The -2518 promotor polymorphism in the MCP-1 gene is associated with systemic sclerosis.
Factors influencing the initiation or progression of sclerosis in patients with systemic sclerosis (SSc) are poorly understood. Monocyte chemotactic protein-1 (MCP-1) is a potent chemokine, which is upregulated in fibroblasts during development of sclerosis. In this study, we investigated the frequency of the functional -2518G MCP-1 promoter polymorphism in 18 patients with SSc and 139 healthy controls. In the lesional skin of the same SSc patients, expression of MCP-1 protein was examined by immunohistochemistry. To investigate a genotype/phenotype correlation, basal as well as tumor necrosis factor (TNF)-induced MCP-1 expression was analyzed in fibroblasts isolated from the skin of SSc patients with different MCP-1 genotypes by quantitative RT-PCR and ELISA. Genotyping for the -2518 (A/G) MCP-1 promotor polymorphism showed that GG homozygotes were significantly more frequent in patients with SSc than in controls (28%vs 6%). Results of immunohistochemistry revealed that MCP-1 was expressed in keratinocytes, infiltrating inflammatory cells, fibroblasts, and endothelial cells in scleroderma skin, whereas normal control skin showed no MCP-1 expression. MCP-1 expression in fibroblasts from GG-homozygote individuals tended to be stronger as compared to AG or AA genotypes. Furthermore, basal as well as TNF-induced MCP-1 expression of fibroblasts isolated from a GG-homozygote SSc patient was significantly higher than MCP-1 expression of fibroblasts isolated from heterozygote or AA-homozygote donors. The A -2518G polymorphism of the MCP-1 gene appears to affect MCP-1 expression of skin fibroblasts of patients with SSc. In accordance, the G/G genotype may predispose patients to SSc.
Karrer
Sigrid
S
Department of Dermatology, University of Regensburg, Regensburg, Germany. sigrid.karrer@klinik.uni-regensburg.de
Bosserhoff
Anja Kathrin
AK
Weiderer
Petra
P
Distler
Oliver
O
Landthaler
Michael
M
Szeimies
Rolf-Markus
RM
Müller-Ladner
Ulf
U
Schölmerich
Jürgen
J
Hellerbrand
Claus
C
D000328:Adult; D000368:Aged; D018932:Chemokine CCL2 / Q000235:genetics*; D020405:Dermis / Q000166:cytology; D005260:Female; D005347:Fibroblasts / Q000502:physiology; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic / Q000235:genetics; D012595:Scleroderma, Systemic / Q000235:genetics*
C111835:CCL2 protein, human; D018932:Chemokine CCL2