title: Association between variation in the actin-binding gene caldesmon and diabetic nephropathy in type 1 diabetes.
abstract: Dysfunction of the actin cytoskeleton is a key event in the pathogenesis of diabetic nephropathy. We previously reported that certain cytoskeletal genes are upregulated in mesangial cells exposed to a high extracellular glucose concentration. One such gene, caldesmon, lies on chromosome 7q35, a region linked to nephropathy in family studies, making it a candidate susceptibility gene for diabetic nephropathy. We screened all exons, untranslated regions, and a 5-kb region upstream of the gene for variation using denaturing high-performance liquid chromatography technology. An A>G single nucleotide polymorphism (SNP) at position -579 in the promoter region was associated with nephropathy in a case-control study using 393 type 1 diabetic patients from Northern Ireland (odds ratio [OR] 1.38, 95% CI 1.02-1.86, P = 0.03). A similar trend was found in an independent sample from a second center. When the sample groups were combined (n = 606), the association between the -579G allele and nephropathy remained significant (OR 1.35, 1.07-1.70, P = 0.01). The haplotype structure in the surrounding 7-kb region was determined. No single haplotype was more strongly associated with nephropathy than the -579A>G SNP. These results suggest a role for the caldesmon gene in susceptibility to diabetic nephropathy in type 1 diabetes.
authors.affiliation: Department of Nephrology, Queen's University Belfast, Belfast, Northern Ireland. bryanconway@ntlworld.com
authors.forename: Bryan R
authors.initials: BR
authors.lastname: Conway
authors.forename: A Peter
authors.initials: AP
authors.lastname: Maxwell
authors.forename: David A
authors.initials: DA
authors.lastname: Savage
authors.forename: Chris C
authors.initials: CC
authors.lastname: Patterson
authors.forename: Peter P
authors.initials: PP
authors.lastname: Doran
authors.forename: Madeline
authors.initials: M
authors.lastname: Murphy
authors.forename: Hugh R
authors.initials: HR
authors.lastname: Brady
authors.forename: Damian G
authors.initials: DG
authors.lastname: Fogarty
mesh_terms: D001483:Base Sequence; D002148:Calmodulin-Binding Proteins / Q000235:genetics*; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D003928:Diabetic Nephropathies / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D007494:Ireland; D009660:Northern Ireland; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics
chemical_list: D002148:Calmodulin-Binding Proteins