Genetic variant in the promoter of connective tissue growth factor gene confers susceptibility to nephropathy in type 1 diabetes.
BACKGROUND The evidence for genetic susceptibility in the pathogenesis of diabetic nephropathy is well recognised, but the genes involved remain to be identified. It is hypothesised that mutations within the gene encoding connective tissue growth factor (CTGF/CCN2) will increase the propensity of diabetic subjects to develop nephropathy. METHODS AND RESULTS Genomic screening was performed for single nucleotide polymorphisms (SNPs) within the CTGF gene in 862 subjects from the DCCT/EDIC cohort of type 1 diabetes. A novel SNP was identified in the promoter region that changes a C-G at the position -20. The frequency of GG genotype in microalbuminuric patients (albumin excretion rate (AER) >40 mg/24 h) is significantly greater than diabetics with AER <40 mg/24 h, p<0.0001. The relative risk (RR) to develop microalbuminuria in diabetic subjects with the polymorphism is 3X higher than diabetic subjects without the polymorphism (RR 3.142, 95% CI 1.9238 to 5.1249; p<0.05). Kaplan-Meier survival curves demonstrated that the GG genotype group developed microalbuminuria and macroalbuminuria at a more rapid rate than the GC or CC genotypes. Functional studies demonstrated that the basal activity of the substituted allele/promoter (-20 GG allele) was significantly greater than that of the wild type promoter (-20 CC genotype). This higher level of basal activity of substituted allele CTGF/CCN2 promoter was abrogated upon suppression of Smad1 levels, indicating that SNP region in the CTGF/CCN2 promoter plays a vital role in the gene expression. CONCLUSIONS These findings provide the first evidence that variants within the promoter region of the CTGF/CCN2 gene predisposes diabetic subjects to develop albuminuria and demonstrate that Smad1 [corrected] controls the expression of CTGF/CCN2 promoter through this region.
Wang
Bing
B
Department of Medicine, Medical University of South Carolina, 114 Doughty Street, P.O. Box 250776 Charleston, SC 29425, USA.
Carter
Rickey E
RE
Jaffa
Miran A
MA
Nakerakanti
Sashidhar
S
Lackland
Daniel
D
Lopes-Virella
Maria
M
Trojanowska
Maria
M
Luttrell
Louis M
LM
Jaffa
Ayad A
AA
D000293:Adolescent; D000328:Adult; D001483:Base Sequence; D015331:Cohort Studies; D055513:Connective Tissue Growth Factor / Q000235:genetics*; D004252:DNA Mutational Analysis; D003922:Diabetes Mellitus, Type 1 / Q000150:complications*; D003928:Diabetic Nephropathies / Q000209:etiology / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic / Q000235:genetics*; D034622:RNA Interference; D051898:Smad1 Protein / Q000235:genetics; D055815:Young Adult
C497399:SMAD1 protein, human; D051898:Smad1 Protein; D055513:Connective Tissue Growth Factor