Association between a CTGF gene polymorphism and systemic sclerosis in a French population.
OBJECTIVE
Systemic sclerosis (SSc) is a life-threatening autoimmune disease characterized by chronic fibrosis of the skin and internal organs. Connective tissue growth factor (CTGF) is believed to be a primary mediator of chronic fibrosis. We assessed the possible association between 7 single-nucleotide polymorphisms (SNP) in the CTGF gene and scleroderma in a French population (registration number 2006/0182).


METHODS
We conducted a case-control study with 241 scleroderma patients and 269 controls. Seven SNP were genotyped using the TaqMan system. Univariate and multivariate analyses were performed. In silico electrophoretic mobility shift assay (EMSA), and reverse transcriptase polymerase chain reaction analyses were done to assess the effect of the SNP on CTGF gene expression.


RESULTS
The frequency of the rs9399005TT genotype was significantly lower in SSc patients than in controls. This association remained significant after adjustment for gender. An association was detected between the rs9399005 and the diffuse and limited cutaneous forms. Multivariate analysis between SSc patients and controls taking into account all 7 SNP and sex revealed that only sex and the rs9399005 SNP were associated with disease. DNA analysis by EMSA indicated that the T allele bound nuclear factors that were also bound by the C allele. The binding affinity was higher for the T allele. Analysis of the human database and experiments with human hepatocyte cell line indicated the existence of an alternative transcript containing the rs9399005 polymorphism in its 3'UTR region. In silico analysis indicated that this polymorphism may alter the structure of CTGF messenger RNA.


CONCLUSIONS
These findings suggest that CTGF gene polymorphisms may contribute to susceptibility to scleroderma.
Granel
Brigitte
B
INSERM, U906, (Institut Nationale de la Santé et de la Recherche Médicale), Laboratoire d'Immunologie et de Génétique des Maladies Parasitaires, Faculté de Médecine, Université de la Méditerranée (UM) Service de Médecine Interne, Hôpital Nord, Assistance Publique-Hôpitaux de Marseille (AP-HM), UM, Marseille, France. brigitte.granel@univmed.fr
Argiro
Laurent
L
Hachulla
Eric
E
Fajardy
Isabelle
I
Weiller
Pierre-Jean
PJ
Durand
Jean-Marc
JM
Frances
Yves
Y
Dombey
Anne-Marie
AM
Marquet
Sandrine
S
Lesavre
Nathalie
N
Disdier
Patrick
P
Bernard
Fanny
F
Hatron
Pierre-Yves
PY
Chevillard
Christophe
C
D000483:Alleles; D016022:Case-Control Studies; D016009:Chi-Square Distribution; D055513:Connective Tissue Growth Factor / Q000235:genetics*; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D005602:France; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012044:Regression Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012595:Scleroderma, Systemic / Q000235:genetics*; D012737:Sex Factors
D055513:Connective Tissue Growth Factor