A polymorphism in the CTGF promoter region associated with systemic sclerosis.
BACKGROUND
Systemic sclerosis (scleroderma) is a life-threatening autoimmune disease that is characterized by the presence of specific autoantibodies and fibrosis of the skin and major internal organs.


METHODS
We genotyped a polymorphism (G-945C) in the promoter of the connective-tissue growth factor (CTGF) gene in 1000 subjects in two groups: group 1, consisting of 200 patients with systemic sclerosis and 188 control subjects; and group 2, consisting of 300 patients with systemic sclerosis and 312 control subjects. The combined groups represented an estimated 10% of patients with systemic sclerosis in the United Kingdom. We tested the effect of the polymorphism on the transcription of CTGF.


RESULTS
The GG genotype was significantly more common in patients with systemic sclerosis than in control subjects in both groups, with an odds ratio for the combined group of 2.2 (95% confidence interval [CI], 1.5 to 3.2; P<0.001 for trend). Analysis of the combined group of patients with systemic sclerosis showed a significant association between homozygosity for the G allele and the presence of anti-topoisomerase I antibodies (odds ratio, 3.3; 95% CI, 2.0 to 5.6; P<0.001) and fibrosing alveolitis (odds ratio, 3.1; 95% CI, 1.9 to 5.0; P<0.001). We observed that the substitution of cytosine for guanine created a binding site of the transcriptional regulators Sp1 and Sp3. The C allele has high affinity for Sp3 and is associated with severely reduced transcriptional activity. A chromatin immunoprecipitation assay showed a marked shift in the ratio of Sp1 to Sp3 binding at this region, demonstrating functional relevance in vivo.


CONCLUSIONS
The G-945C substitution represses CTGF transcription, and the -945G allele is significantly associated with susceptibility to systemic sclerosis.
Fonseca
Carmen
C
Centre for Rheumatology, Royal Free and University College Medical School, London, United Kingdom.
Lindahl
Gisela E
GE
Ponticos
Markella
M
Sestini
Piersante
P
Renzoni
Elisabetta A
EA
Holmes
Alan M
AM
Spagnolo
Paolo
P
Pantelidis
Panagiotis
P
Leoni
Patricia
P
McHugh
Neil
N
Stock
Carmel J
CJ
Shi-Wen
Xu
X
Denton
Christopher P
CP
Black
Carol M
CM
Welsh
Kenneth I
KI
du Bois
Roland M
RM
Abraham
David J
DJ
D016022:Case-Control Studies; D055513:Connective Tissue Growth Factor; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics*; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D012307:Risk Factors; D012595:Scleroderma, Systemic / Q000235:genetics*; D017422:Sequence Analysis, DNA; D014158:Transcription, Genetic
C526317:CCN2 protein, human; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D055513:Connective Tissue Growth Factor