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

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 RAGE(2) 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 P(corr)<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 RAGE(2) diplotype groups (P<0.05); median DN-free interval was 9.6 years in RAGE(2) +/+ homozygotes, 15.2 years in +/- heterozygotes and 17.0 years in the -/- combination.

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