OBJECTIVE: To examine associations of single-nucleotide polymorphisms (SNPs) within genes for hepatocyte growth factor (HGF) and its receptor c-met with disease susceptibility and organ involvement in Japanese patients with systemic sclerosis (SSc). METHODS: Four SNPs (HGF -1652 C/T, +44222 C/T, and +63555 G/T, and c-met -980 T/A) were analyzed in 159 SSc patients and 103 healthy control subjects with the use of a polymerase chain reaction-based assay. The influence of the HGF -1652 SNP on transcription activity was evaluated with a luciferase reporter assay and an electrophoretic mobility shift assay (EMSA). RESULTS: There was no difference in the distribution of HGF/c-met SNPs between SSc patients and controls. HGF -1652 TT was found much more frequently in SSc patients with end-stage lung disease (ESLD) than in those without (41% versus 8%; P = 0.0004). This association was confirmed by a replication study involving a separate cohort of 155 SSc patients. Kaplan-Meyer analysis revealed that HGF -1652 TT carriers had a higher probability of developing ESLD than did CT or CC carriers. The HGF promoter carrying the HGF -1652 T allele had lower transcription activity than did the promoter carrying the C allele. EMSA showed the presence of a potential negative transcription regulator that binds specifically to the HGF promoter carrying a T allele at position -1652. Finally, TT carriers had a relative inability to increase circulating HGF levels even in the presence of advanced interstitial lung disease. CONCLUSION: A SNP in the HGF promoter region may modulate the severity of interstitial lung disease by controlling the transcriptional efficiency of the HGF gene.
OBJECTIVE: To examine associations of single-nucleotide polymorphisms (SNPs) within genes for hepatocyte growth factor (HGF) and its receptor c-met with disease susceptibility and organ involvement in Japanese patients with systemic sclerosis (SSc). METHODS: Four SNPs (HGF-1652 C/T, +44222 C/T, and +63555 G/T, and c-met-980 T/A) were analyzed in 159 SSc patients and 103 healthy control subjects with the use of a polymerase chain reaction-based assay. The influence of the HGF -1652 SNP on transcription activity was evaluated with a luciferase reporter assay and an electrophoretic mobility shift assay (EMSA). RESULTS: There was no difference in the distribution of HGF/c-met SNPs between SSc patients and controls. HGF -1652 TT was found much more frequently in SSc patients with end-stage lung disease (ESLD) than in those without (41% versus 8%; P = 0.0004). This association was confirmed by a replication study involving a separate cohort of 155 SSc patients. Kaplan-Meyer analysis revealed that HGF -1652 TT carriers had a higher probability of developing ESLD than did CT or CC carriers. The HGF promoter carrying the HGF -1652 T allele had lower transcription activity than did the promoter carrying the C allele. EMSA showed the presence of a potential negative transcription regulator that binds specifically to the HGF promoter carrying a T allele at position -1652. Finally, TT carriers had a relative inability to increase circulating HGF levels even in the presence of advanced interstitial lung disease. CONCLUSION: A SNP in the HGF promoter region may modulate the severity of interstitial lung disease by controlling the transcriptional efficiency of the HGF gene.
Authors: Wolfgang Lieb; Ming-Huei Chen; Martin G Larson; Radwan Safa; Alexander Teumer; Sebastian E Baumeister; Honghuang Lin; Holly M Smith; Manja Koch; Roberto Lorbeer; Uwe Völker; Matthias Nauck; Henry Völzke; Henri Wallaschofski; Douglas B Sawyer; Ramachandran S Vasan Journal: Circ Cardiovasc Genet Date: 2014-12-31
Authors: Richard M Silver; Galina Bogatkevich; Elena Tourkina; Paul J Nietert; Stanley Hoffman Journal: Curr Opin Rheumatol Date: 2012-11 Impact factor: 5.006
Authors: Lara Bossini-Castillo; Carmen P Simeon; Lorenzo Beretta; Jasper C Broen; Madelon C Vonk; Raquel Ríos-Fernández; Gerard Espinosa; Patricia Carreira; María T Camps; Maria J Castillo; Miguel A González-Gay; Emma Beltrán; María del Carmen Freire; Javier Narváez; Carlos Tolosa; Torsten Witte; Alexander Kreuter; Annemie J Schuerwegh; Anna-Maria Hoffmann-Vold; Roger Hesselstrand; Claudio Lunardi; Jacob M van Laar; Meng May Chee; Ariane Herrick; Bobby Pc Koeleman; Christopher P Denton; Carmen Fonseca; Timothy Rdj Radstake; Javier Martin Journal: Arthritis Res Ther Date: 2012-04-24 Impact factor: 5.156
Authors: Lara Bossini-Castillo; Carmen P Simeon; Lorenzo Beretta; Jasper Broen; Madelon C Vonk; José Luis Callejas; Patricia Carreira; Luis Rodríguez-Rodríguez; Rosa García-Portales; Miguel A González-Gay; Ivan Castellví; María Teresa Camps; Carlos Tolosa; Esther Vicente-Rabaneda; María Victoria Egurbide; Annemie J Schuerwegh; Roger Hesselstrand; Claudio Lunardi; Jacob M van Laar; Paul Shiels; Ariane Herrick; Jane Worthington; Christopher Denton; Timothy R D J Radstake; Carmen Fonseca; Javier Martin Journal: Arthritis Res Ther Date: 2012-12-27 Impact factor: 5.156