Haplotype analysis of the RAGE gene: identification of a haplotype marker for diabetic nephropathy in type 2 diabetes mellitus
| Authors | |
|---|---|
| Year of publication | 2005 |
| Type | Article in Periodical |
| Magazine / Source | Nephrology Dialysis Transplantation |
| MU Faculty or unit | |
| Citation | |
| Field | Endocrinology, diabetology, metabolism, nutrition |
| Keywords | AGEs; complications; diabetic nephropathy; haplotype analysis; polymorphism; RAGE |
| Description | 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 SNPs in 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 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 P=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); ORs 1.65 [95% 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. |
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