title: Investigation of DNA polymorphisms in SMAD genes for genetic predisposition to diabetic nephropathy in patients with type 1 diabetes mellitus.
abstract: OBJECTIVE
  SMAD proteins are involved in multiple signalling pathways and are key modulators of gene expression. We hypothesised that genetic variation in selected SMAD genes contributes to susceptibility to diabetic nephropathy.
  
  
  METHODS
  We selected 13 haplotype tag (ht) single nucleotide polymorphisms (SNPs) from 67 variants identified by resequencing the SMAD2 and SMAD3 genes. For SMAD1, SMAD4 and SMAD5 genes, genotype data were downloaded for 217 SNPs from Phase II of the International HapMap project. Of these, 85 SNPs met our inclusion criteria, resulting in the selection of 13 tag SNPs for further investigation. A case-control approach was employed, using 267 nephropathic patients and 442 controls with type 1 diabetes from Ireland. Two further populations (totalling 1,407 patients, 2,238 controls) were genotyped to validate initial findings. Genotyping was conducted using iPLEX, TaqMan and gel electrophoresis.
  
  
  RESULTS
  The distribution of genotypes was in Hardy-Weinberg equilibrium. Analysis by the chi(2) test of genotype and allele frequencies in patients versus controls in the Irish population (n = 709) revealed evidence for the association of one allele at 5% level of significance (rs10515478, p(uncorrected) = 0.006; p(corrected) = 0.04). This finding represents a relatively small difference in allele frequency of 6.4% in the patient group compared with 10.7% in the control group; this difference was not supported in subsequent investigations using DNA from European individuals with similar phenotypic characteristics.
  
  
  CONCLUSIONS
  We selected an appropriate subset of variants for the investigation of common genetic risk factors and assessed SMAD1 to SMAD5 genes for association with diabetic nephropathy. We conclude that common polymorphisms in these genes do not strongly influence genetic susceptibility to diabetic nephropathy in white individuals with type 1 diabetes mellitus.
authors.affiliation: Nephrology Research Group, Queen's University of Belfast, c/o Regional Genetics Centre, Belfast City Hospital, Belfast, Northern Ireland, UK. a.j.mcknight@qub.ac.uk
authors.forename: A J
authors.initials: AJ
authors.lastname: McKnight
authors.forename: A M
authors.initials: AM
authors.lastname: Woodman
authors.forename: M
authors.initials: M
authors.lastname: Parkkonen
authors.forename: C C
authors.initials: CC
authors.lastname: Patterson
authors.forename: D A
authors.initials: DA
authors.lastname: Savage
authors.forename: C
authors.initials: C
authors.lastname: Forsblom
authors.forename: K A
authors.initials: KA
authors.lastname: Pettigrew
authors.forename: D
authors.initials: D
authors.lastname: Sadlier
authors.forename: P H
authors.initials: PH
authors.lastname: Groop
authors.forename: A P
authors.initials: AP
authors.lastname: Maxwell
mesh_terms: D000293:Adolescent; D001794:Blood Pressure; D003922:Diabetes Mellitus, Type 1 / Q000150:complications / Q000235:genetics* / Q000503:physiopathology; D003928:Diabetic Nephropathies / Q000235:genetics* / Q000503:physiopathology; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006442:Glycated Hemoglobin / Q000378:metabolism; D006801:Humans; D007676:Kidney Failure, Chronic / Q000453:epidemiology / Q000235:genetics; D008875:Middle Aged; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D051785:Smad Proteins / Q000235:genetics*; D051898:Smad1 Protein / Q000235:genetics; D051901:Smad4 Protein / Q000235:genetics; D051902:Smad5 Protein / Q000235:genetics
chemical_list: D006442:Glycated Hemoglobin; D051785:Smad Proteins; D051898:Smad1 Protein; D051901:Smad4 Protein; D051902:Smad5 Protein; C497399:SMAD1 protein, human; C497796:SMAD4 protein, human; C497797:SMAD5 protein, human