Haplotype-based association study between the region of 6p chromosome spanning the AGER - TNFA - LTA - NFKBIL1 - BAT1 and diabetic nephropathy



Rok publikování 2007
Druh Konferenční abstrakty
Fakulta / Pracoviště MU

Lékařská fakulta

Popis Aims: Previously we identified certain haplotype in the AGER gene (encoding Receptor of Advanced Glycation End-products) as a risk factor for diabetic nephropathy (DN) [Kankova et al., Nephrol Dial Transpl 2005]. Recently, multiple SNPs in the BAT1, NFKBIL1 and LTA genes have been found associated with myocardial infarction in the genome-wide association study. Detail analysis of the given MHC III region on chromosome 6p spanning the AGER - TNFA - LTA - NFKBIL1 - BAT1 loci could further elucidate the character of association and help to identify causal variant. The aims of the study were (1) to perform more detail haplotype analysis based on genotypes of multiple single nucleotide polymorphisms in the five genes and (2) to ascertain eventual association between certain haplotype(s) with DN and identify en eventual causal variant among them. Methods: A total of 600 diabetic subjects were included in the cross-sectional case - control study. Cases (~ half of the total number) were subjects with T1DM or T2DM and parallel DN; controls were diabetics without organ complications (gender- and age-matched). Genotypes were detected with PCR-based methodology using fluorescent-labelled probes (TaqMan). Haplotypes were inferred in silico using Bayesian algorithm (PHASE). Differences in haplotype frequencies were tested by permutation testing. Logistic regression (incl. input variables such as age and gender, DM duration, fasting glycemia, HbA1c, microalbuminuria, proteinuria and GFR), survival analysis (Kaplan-Meier) and Cox proportional hazard regression were be used to assess the risk of particular haplotypes eventually exhibiting association with diabetic nephropathy. Results: Haplotype distribution differed significantly between DN vs. non-DN groups (P<0.05, 10 000 permutations). Group of pooled haplotypes containing either AGER -429C or 2184G allele was significantly associated with DN (~23% DN vs. 16% non-DN, P<0.05). Conclusions: Based on the results of detail haplotype analysis of a candidate region of MHC III on chromosome 6p we identify markers in AGER gene as substitutions solely responsible for previously ascertained association with DN and are thus likely to be causal variants. Functional analysis of both substitutions is in progress
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