Genetic risk factors for diabetic nephropathy on chromosomes 6p and 7q identified by the set-association approach
| Authors | |
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| Year of publication | 2007 |
| Type | Article in Periodical |
| Magazine / Source | Diabetologia |
| MU Faculty or unit | |
| Citation | |
| Field | Endocrinology, diabetology, metabolism, nutrition |
| Keywords | diabetic nephropathy; endothelin; haplotype; LTA; lymphotoxin A; nitric oxide synthase; NOS3; RAGE; Receptor of Advanced Glycation End products; set-association |
| Description | Aims: We studied association of a set of 45 SNPs in 20 candidate genes on 8 chromosomes with diabetic nephropathy (DN) in type 2 diabetes mellitus. We aimed to compare two methodological approaches suitable for analysing susceptibility to complex traits - single vs. multilocus analysis. Methods: The study comprised a total of 647 in one of the three groups: diabetics with or without DN or non-diabetics. Genotypes were detected by PCR-based methodology (PCR only, PCR + RFLP or allele-specific PCR). Haplotypes were inferred in silico, Set association (programme SUMSTAT) was used for multilocus analysis. Results: After correction for multiple comparisons, one SNP only - RAGE 2184A/G (AGER gene) - showed a significant association with DN (p=0.0006) in single-locus analysis. In multilocus analysis, six SNPs exhibited significant association with DN: 4 SNPs on chromosome 6p (AGER 2184A/G, LTA 252A/G, EDN1 8002G/A, and AGER -429T/C) and 2 SNPs on chromosome 7q (NOS3 774C/T and NOS3 E298D), omnibus p=0.033. Haplotype analysis revealed significant differences between DN and control groups in haplotype frequencies on chromosome 6 (p=0.0002), however, no significant difference in frequencies of the NOS3 haplotypes on chromosome 7. Logistic regression identified SNPs AGER 2184A/G and NOS3 774C/T together with diabetes duration and HbA1c as significant predictors of DN. Finally, testing for interactions between SNPs on chromosomes 6 and 7 did not furnish significant evidence for epistatic interaction. Conclusions: Using set-association approach we identified significant association of several SNPs on chromosomes 6 and 7 with DN. Both approaches - single and multilocus - represent complementary methods. |
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