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J Clin Invest. Apr 1, 1997; 99(7): 1585–1595.
PMCID: PMC507978

Contribution of genetic polymorphism in the renin-angiotensin system to the development of renal complications in insulin-dependent diabetes: Genetique de la Nephropathie Diabetique (GENEDIAB) study group.

Abstract

Diabetic nephropathy is a glomerular disease due to uncontrolled diabetes and genetic factors. It can be caused by glomerular hypertension produced by capillary vasodilation, due to diabetes, against constitutional glomerular resistance. As angiotensin II increases glomerular pressure, we studied the relationship between genetic polymorphisms in the renin-angiotensin system-angiotensin I converting enzyme (ACE), angiotensinogen (AGT), and angiotensin II, subtype 1, receptor-and the renal involvement of insulin-dependent diabetic subjects with proliferative retinopathy: those exposed to the risk of nephropathy due to diabetes. Of 494 subjects recruited in 17 centers in France and Belgium (GENEDIAB Study), 157 (32%) had no nephropathy, 104 (21%) incipient (microalbuminuria), 126 (25 %) established (proteinuria), and 107 (22%) advanced (plasma creatinine > or = 150 micromol/liter or renal replacement therapy) nephropathy. The severity of renal involvement was associated with ACE insertion/deletion (I/D) polymorphism: chi2 for trend 5.135, P = 0.023; adjusted odds ratio attributable to the D allele 1.889 (95% CI 1.209-2.952, P = 0.0052). Renal involvement was not directly linked to other polymorphisms. However, ACE I-D and AGT M235T polymorphisms interacted significantly (P = 0.0166): in subjects with ACE ID and DD genotypes, renal involvement increased from the AGT MM to TT genotypes. Thus, genetic determinants that affect renal angiotensin II and kinin productions are risk factors for the progression of glomerular disease in uncontrolled insulin-dependent diabetic patients.

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Selected References

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  • Krolewski AS, Warram JH, Rand LI, Kahn CR. Epidemiologic approach to the etiology of type I diabetes mellitus and its complications. N Engl J Med. 1987 Nov 26;317(22):1390–1398. [PubMed]
  • Borch-Johnsen K, Kreiner S. Proteinuria: value as predictor of cardiovascular mortality in insulin dependent diabetes mellitus. Br Med J (Clin Res Ed) 1987 Jun 27;294(6588):1651–1654. [PMC free article] [PubMed]
  • Pirart J. Diabète et complications dégénératives présentation d'une étude prospective portant sur 4400 cas observés entre 1947 et 1973. (Première partie). Diabete Metab. 1977 Jun;3(2):97–107. [PubMed]
  • Seaquist ER, Goetz FC, Rich S, Barbosa J. Familial clustering of diabetic kidney disease. Evidence for genetic susceptibility to diabetic nephropathy. N Engl J Med. 1989 May 4;320(18):1161–1165. [PubMed]
  • Pettitt DJ, Saad MF, Bennett PH, Nelson RG, Knowler WC. Familial predisposition to renal disease in two generations of Pima Indians with type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia. 1990 Jul;33(7):438–443. [PubMed]
  • Earle K, Walker J, Hill C, Viberti G. Familial clustering of cardiovascular disease in patients with insulin-dependent diabetes and nephropathy. N Engl J Med. 1992 Mar 5;326(10):673–677. [PubMed]
