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Genomics of complexdisorders I 2008 год

Genomics of complex disorders I
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Аннотация: Diabetic nephropathy (DNP) is an important complication of type 2 diabetes, with 15-60% of patients developing persistent microalbuminuria, progressing to nephropathy and renal failure.Genetic predisposition is a major determinant in the development of renal complications of diabetes.The renin angiotensin system (RAS) and the interlinked inflammatory cascade modulate the progression of renal disease.We hypothesize that gene polymorphisms in the RAScytokine pathway, through altered gene expression of inflammatory cytokines, are potential factors that influence the susceptibility to DNP.In the present study, we examined association of 13 single nucleotide polymorphisms (SNPs) within seven candidate loci of RAS cytokine pathway with DNP in Asian Indian subjects.Research Design and Methods: We analyzed 13 SNPs (rs4311, I/D, rs4343 in ACE, rs5050, rs4762, rs699 in AGT, rs5186 in AGTR1, rs1024611, rs3917887 in CCL2, rs1982073, Tyr81His in TGFB1, rs4073 in IL8, and Del 32 variant in the CCR5 genes) in 495 North Indian subjects with type 2 diabetes [with and without nephropathy (DM)] by using PCR-RFLP assay.We then reconstructed haplotypes by combination of two genes (ACE and CCL2) present on the common locus chromosome 17q.We also assessed the gene-gene interaction among the studied loci using multi-factor dimensionality reduction (MDR) technique.Results: Among the 13 loci examined, 6 were significantly associated with increased risk of DNP in our population (ACE I/D, p = 0.004; AGT, p = 0.0001; MCP I/D, p = 0.006; IL8, p = 0.02; CCR5, p = 0.0001).Haplotype analysis (ACE and CCL2) revealed that frequency of haplotype (G-I-T-D-G) was significantly higher (p = 0.03) in DNP group as compared to DM group.Haplotypes (A-D-C-I-A, A-D-C-I-G and G-D-C-I-G) conferred significantly (p \ 0.04) lower risk and were protective.Epistasis observed with MDR showed synergy between two loci rs699 (AGT) and CCR5 del 32 variant further conferring a four fold risk of developing DNP in diabetics. Conclusion:The RAS cytokine pathway is predisposing with ACE, AGT, CCL2, IL8 and CCR5 gene variants being associated with DNP.Gene gene interaction reveals synergy between CCR5 Del 32 and rs699 variants towards DNP development.Also, a high risk haplotype on chromosome 17q, is associated with DNP in Asian Indians.
Год издания: 2008
Издательство: Springer Science+Business Media
Источник: Genomic Medicine
Ключевые слова: Genomics and Rare Diseases, Nutrition, Genetics, and Disease
Другие ссылки: Genomic Medicine (PDF)
Genomic Medicine (HTML)
Europe PMC (PubMed Central) (PDF)
Europe PMC (PubMed Central) (HTML)
PubMed Central (HTML)
PubMed (HTML)