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NDT Advance Access originally published online on March 24, 2005
Nephrology Dialysis Transplantation 2005 20(6):1093-1102; doi:10.1093/ndt/gfh711
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© The Author [2005]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org

Original Article

Haplotype analysis of the RAGE gene: identification of a haplotype marker for diabetic nephropathy in type 2 diabetes mellitus

Katerina Kanková1, Andrea Stejskalová1, Miluse Hertlová2 and Vladimír Znojil1

1 Department of Pathophysiology, Faculty of Medicine, Masaryk University Brno and 2 Third Department of Internal Medicine, University Hospital Brno-Bohunice, Czech Republic

Correspondence and offprint requests to: Katerina Kanková, MD, PhD, Masaryk University Brno, Faculty of Medicine, Department of Pathophysiology, Komenského nám. 2, 66243 Brno, Czech Republic. Tel: +420 549 494 525, Fax: +420 549 494 340, Email: kankov{at}med.muni.cz

Background. Diabetic nephropathy (DN) represents a devastating complication of diabetes. Family clustering, heterogeneity in the onset and progression and results of segregation studies indicate that susceptibility to DN is a complex trait.

Methods. Common single nucleotide polymorphisms in the RAGE (receptor of advanced glycation end-products) gene (–429T/C, –374T/A, G82S, 1704G/T, 2184A/G and 2245G/A) were studied in the association study comprising 605 Caucasian subjects by means of haplotype analysis in order to identify an eventual haplotype marker for DN in type 2 diabetes. Haplotypes were constructed computationally; frequencies were compared among groups of subjects with type 2 diabetes (DM) and DN, diabetics without DN and non-diabetics. Survival analysis was carried out to ascertain whether certain RAGE haplotypes influence onset of DN in type 2 diabetics.

Results. Significant differences in haplotype frequencies among DM + DN vs DM non-DN and non-DM groups were found (P = 0.0007 and 0.0013, respectively; permutation test). Frequency of the RAGE2 haplotype containing minor alleles in positions –429 and 2184 (CTGGGG) in the DN group was significantly higher than in the two control groups (21.7% vs 12.8% and 13.8%, both Pcorr<0.003; two-tail Fisher exact test); odds ratios 1.65 [95% confidence interval (CI): 1.08–2.50; P = 0.020] and 1.79 (95% CI: 1.22–2.62; P = 0.003), respectively. In survival analysis, duration of diabetes until the onset of DN (e.g. appearance of persistent proteinuria) was significantly different among RAGE2 diplotype groups (P<0.05); median DN-free interval was 9.6 years in RAGE2 +/+ homozygotes, 15.2 years in +/– heterozygotes and 17.0 years in the –/– combination.

Conclusions. The RAGE2 haplotype is associated with DN in type 2 diabetics and with earlier DN onset and, thus, can be regarded a marker for DN.

Keywords: advanced glycation end-products; complications; diabetic nephropathy; haplotype analysis; polymorphism; RAGE


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