ (1997) Angiotensin-converting enzyme (ACE) gene polymorphisms in patients characterised by coronary angiography. Hum Genet 100:420–425PubMedCrossRefGoogle Scholar
  17. Gardemann A, Weiss T, Schwartz O, Eberbach A, Katz N, Hehrlein FW, Tillmanns H, Waas W, Haberbosch W (1995) Gene polymorphism but not catalytic activity of angiotensin I-converting enzyme is associated with coronary artery disease and myocardial infarction in low-risk patients. Circulation 92:2796–2799PubMedGoogle Scholar
  18. Grambsch P, Therneau T (1994) Proportional hazards tests and diagnostics based on weighted residuals. Biometrika 81:512–526Google Scholar
  19. Progress Collaborative Group (2001) Randomised trial of a perindopril-based blood- pressure-lowering regimen among 6,105 individuals with previous stroke or transient ischaemic attack. Lancet 358:1033–1041CrossRefGoogle Scholar
  20. Harrap SB, Tzourio C, Cambien F, Poirier O, Raoux S, Chalmers J, Chapman N, Colman S, Leguennec S, MacMahon S, Neal B, Ohkubo T, Woodward M (2003) The ACE gene I/D polymorphism is not associated with the blood pressure and cardiovascular benefits of ACE inhibition. Hypertension 42:297–303PubMedCrossRefGoogle Scholar
  21. Jaffe IZ, Mendelsohn ME (2005) Angiotensin II and aldosterone regulate gene transcription via functional mineralocortocoid receptors in human coronary artery smooth muscle cells. Circ Res 96:643–650PubMedCrossRefGoogle Scholar
  22. Johnston CI (1994) Tissue angiotensin converting enzyme in cardiac and vascular hypertrophy, repair, and remodeling. Hypertension 23:258–268PubMedGoogle Scholar
  23. Karagiannis A, Balaska K, Tziomalos K, Tokalaki-Nikolaidou L, Papayeoryiou A, Zamboulis C (2004) Lack of an association between angiotensin-converting enzyme gene insertion/deletion polymorphism and ischaemic stroke. Eur Neurol 51:148–152PubMedCrossRefGoogle Scholar
  24. Keavney B, McKenzie CA, Connell JM, Julier C, Ratcliffe PJ, Sobel E, Lathrop M, Farrall M (1998) Measured haplotype analysis of the angiotensin-I converting enzyme gene. Hum Mol Genet 7:1745–1751PubMedCrossRefGoogle Scholar
  25. Kehoe PG, Katzov H, Feuk L, Bennet AM, Johansson B, Wiman B, de Faire U, Cairns NJ, Wilcock GK, Brookes AJ, Blennow K, Prince JA (2003) Haplotypes extending across ACE are associated with Alzheimer’s disease. Hum Mol Genet 12:859–867PubMedCrossRefGoogle Scholar
  26. Kehoe PG, Katzov H, Andreasen N, Gatz M, Wilcock GK, Cairns NJ, Palmgren J, de Faire U, Brookes AJ, Pedersen NL, Blennow K, Prince JA (2004) Common variants of ACE contribute to variable age-at-onset of Alzheimer’s disease. Hum Genet 114:478–483PubMedCrossRefGoogle Scholar
  27. Kjeldsen SE, Julius S (2004) Hypertension mega-trials with cardiovascular end points: effect of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. Am Heart J 148:747–754PubMedCrossRefGoogle Scholar
  28. Li DY, Zhang YC, Philips MI, Sawamura T, Mehta JL (1999) Upregulation of endothelial receptor for oxidized low-density lipoprotein (LOX-1) in cultured human coronary artery endothelial cells by angiotensin II type 1 receptor activation. Circ Res 84:1043–1049PubMedGoogle Scholar
  29. Lindholm LH, Ibsen H, Borch-Johnsen K, Olsen MH, Wachtell K, Dahlof B, Devereux RB, Beevers G, de Faire U, Fyhrquist F, Julius S, Kjeldsen SE, Kristianson K, Lederballe-Pedersen O, Nieminen MS, Omvik P, Oparil S, Wedel H, Aurup P, Edelman JM, Snapinn S (2002) Risk of new-onset diabetes in the Losartan intervention for endpoint reduction in hypertension study. J Hypertens 20:1879–1886PubMedCrossRefGoogle Scholar
  30. Nadar S, Blann AD, Lip GY (2004) Antihypertensive therapy and endothelial function. Curr Pharm Des 10:3607–3614PubMedCrossRefGoogle Scholar
  31. Okuno S, Utsugi T, Ohno T, Ohyama Y, Uchiyama T, Tomono S, Kurabayashi M (2003) Angiotensin-converting enzyme gene polymorphism as a potent risk factor for developing microalbuminuria in Japanese patients with type 2 diabetes mellitus: a 9-year follow-up study. J Int Med Res 31:290–298PubMedGoogle Scholar