  • Hostetter TH, Troy JL, Brenner BM. Glomerular hemodynamics in experimental diabetes mellitus. Kidney Int. 1981 Mar;19(3):410–415. [PubMed]
  • Marre M, Leblanc H, Suarez L, Guyenne TT, Ménard J, Passa P. Converting enzyme inhibition and kidney function in normotensive diabetic patients with persistent microalbuminuria. Br Med J (Clin Res Ed) 1987 Jun 6;294(6585):1448–1452. [PMC free article] [PubMed]
  • Hall JE, Guyton AC, Jackson TE, Coleman TG, Lohmeier TE, Trippodo NC. Control of glomerular filtration rate by renin-angiotensin system. Am J Physiol. 1977 Nov;233(5):F366–F372. [PubMed]
  • Cambien F, Alhenc-Gelas F, Herbeth B, Andre JL, Rakotovao R, Gonzales MF, Allegrini J, Bloch C. Familial resemblance of plasma angiotensin-converting enzyme level: the Nancy Study. Am J Hum Genet. 1988 Nov;43(5):774–780. [PMC free article] [PubMed]
  • Costerousse O, Allegrini J, Lopez M, Alhenc-Gelas F. Angiotensin I-converting enzyme in human circulating mononuclear cells: genetic polymorphism of expression in T-lymphocytes. Biochem J. 1993 Feb 15;290(Pt 1):33–40. [PMC free article] [PubMed]
  • Jeunemaitre X, Soubrier F, Kotelevtsev YV, Lifton RP, Williams CS, Charru A, Hunt SC, Hopkins PN, Williams RR, Lalouel JM, et al. Molecular basis of human hypertension: role of angiotensinogen. Cell. 1992 Oct 2;71(1):169–180. [PubMed]
  • Caulfield M, Lavender P, Farrall M, Munroe P, Lawson M, Turner P, Clark AJ. Linkage of the angiotensinogen gene to essential hypertension. N Engl J Med. 1994 Jun 9;330(23):1629–1633. [PubMed]
  • 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 Oct;86(4):1343–1346. [PMC free article] [PubMed]
  • Cambien F, Poirier O, Lecerf L, Evans A, Cambou JP, Arveiler D, Luc G, Bard JM, Bara L, Ricard S, et al. Deletion polymorphism in the gene for angiotensin-converting enzyme is a potent risk factor for myocardial infarction. Nature. 1992 Oct 15;359(6396):641–644. [PubMed]
  • Ruiz J, Blanché H, Cohen N, Velho G, Cambien F, Cohen D, Passa P, Froguel P. 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 U S A. 1994 Apr 26;91(9):3662–3665. [PMC free article] [PubMed]
  • Nakai K, Itoh C, Miura Y, Hotta K, Musha T, Itoh T, Miyakawa T, Iwasaki R, Hiramori K. Deletion polymorphism of the angiotensin I-converting enzyme gene is associated with serum ACE concentration and increased risk for CAD in the Japanese. Circulation. 1994 Nov;90(5):2199–2202. [PubMed]
  • Mattu RK, Needham EW, Galton DJ, Frangos E, Clark AJ, Caulfield M. A DNA variant at the angiotensin-converting enzyme gene locus associates with coronary artery disease in the Caerphilly Heart Study. Circulation. 1995 Jan 15;91(2):270–274. [PubMed]
  • Badenhop RF, Wang XL, Wilcken DE. Angiotensin-converting enzyme genotype in children and coronary events in their grandparents. Circulation. 1995 Mar 15;91(6):1655–1658. [PubMed]
  • Ludwig E, Corneli PS, Anderson JL, Marshall HW, Lalouel JM, Ward RH. Angiotensin-converting enzyme gene polymorphism is associated with myocardial infarction but not with development of coronary stenosis. Circulation. 1995 Apr 15;91(8):2120–2124. [PubMed]
  • Keavney BD, Dudley CR, Stratton IM, Holman RR, Matthews DR, Ratcliffe PJ, Turner RC. UK prospective diabetes study (UKPDS) 14: association of angiotensin-converting enzyme insertion/deletion polymorphism with myocardial infarction in NIDDM. Diabetologia. 1995 Aug;38(8):948–952. [PubMed]
