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Polymorphism of Angiotensin Converting Enzyme, Angiotensinogen, and Angiotensin II Type 1 Receptor Genes and End-Stage Renal Failure in IgA Nephropathy

IGARAS—A Study of 274 Men

LUC FRIMAT^*, CHRISTOPHE PHILIPPE, MARIE-NOËLLE MAGHAKIAN^*, PHILIPPE JONVEAUX, BRUNO HURAULT DE LIGNY^§, FRANCIS GUILLEMIN and MICHÈLE KESSLER^*

^* Department of Nephrology, University Hospital, Nancy, France.
Department of Genetics, University Hospital, Nancy, France.
Department of Biostatistics, University Hospital, Nancy, France.
^§ Department of Nephrology, University Hospital Caen, France.

Correspondence to Dr. Luc Frimat, Service de Néphrologie, CHU de Nancy, Hôpitaux de Brabois, 54500 Vandoeuvre-les-Nancy, France. Phone: 33 3 83 15 31 69; Fax: 33 3 83 15 35 31; E-mail: l.frimat{at}chu-nancy.fr

Abstract. The impact of renin-angiotensin system (RAS) gene polymorphism on the prognosis of IgA nephropathy (IgAN) is still debated. A longitudinal study of renal prognosis in patients with IgAN was conducted to search retrospectively for a genotype-phenotype association between RAS polymorphisms and end-stage renal failure (ESRF). A classification based on serum creatinine (S_cr) and 24-h proteinuria (24-P) measured at the time of renal biopsy was used to estimate the risk of ESRF in IgAN: stage 1 (S_cr 150 µmol/L and 24-P < 1 g), stage 2 (S_cr > 150 µmol/L and 24-P < 1 g or S_cr 150 µmol/L and 24-P 1 g), stage 3 (S_cr > 150 µmol/L and 24-P 1 g). Deletion/insertion polymorphism (D/I) of the angiotensin I converting enzyme gene, M235T polymorphism (T/M) of the angiotensinogen gene and A1166C polymorphism (C/A) of the angiotensin II type 1 receptor gene were determined in 274 Caucasian men with biopsy-proven IgAN (n = 86, 112, and 76 in stages 1, 2, and 3, respectively). Mean global follow-up was 6 ± 5 yr after renal biopsy. For stages 1, 2, and 3, ESRF developed in 7 (8.1%), 39 (34.8%), and 49 (64.4%) cases (P < 0.0001), 11.7 ± 4, 5.4 ± 4, and 2 ± 2 yr, respectively, after renal biopsy (P < 0.001). The distributions of the three genotypes into the three stages were similar. Different distributions were observed when patients were grouped by stage and genotype: ID+DD: 72% in stage 1 versus 84.6% in stages 2 + 3 (P = 0.02; = 0.14); MT+TT: 66.2% in stages 1 + 2 versus 78.9% in stage 3 (P = 0.04; = 0.09); and AA+AC: 89.9% in stages 1 + 2 versus 97.4% in stage 3 (P = 0.04; = -0.1). However, with the use of the Cox proportional hazard model, none of the three genotypes was found to have predictive value for renal survival. Compared with S_cr and 24-P, genotypes DD, TT, and AA are unlikely to serve as clinically useful predictors of ESRF in IgAN.

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Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673