Association between angiotensin-converting enzyme gene polymorphisms and diabetic nephropathy: case-control, haplotype, and family-based study in three European populations.

Angiotensin 1-converting enzyme gene (ACE) is a risk factor for diabetic nephropathy (DN) in patients with type 1 diabetes. The selection of this candidate gene is supported by cross-sectional and follow-up studies, but no convincing family-based studies are available. Recruited were 1057 patients (with DN: persistent albuminuria with or without renal failure) and 1127 control subjects (long-standing [> or =15 yr] normoalbuminuric patients with type 1 diabetes) in Denmark, Finland, and France and 532 family trios that were composed of 244 trios with DN probands and 288 trios with non-DN probands. Five ACE polymorphisms were studied. In the case-control analysis, the rs1800764-C, rs4311-T, Insertion/deletion (I/D or rs1799752)-D, rs4366-G, and rs12449782-G alleles were associated with an increased risk for DN, homogeneously across populations, with allelic odds ratios of 1.11 (95% confidence interval 1.00 to 1.22), 1.18 (1.04 to 1.33), 1.13 (1.02 to 1.23), 1.10 (0.99 to 1.20), and 1.12 (1.01 to 1.23), respectively. Haplotype analysis further demonstrated that the haplotype defined by the D, rs4366_G and rs12449782_G alleles was associated with a greater risk for DN. Even though no significant allelic overtransmission to DN or non-DN probands was detected, the family-based study provided consistent results with the case-control analysis. In a large case-control study, it was shown that the ACE polymorphisms were associated with DN; these findings were not confirmed in a family-based association study. This study population is suitable to search for additional candidate genes for DN.

[1]  K. Chia,et al.  A Disease Haplotype for Advanced Nephropathy in Type 2 Diabetes at the ACE Locus , 2006, Diabetes.

[2]  Andrzej S Krolewski,et al.  Genetics of Kidneys in Diabetes (GoKinD) study: a genetics collection available for identifying genetic susceptibility factors for diabetic nephropathy in type 1 diabetes. , 2006, Journal of the American Society of Nephrology : JASN.

[3]  M Farrall,et al.  Integrating case-control and TDT studies. , 2005, Annals of human genetics.

[4]  M. Farrall,et al.  Integrating Case‐control and TDT Studies , 2005 .

[5]  K. Chia,et al.  Angiotensin-I converting enzyme insertion/deletion polymorphism and its association with diabetic nephropathy: a meta-analysis of studies reported between 1994 and 2004 and comprising 14,727 subjects , 2005, Diabetologia.

[6]  S. Scherer,et al.  Genetic variation at the ACE gene is associated with persistent microalbuminuria and severe nephropathy in type 1 diabetes: the DCCT/EDIC Genetics Study. , 2005, Diabetes.

[7]  V. Rigalleau,et al.  Different patterns of insulin resistance in relatives of type 1 diabetic patients with retinopathy or nephropathy: the Genesis France-Belgium Study. , 2004, Diabetes care.

[8]  H. Parving,et al.  Predictors for the development of microalbuminuria and macroalbuminuria in patients with type 1 diabetes: inception cohort study , 2004, BMJ : British Medical Journal.

[9]  D. Tregouet,et al.  A new algorithm for haplotype‐based association analysis: the Stochastic‐EM algorithm , 2004, Annals of human genetics.

[10]  S. Bandinelli,et al.  Microalbuminuria in type 1 diabetes: rates, risk factors and glycemic threshold. , 2001, Kidney international.

[11]  N. Chaturvedi.  Should all patients with type 1 diabetes mellitus and microalbuminuria receive angiotensin-converting enzyme inhibitors? A meta-analysis of individual patient data. , 2001, Annals of internal medicine.

[12]  G. Chatellier,et al.  Prognostic value of angiotensin-I converting enzyme I/D polymorphism for nephropathy in type 1 diabetes mellitus: a prospective study. , 2001, Journal of the American Society of Nephrology : JASN.

[13]  L. E. Mitchell.  Relationship between case‐control studies and the transmission/disequilibrium test , 2000, Genetic epidemiology.

[14]  R. Osterby,et al.  Influence of insertion/deletion polymorphism in the ACE-I gene on the progression of diabetic glomerulopathy in type 1 diabetic patients with microalbuminuria. , 2000, Diabetes care.

[15]  H. Lehrach,et al.  A novel procedure for efficient genotyping of single nucleotide polymorphisms. , 2000, Nucleic acids research.

[16]  D. Clayton,et al.  A generalization of the transmission/disequilibrium test for uncertain-haplotype transmission. , 1999, American journal of human genetics.

[17]  A. Krolewski.  Genetics of diabetic nephropathy: evidence for major and minor gene effects. , 1999, Kidney international.

[18]  G Chatellier,et al.  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. , 1997, The Journal of clinical investigation.

[19]  A. Krolewski,et al.  Familial factors determine the development of diabetic nephropathy in patients with IDDM , 1996, Diabetologia.

[20]  H. Parving,et al.  Lack of Relationship Between an Insertion/Deletion Polymorphism in the Angiotensin I–Converting Enzyme Gene and Diabetic Nephropathy and Proliferative Retinopathy in IDDM Patients , 1995, Diabetes.

[21]  F. Cambien,et al.  Relationships Between Angiotensin I Converting Enzyme Gene Polymorphism, Plasma Levels, and Diabetic Retinal and Renal Complications , 1994, Diabetes.

[22]  R. Bain,et al.  The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group. , 1993, The New England journal of medicine.

[23]  H. Parving,et al.  Is diabetic nephropathy an inherited complication? , 1992, Kidney international.

[24]  P Corvol,et al.  An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels. , 1990, The Journal of clinical investigation.

[25]  L. Kuller,et al.  Prevalence of Complications in IDDM by Sex and Duration: Pittsburgh Epidemiology of Diabetes Complications Study II , 1990, Diabetes.

[26]  E. Seaquist,et al.  Familial clustering of diabetic kidney disease. Evidence for genetic susceptibility to diabetic nephropathy. , 1989, The New England journal of medicine.

[27]  C. Mogensen.  The kidney and hypertension in diabetes mellitus , 1989, Springer US.

[28]  F. Cambien,et al.  Familial resemblance of plasma angiotensin-converting enzyme level: the Nancy Study. , 1988, American journal of human genetics.

[29]  B. Brenner,et al.  Prevention of diabetic glomerulopathy by pharmacological amelioration of glomerular capillary hypertension. , 1986, The Journal of clinical investigation.

[30]  T. Lohmeier,et al.  Control of glomerular filtration rate by renin-angiotensin system. , 1977, The American journal of physiology.

[31]  G. Lathrop,et al.  High-resolution genetic mapping of the ACE-linked QTL influencing circulating ACE activity , 2002, European Journal of Human Genetics.

[32]  C. Mogensen.  Definition of Diabetic Renal Disease in Insulin-Dependent Diabetes Mellitus Based on Renal Function Tests , 2000 .

[33]  F. Cambien,et al.  Relationships between angiotensin I converting enzyme gene polymorphism, plasma levels, and diabetic retinal and renal complications. , 1994, Diabetes.

[34]  A Fournier,et al.  The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. , 1994, The New England journal of medicine.

[35]  P. Corvol,et al.  Distribution of plasma angiotensin I-converting enzyme levels in healthy men: relationship to environmental and hormonal parameters. , 1991, The Journal of laboratory and clinical medicine.