  • Bonnardeaux A, Davies E, Jeunemaitre X, Féry I, Charru A, Clauser E, Tiret L, Cambien F, Corvol P, Soubrier F. Angiotensin II type 1 receptor gene polymorphisms in human essential hypertension. Hypertension. 1994 Jul;24(1):63–69. [PubMed]
  • Marre M, Bernadet P, Gallois Y, Savagner F, Guyene TT, Hallab M, Cambien F, Passa P, Alhenc-Gelas F. Relationships between angiotensin I converting enzyme gene polymorphism, plasma levels, and diabetic retinal and renal complications. Diabetes. 1994 Mar;43(3):384–388. [PubMed]
  • Doria A, Warram JH, Krolewski AS. Genetic predisposition to diabetic nephropathy. Evidence for a role of the angiotensin I--converting enzyme gene. Diabetes. 1994 May;43(5):690–695. [PubMed]
  • Powrie JK, Watts GF, Ingham JN, Taub NA, Talmud PJ, Shaw KM. Role of glycaemic control in development of microalbuminuria in patients with insulin dependent diabetes. BMJ. 1994 Dec 17;309(6969):1608–1612. [PMC free article] [PubMed]
  • Tarnow L, Cambien F, Rossing P, Nielsen FS, Hansen BV, Lecerf L, Poirier O, Danilov S, Parving HH. 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. 1995 May;44(5):489–494. [PubMed]
  • Schmidt S, Schöne N, Ritz E. Association of ACE gene polymorphism and diabetic nephropathy? The Diabetic Nephropathy Study Group. Kidney Int. 1995 Apr;47(4):1176–1181. [PubMed]
  • Mizuiri S, Hemmi H, Inoue A, Yoshikawa H, Tanegashima M, Fushimi T, Ishigami M, Amagasaki Y, Ohara T, Shimatake H, et al. Angiotensin-converting enzyme polymorphism and development of diabetic nephropathy in non-insulin-dependent diabetes mellitus. Nephron. 1995;70(4):455–459. [PubMed]
  • Doi Y, Yoshizumi H, Yoshinari M, Iino K, Yamamoto M, Ichikawa K, Iwase M, Fujishima M. Association between a polymorphism in the angiotensin-converting enzyme gene and microvascular complications in Japanese patients with NIDDM. Diabetologia. 1996 Jan;39(1):97–102. [PubMed]
  • Dudley CR, Keavney B, Stratton IM, Turner RC, Ratcliffe PJ. U.K. Prospective Diabetes Study. XV: Relationship of renin-angiotensin system gene polymorphisms with microalbuminuria in NIDDM. Kidney Int. 1995 Dec;48(6):1907–1911. [PubMed]
  • Marre M, Leblanc H, Bruel D, Leroy M, Passa P. Relations entre excrétion urinaire d'albumine et rétinopathie chez les diabétiques insulino-dépendants. Presse Med. 1986 Sep 27;15(32):1621–1624. [PubMed]
  • Gallois Y, Vol S, Cacès E, Balkau B. Distribution of fasting serum insulin measured by enzyme immunoassay in an unselected population of 4,032 individuals. Reference values according to age and sex. D.E.S.I.R. Study Group. Données Epidémiologiques sur le Syndrome d'Insulino-Résistance. Diabetes Metab. 1996 Dec;22(6):427–431. [PubMed]
  • Blackburn H. Classification of the electrocardiogram for population studies: Minnesota Code. J Electrocardiol. 1969 Jul;2(3):305–310. [PubMed]
  • Rigat B, Hubert C, Corvol P, Soubrier F. PCR detection of the insertion/deletion polymorphism of the human angiotensin converting enzyme gene (DCP1) (dipeptidyl carboxypeptidase 1). Nucleic Acids Res. 1992 Mar 25;20(6):1433–1433. [PMC free article] [PubMed]
  • Shanmugam V, Sell KW, Saha BK. Mistyping ACE heterozygotes. PCR Methods Appl. 1993 Oct;3(2):120–121. [PubMed]
  • Neels HM, van Sande ME, Scharpé SL. Sensitive colorimetric assay for angiotensin converting enzyme in serum. Clin Chem. 1983 Jul;29(7):1399–1403. [PubMed]
