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Examination of two genetic polymorphisms within the renin-angiotensin system: no evidence for an association with nephropathy in IDDM

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Summary

Premature cardiovascular disease is common in insulin-dependent diabetic (IDDM) patients who develop diabetic nephropathy. Genetic polymorphism within the renin-angiotensin system has been implicated in the aetiology of a number of cardiovascular disorders; these loci are therefore candidate genes for susceptibility to diabetic renal disease. We have examined the angiotensin converting enzyme insertion/deletion polymorphism and angiotensinogen methionine 235 threonine polymorphism in a large cohort of Caucasian patients with IDDM and diabetic nephropathy. Patients were classified as having nephropathy by the presence of persistent dipstick positive proteinuria (in the absence of other causes), retinopathy and hypertension (n=242). Three groups were examined for comparison: ethnically matched non-diabetic subjects (n=187); a geographically defined cohort of newly diagnosed diabetic patients (n=341); and IDDM patients with long duration of disease (>15 years) and no evidence of overt nephropathy (n=166). No significant difference was seen in distribution of angiotensin converting enzyme or angiotensinogen genotypes between IDDM patients with nephropathy and recently diagnosed diabetic subjects (p=0.282 and 0.584, respectively), nor the long-duration non-nephropathy diabetic subjects (p=0.701 and 0.190, respectively). We conclude that these genetic loci are unlikely to influence susceptibility to diabetic nephropathy in IDDM in the United Kingdom.

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Abbreviations

IDDM:

Insulin-dependent diabetes mellitus

ACE:

angiotensin converting enzyme

PCR:

polymerase chain reaction

LDNN:

long duration-non-nephropathy group

I/D:

insertion/deletion

RAS:

renin-angiotension system

References

  1. Borch-Johnsen K, Andersen JK, Deckert T (1985) The effect of proteinuria on relative mortality in type 1 diabetes. Am J Med 78: 785–794

    Google Scholar 

  2. Andersen AR, Christiansen JS, Andersen JK, Kreiner JK, Deckert T (1983) Diabetic nephropathy in type 1 (insulin-dependent) diabetes: an epidemiological study. Diabetologia 25: 496–501

    Google Scholar 

  3. Seaquist ER, Goetz FC, Rich S, Barbosa J (1989) Familial clustering of diabetic kidney disease. Evidence of genetic susceptibility to diabetic nephropathy. N Engl J Med 320: 1161–1165

    Google Scholar 

  4. Borch-Johnsen K, Norgaard K, Hommel E et al. (1992) Is diabetic nephropathy an inherited complication? Kidney Int 41: 719–722

    Google Scholar 

  5. Rigat B, Hubert C, Corvol P, Soubrier F (1992) PCR detection of the insertion/deletion polymorphism of the human angiotensin converting gene (DCP)(dipeptidyl carboxypeptidase 1). Nuc Acid Res 20: 1433

    Google Scholar 

  6. Rigat B, Hubert C, Alhenc-Gelas F, Cambien F, Corvol P, Soubrier F (1990) An insertion deletion polymorphism in the angiotensin 1 converting enzyme gene accounting for half the variance of serum enzyme levels. J Clin Invest 86: 1343–1346

    Google Scholar 

  7. Cambien F, Poirier O, Lecerf L et al. (1992) Deletion polymorphism in the gene for angiotensin converting enzyme is a potent risk factor for myocardial infarction. Nature 359: 641–644

    Google Scholar 

  8. Raynolds MV, Bristow MR, Bush EW et al. (1993) Angiotensin-converting enzyme DD genotype in patients with ischaemic or idiopathic dilated cardiomyopathy. Lancet 342: 1073–1075

    Google Scholar 

  9. Schunkert H, Hense HW, Holmer SR et al. (1994) Association between a deletion polymorphism of the angiotensin-converting enzyme gene and left ventricular hypertrophy. N Engl J Med 330: 1634–1638

    Google Scholar 

  10. Marian AJ, Yu QT, Workman R, Greve G, Roberts R (1993) Angiotensin converting enzyme polymorphism in hypertrophic cardiomyopathy and sudden cardiac death. Lancet 342: 1085–1086