  32. Pei YP, Greenwood CM, Chery AL, Wu GG (2000) Racial differences in survival of patients on dialysis. Kidney Int 58:1293–1299PubMedCrossRefGoogle Scholar
  33. Price DA, Owen WF Jr (1997) African-Americans on maintenance dialysis: a review of racial differences in incidence, treatment, and survival. Adv Ren Replace Ther 4:3–12PubMedGoogle Scholar
  34. Pueyo ME, Challah M, Gauguier D, Louedec L, Philippe M, Gaertner R, Marre M, Michel JB, Jacob MP (2004) Transforming growth factor-beta 1 production is correlated with genetically determined ACE expression in congenic rats: a possible link between ACE genotype and diabetic nephropathy. Diabetes 53:1111–1118PubMedCrossRefGoogle Scholar
  35. Rieder MJ, Taylor SL, Clark AG, Nickerson DA (1999) Sequence variation in the human angiotensin converting enzyme. Nat Genet 22:59–62PubMedCrossRefGoogle Scholar
  36. Samani NJ, Thompson JR, O’Toole L, Channer K, Woods KL (1996) A meta-analysis of the association of the deletion allele of the angiotensin-converting enzyme gene with myocardial infarction. Circulation 94:708–712PubMedGoogle Scholar
  37. Sokol SI, Portnay EL, Curtis JP, Nelson MA, Hebert PR, Setaro JF, Foody JM (2004) Modulation of the renin-angiotensin-aldosterone system for the secondary prevention of stroke. Neurology 63:208–213PubMedGoogle Scholar
  38. Soubrier F, Martin S, Alonso A, Visvikis S, Tiret L, Matsuda F, Lathrop GM, Farrall M (2002) High-resolution genetic mapping of the ACE-linked QTL influencing circulating ACE activity. Eur J Hum Genet 10:553–561PubMedCrossRefGoogle Scholar
  39. Struthers AD (2004) Aldosterone blockade in cardiovascular disease. Heart 90:1229–1234PubMedCrossRefGoogle Scholar
  40. Thomas GN, Critchley JA, Tomlinson B, Cockram CS, Chan JC (2003) Peripheral vascular disease in Type 2 diabetic Chinese patients: associations with metabolic indices, concomitant vascular disease and genetic factors. Diabet Med 20:988–995PubMedCrossRefGoogle Scholar
  41. Villard E, Tiret L, Visvikis S, Rakotovao R, Cambien F, Soubrier F (1996) Identification of new polymorphisms of the angiotensin I-converting enzyme (ACE) gene, and study of their relationship to plasma ACE levels by two-QTL segregation-linkage analysis. Am J Hum Genet 58:1268–1278PubMedGoogle Scholar
  42. Winkelmann BR, Nauck M, Klein B, Russ AP, Bohm BO, Siekmeier R, Ihnken K, Verho M, Gross W, Marz W (1996) Deletion polymorphism of the angiotensin I-converting enzyme gene is associated with increased plasma angiotensin-converting enzyme activity but not with increased risk for myocardial infarction and coronary artery disease. Ann Intern Med 125:19–25PubMedGoogle Scholar
  43. Zhu X, McKenzie CA, Forrester T, Nickerson DA, Broeckel U, Schunkert H, Doering A, Jacob HJ, Cooper RS, Rieder MJ (2000) Localization of a small genomic region associated with elevated ACE. Am J Hum Genet 67:1144–1153PubMedGoogle Scholar
  44. Zhu X, Bouzekri N, Southam L, Cooper RS, Adeyemo A, McKenzie CA, Luke A, Chen G, Elston RC, Ward R (2001) Linkage and association analysis of angiotensin I-converting enzyme (ACE)-gene polymorphisms with ACE concentration and blood pressure. Am J Hum Genet 68:1139–1148PubMedCrossRefGoogle Scholar
  45. Zhu X, Yan D, Cooper RS, Luke A, Ikeda MA, Chang YP, Weder A, Chakravarti A (2003) Linkage disequilibrium and haplotype diversity in the genes of the renin-angiotensin system: findings from the family blood pressure program. Genome Res 13:173–181PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • James B. Wetmore
    • 1
    • 3
  • Kirsten L. Johansen
    • 1
  • Saunak Sen
    • 2
  • Adriana M. Hung
    • 1
    • 4
  • David H. Lovett
    • 1
  1. 1.The Department of MedicineSan Francisco VAMC/University of CaliforniaSan FranciscoUSA
  2. 2.Department of Epidemiology and BiostatisticsUniversity of CaliforniaSan FranciscoUSA
  3. 3.Medical Service (111J)SFVAMCSan FranciscoUSA
  4. 4.Tampa VAMCUniversity of South FloridaTampaUSA

Personalised recommendations