  • Marre M, Claudel JP, Ciret P, Luis N, Suarez L, Passa P. Laser immunonephelometry for routine quantification of urinary albumin excretion. Clin Chem. 1987 Feb;33(2 Pt 1):209–213. [PubMed]
  • Bouhanick B, Berrut G, Chameau AM, Hallar M, Bled F, Chevet B, Vergely J, Rohmer V, Fressinaud P, Marre M. Predictive value of testing random urine sample to detect microalbuminuria in diabetic subjects during outpatient visit. Diabete Metab. 1992 Jan-Feb;18(1):54–58. [PubMed]
  • Fabiny DL, Ertingshausen G. Automated reaction-rate method for determination of serum creatinine with the CentrifiChem. Clin Chem. 1971 Aug;17(8):696–700. [PubMed]
  • Brenner BM. Hemodynamically mediated glomerular injury and the progressive nature of kidney disease. Kidney Int. 1983 Apr;23(4):647–655. [PubMed]
  • Williamson JR, Chang K, Frangos M, Hasan KS, Ido Y, Kawamura T, Nyengaard JR, van den Enden M, Kilo C, Tilton RG. Hyperglycemic pseudohypoxia and diabetic complications. Diabetes. 1993 Jun;42(6):801–813. [PubMed]
  • Alhenc-Gelas F, Baussant T, Hubert C, Soubrier F, Corvol P. The angiotensin converting enzyme in the kidney. J Hypertens Suppl. 1989 Sep;7(7):S9–S14. [PubMed]
  • Erdös EG. Angiotensin I converting enzyme and the changes in our concepts through the years. Lewis K. Dahl memorial lecture. Hypertension. 1990 Oct;16(4):363–370. [PubMed]
  • Jaffa AA, Rust PF, Mayfield RK. Kinin, a mediator of diabetes-induced glomerular hyperfiltration. Diabetes. 1995 Feb;44(2):156–160. [PubMed]
  • Parving HH, Hommel E, Mathiesen E, Skøtt P, Edsberg B, Bahnsen M, Lauritzen M, Hougaard P, Lauritzen E. Prevalence of microalbuminuria, arterial hypertension, retinopathy and neuropathy in patients with insulin dependent diabetes. Br Med J (Clin Res Ed) 1988 Jan 16;296(6616):156–160. [PMC free article] [PubMed]
  • Kofoed-Enevoldsen A, Borch-Johnsen K, Kreiner S, Nerup J, Deckert T. Declining incidence of persistent proteinuria in type I (insulin-dependent) diabetic patients in Denmark. Diabetes. 1987 Feb;36(2):205–209. [PubMed]
  • Borch-Johnsen K, Nørgaard K, Hommel E, Mathiesen ER, Jensen JS, Deckert T, Parving HH. Is diabetic nephropathy an inherited complication? Kidney Int. 1992 Apr;41(4):719–722. [PubMed]
  • Quinn M, Angelico MC, Warram JH, Krolewski AS. Familial factors determine the development of diabetic nephropathy in patients with IDDM. Diabetologia. 1996 Aug;39(8):940–945. [PubMed]
  • Chase HP, Garg SK, Marshall G, Berg CL, Harris S, Jackson WE, Hamman RE. Cigarette smoking increases the risk of albuminuria among subjects with type I diabetes. JAMA. 1991 Feb 6;265(5):614–617. [PubMed]
  • Tarnow L, Cambien F, Rossing P, Nielsen FS, Hansen BV, Lecerf L, Poirier O, Danilov S, Boelskifte S, Borch-Johnsen K. Insertion/deletion polymorphism in the angiotensin-I-converting enzyme gene is associated with coronary heart disease in IDDM patients with diabetic nephropathy. Diabetologia. 1995 Jul;38(7):798–803. [PubMed]
  • Lieberman J, Sastre A. Serum angiotensin-converting enzyme: elevations in diabetes mellitus. Ann Intern Med. 1980 Dec;93(6):825–826. [PubMed]
  • Marre M, Chatellier G, Leblanc H, Guyene TT, Menard J, Passa P. Prevention of diabetic nephropathy with enalapril in normotensive diabetics with microalbuminuria. BMJ. 1988 Oct 29;297(6656):1092–1095. [PMC free article] [PubMed]