    Google Scholar 

  11. Ruiz J, Blanche H, Cohen N (1994) Insertion/deletion polymorphism of the angiotensin converting enzyme gene is strongly associated with coronary heart disease in non-insulin dependent diabetes mellitus. Proc Natl Acad Sci 91: 3662–3665

    Google Scholar 

  12. Hallab M, Bled F, Ebran JM et al. (1992) Elevated serum angiotensin converting enzyme activity in type 1, insulin dependent diabetic subjects with persistent microalbuminuria. Acta Diabetol 29: 82–85

    Google Scholar 

  13. Bjork S, Mulec H, Johnsen SA, Norden G, Aurell M (1992) Renal protective effect of enalapril in diabetic nephropathy. BMJ 304: 339–343

    Google Scholar 

  14. Hilbert P, Lindpainter K, Lincoln SE et al. (1991) Chromosomal mapping of two genetic loci associated with blood pressure in hereditary hypertensive rats. Nature 353: 521–529

    Google Scholar 

  15. Doria A, Warram JH, Krolewski AS (1994) Genetic predisposition to diabetic nephropathy. Evidence for a role of the angiotensin 1 converting enzyme gene. Diabetes 43: 690–695

    Google Scholar 

  16. Marre M, Bernadet P, Gallois Y et. al. (1994) Relationships between angiotensin 1 converting enzyme gene polymorphism, plasma levels and diabetic retinal and renal complications. Diabetes 43: 384–388

    Google Scholar 

  17. Schmidt S, Schone N, Ritz E (1995) Association of ACE gene polymorphism and diabetic nephropathy? Kid Int 47: 1176–1181

    Google Scholar 

  18. Tarnow L, Cambien F, Rossing P et al. (1995) Lack of relationship between an insertion/deletion polymorphism in the angiotensin I converting enzyme gene and diabetic nephropathy and proliferative retinopathy in IDDM patients. Diabetes 44: 489–494

    Google Scholar 

  19. Rabensteiner D, Mayer G, Abrahamian H et al. (1995) Relationship between angiotensin-1-converting enzyme polymorphism and microangiopathy in IDDM subjects. Diabetologia 38 [Suppl] 1: A227 (Abstract)

    Google Scholar 

  20. Hibberd ML, Millward BA, Demaine AG (1995) Angiotensin converting enzyme genotypes and complications in type 1 diabetes. Diabetologia 38 [Suppl] 1: A227 (Abstract)

    Google Scholar 

  21. Chaturverdi N, Talmud P, Fuller JH (1995) Angiotensin converting enzyme (ACE) gene polymorphisms and complications in insulin dependent diabetes mellitus (IDDM). Diabetologia 38 [Suppl] 1: A227 (Abstract)

    Google Scholar 

  22. Jeunemaitre X, Soubrier F, Kotelevtsev YV et al. (1992) Molecular basis of human hypertension: role of angiotensinogen. Cell 71: 169–180

    Google Scholar 

  23. Walker WG, Whelton PK, Saito H, Russell RP, Hermann J (1979) Relation between blood pressure and renin, renin substrate, angiotensin II, aldosterone and urinary sodium and potassium in 574 ambulatory subjects. Hypertension 1: 287–291

    Google Scholar 

  24. Viberti GC, Keen H, Wiseman MJ (1985) Raised arterial pressure in parents of proteinuric insulin dependent diabetics. BMJ 295: 515–517

    Google Scholar 

  25. Forsblom CM, Groop PH, Ekstrand A, Groop LC (1992) Predictive value of microalbuminuria in patients with insulin dependent diabetes of long duration. BMJ 305: 1051–1053

    Google Scholar 

  26. Shanmugam V, Sell KW, Saha BK (1993) Mistyping ACE heterozygotes. PCR Methods and Applications 3: 120–121

    Google Scholar 

  27. Russ AP, Maerz W, Ruzicka V, Stein U, Gross W (1993) Rapid detection of the hypertension associated Met 235-Thr allele of the human angiotensinogen gene. Hum Mol Gen 2: 609–610

    Google Scholar 

  28. Satsangi J, Jewell DP, Welsh K, Bunce M, Bell JI (1994) Effect of heparin on polymerase chain reaction. Lancet 343: 1509–1510(letter)

    Google Scholar 

  29. Katsuya T, Koike G, Yee TW et al. (1995) Association of angiotensinogen gene T235 variant with increased risk of coronary heart disease. Lancet 345: 1600–1603