  • Hallab M, Gallois Y, Chatellier G, Rohmer V, Fressinaud P, Marre M. Comparison of reduction in microalbuminuria by enalapril and hydrochlorothiazide in normotensive patients with insulin dependent diabetes. BMJ. 1993 Jan 16;306(6871):175–182. [PMC free article] [PubMed]
  • Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group. N Engl J Med. 1993 Nov 11;329(20):1456–1462. [PubMed]
  • Harden PN, Geddes C, Rowe PA, McIlroy JH, Boulton-Jones M, Rodger RS, Junor BJ, Briggs JD, Connell JM, Jardine AG. Polymorphisms in angiotensin-converting-enzyme gene and progression of IgA nephropathy. Lancet. 1995 Jun 17;345(8964):1540–1542. [PubMed]
  • Yoshida H, Mitarai T, Kawamura T, Kitajima T, Miyazaki Y, Nagasawa R, Kawaguchi Y, Kubo H, Ichikawa I, Sakai O. Role of the deletion of polymorphism of the angiotensin converting enzyme gene in the progression and therapeutic responsiveness of IgA nephropathy. J Clin Invest. 1995 Nov;96(5):2162–2169. [PMC free article] [PubMed]
  • van Essen GG, Rensma PL, de Zeeuw D, Sluiter WJ, Scheffer H, Apperloo AJ, de Jong PE. Association between angiotensin-converting-enzyme gene polymorphism and failure of renoprotective therapy. Lancet. 1996 Jan 13;347(8994):94–95. [PubMed]
  • Hannedouche T, Landais P, Goldfarb B, el Esper N, Fournier A, Godin M, Durand D, Chanard J, Mignon F, Suo JM, et al. Randomised controlled trial of enalapril and beta blockers in non-diabetic chronic renal failure. BMJ. 1994 Oct 1;309(6958):833–837. [PMC free article] [PubMed]
  • Maschio G, Alberti D, Janin G, Locatelli F, Mann JF, Motolese M, Ponticelli C, Ritz E, Zucchelli P. Effect of the angiotensin-converting-enzyme inhibitor benazepril on the progression of chronic renal insufficiency. The Angiotensin-Converting-Enzyme Inhibition in Progressive Renal Insufficiency Study Group. N Engl J Med. 1996 Apr 11;334(15):939–945. [PubMed]
  • Tarnow L, Cambien F, Rossing P, Nielsen FS, Hansen BV, Ricard S, Poirier O, Parving HH. Angiotensinogen gene polymorphisms in IDDM patients with diabetic nephropathy. Diabetes. 1996 Mar;45(3):367–369. [PubMed]
  • Doria A, Onuma T, Gearin G, Freire MB, Warram JH, Krolewski AS. Angiotensinogen polymorphism M235T, hypertension, and nephropathy in insulin-dependent diabetes. Hypertension. 1996 May;27(5):1134–1139. [PubMed]
  • Fogarty DG, Harron JC, Hughes AE, Nevin NC, Doherty CC, Maxwell AP. A molecular variant of angiotensinogen is associated with diabetic nephropathy in IDDM. Diabetes. 1996 Sep;45(9):1204–1208. [PubMed]
  • Viberti GC, Keen H, Wiseman MJ. Raised arterial pressure in parents of proteinuric insulin dependent diabetics. Br Med J (Clin Res Ed) 1987 Aug 29;295(6597):515–517. [PMC free article] [PubMed]
  • Christlieb AR, Janka HU, Kraus B, Gleason RE, Icasas-Cabral EA, Aiello LM, Cabral BV, Solano A. Vascular reactivity to angiotensin II and to norepinephrine in diabetic subjects. Diabetes. 1976 Apr;25(4):268–274. [PubMed]
  • Ballermann BJ, Skorecki KL, Brenner BM. Reduced glomerular angiotensin II receptor density in early untreated diabetes mellitus in the rat. Am J Physiol. 1984 Jul;247(1 Pt 2):F110–F116. [PubMed]
  • Rossing P, Tarnow L, Nielsen FS, Boelskifte S, Brenner BM, Parving HH. Short stature and diabetic nephropathy. BMJ. 1995 Feb 4;310(6975):296–297. [PMC free article] [PubMed]

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