    Google Scholar 

  30. Richards NT, Greaves I, Lee SJ, Howie AJ, Adu D, Michael J (1992) Increased prevalence of renal biopsy findings other than diabetic glomerulopathy in type 2 diabetes mellitus. Nephrol Dial Trans 7: 397–399

    Google Scholar 

  31. Cox NJ, Bell GI (1989) Disease associations. Chance, artifact or susceptibility genes? Diabetes 38: 947–950

    Google Scholar 

  32. Tarnow L, Cambien F, Rossing P et al. (1995) Insertion/deletion polymorphism in the angiotensin 1 converting enzyme gene is associated with coronary heart disease in IDDM patients with diabetic nephropathy. Diabetologia 38: 798–803

    Google Scholar 

  33. Harden PN, Geddes C, Rowe PA et al. (1995) Polymorphisms in angiotensin converting enzyme gene and progression of IgA nephropathy. Lancet 345: 1540–1542

    Google Scholar 

  34. Khan I, MacCleod AM (1995) ACE genotype and progression of IgA nephropathy. Lancet 345: 570

    Google Scholar 

  35. Van Essen G, Rensma PL, de Zeeuw D, Sluiter H, Apperloo A, de Jong PE (1996) Association between angiotensin coverting enzyme gene polymorphism and failure of renoprotective therapy. Lancet 347: 94–95

    Google Scholar 

  36. Walker JD, Tariq T, Viberti GC (1990) Sodium lithium countertransport activity in red cells of patients with insulin dependent diabetes and nephropathy and their parents. BMJ 301: 635–638

    Google Scholar 

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Authors and Affiliations

  1. Department of Medicine, University of Birmingham, Birmingham Heartlands Hospital, Birmingham, UK

    T. A. Chowdhury, S. Kumar, S. L. C. Gough, B. R. Rowe, J. Webber, P. R. Smith, A. H. Barnett & S. C. Bain

  2. Department of Medicine, University of Birmingham, Queen Elizabeth Hospital, Birmingham, UK

    M. J. Dronsfield

  3. Nuffield Department of Surgery, The Wellcome Trust Centre for Human Genetics, Oxford, UK

    P. J. M. Morris & J. A. Todd

  4. The Richard Bright Renal Unit, Southmead Hospital, Bristol, UK

    S. P. Gibson

  5. Department of Clinical Genetics, University of Birmingham, Birmingham Heartlands Hospital, Birmingham, UK

    A. Khatoon & F. MacDonald

  6. Department of Paediatrics, John Radchffe Hospital, Headington, Oxford, UK

    D. B. Dunger

  7. Department of Medicine, Bolton General Hospital, Bolton, UK

    J. D. Dean

  8. Department of Renal Medicine, Royal Infirmary, Stoke-on-Trent, UK

    S. J. Davies

  9. Department of Medicine, The Medical School, Newcastle upon Tyne, UK

    P. Mackin & S. M. Marshall

  10. Department of Nephrology, University of Birmingham, Queen Elizabeth Hospital, Birmingham, UK

    D. Adu

  11. Department of Medicine, Manchester Royal Infirmary, Manchester, UK

    A. J. M. Boulton

Authors
  1. T. A. Chowdhury
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  2. M. J. Dronsfield
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  3. S. Kumar
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  4. S. L. C. Gough
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  5. S. P. Gibson
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  6. A. Khatoon
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  7. F. MacDonald
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  8. B. R. Rowe
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  9. D. B. Dunger
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  10. J. D. Dean
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  11. S. J. Davies
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  12. J. Webber
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  13. P. R. Smith
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  14. P. Mackin
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  15. S. M. Marshall
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  16. D. Adu
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  17. P. J. M. Morris
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  18. J. A. Todd
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  19. A. H. Barnett
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  20. A. J. M. Boulton
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  21. S. C. Bain
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Chowdhury, T.A., Dronsfield, M.J., Kumar, S. et al. Examination of two genetic polymorphisms within the renin-angiotensin system: no evidence for an association with nephropathy in IDDM. Diabetologia 39, 1108–1114 (1996). https://doi.org/10.1007/BF00400661

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  • DOI: https://doi.org/10.1007/BF00400661

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