BACKGROUND: The damaging cholestasis inherent to primary sclerosing cholangitis (PSC) results from bile duct stricturing because of progressive fibrosis. The matrix metalloproteinase 3 (MMP3) degrades a wide range of matrix components and is expressed by activated liver stellate cells, and so is a candidate for involvement with the fibrotic processes underlying PSC. Moreover, the MMP3 gene harbours polymorphisms associated with variation in its activity directly impacting clinical phenotypes. AIMS: We aimed to examine the influence of MMP3 polymorphisms on PSC risk and progression. METHODS: Nine single nucleotide polymorphisms (SNPs) tagging the common genetic variation of MMP3 were genotyped in 266 PSC patients and 407 controls. SNPs and inferred haplotypes were assessed for PSC association by logistic regression and score tests. The effect of SNPs on survival to liver transplant or death was analysed using Cox regression, and Kaplan-Meier curves were constructed. RESULTS: No association of PSC with individual SNPs or haplotypes of MMP3 was detected. However, progression to death or liver transplant was significantly associated with homozygosity for minor alleles of rs522616, rs650108 and rs683878, particularly among PSC patients with concurrent ulcerative colitis (UC) (strongest in redundant SNPs rs650108/rs683878, hazard ratio=3.23, 95% confidence interval 1.45-7.25, P=0.004). CONCLUSIONS: Genetic variation in MMP3 influences PSC progression, possibly in the context of coexisting UC. While the functional variants and specific mechanisms remain unknown, this finding implicates the turnover of the extracellular matrix as an important and variable component of PSC pathogenesis. Efforts to understand this process could form the basis for developing effective treatments, which are currently lacking for PSC.
BACKGROUND: The damaging cholestasis inherent to primary sclerosing cholangitis (PSC) results from bile duct stricturing because of progressive fibrosis. The matrix metalloproteinase 3 (MMP3) degrades a wide range of matrix components and is expressed by activated liver stellate cells, and so is a candidate for involvement with the fibrotic processes underlying PSC. Moreover, the MMP3 gene harbours polymorphisms associated with variation in its activity directly impacting clinical phenotypes. AIMS: We aimed to examine the influence of MMP3 polymorphisms on PSC risk and progression. METHODS: Nine single nucleotide polymorphisms (SNPs) tagging the common genetic variation of MMP3 were genotyped in 266 PSCpatients and 407 controls. SNPs and inferred haplotypes were assessed for PSC association by logistic regression and score tests. The effect of SNPs on survival to liver transplant or death was analysed using Cox regression, and Kaplan-Meier curves were constructed. RESULTS: No association of PSC with individual SNPs or haplotypes of MMP3 was detected. However, progression to death or liver transplant was significantly associated with homozygosity for minor alleles of rs522616, rs650108 and rs683878, particularly among PSCpatients with concurrent ulcerative colitis (UC) (strongest in redundant SNPs rs650108/rs683878, hazard ratio=3.23, 95% confidence interval 1.45-7.25, P=0.004). CONCLUSIONS: Genetic variation in MMP3 influences PSC progression, possibly in the context of coexisting UC. While the functional variants and specific mechanisms remain unknown, this finding implicates the turnover of the extracellular matrix as an important and variable component of PSC pathogenesis. Efforts to understand this process could form the basis for developing effective treatments, which are currently lacking for PSC.
Authors: Andre Franke; Tobias Balschun; Christian Sina; David Ellinghaus; Robert Häsler; Gabriele Mayr; Mario Albrecht; Michael Wittig; Eva Buchert; Susanna Nikolaus; Christian Gieger; H Erich Wichmann; Jurgita Sventoraityte; Limas Kupcinskas; Clive M Onnie; Maria Gazouli; Nicholas P Anagnou; David Strachan; Wendy L McArdle; Christopher G Mathew; Paul Rutgeerts; Séverine Vermeire; Morten H Vatn; Michael Krawczak; Philip Rosenstiel; Tom H Karlsen; Stefan Schreiber Journal: Nat Genet Date: 2010-03-14 Impact factor: 38.330
Authors: Yu-Ching Cheng; Wen-Hong L Kao; Braxton D Mitchell; Jeffrey R O'Connell; Haiqing Shen; Patrick F McArdle; Quince Gibson; Kathleen A Ryan; Alan R Shuldiner; Toni I Pollin Journal: Circ Cardiovasc Genet Date: 2009-05-14
Authors: Craig Lammert; Brian D Juran; Erik Schlicht; Xiao Xie; Elizabeth J Atkinson; Mariza de Andrade; Konstantinos N Lazaridis Journal: Clin Gastroenterol Hepatol Date: 2014-01-16 Impact factor: 11.382
Authors: Roongruedee Chaiteerakij; Brian D Juran; Mohammed M Aboelsoud; William S Harmsen; Catherine D Moser; Nasra H Giama; Loretta K Allotey; Teresa A Mettler; Esha Baichoo; Xiaodan Zhang; Terry M Therneau; Konstantinos N Lazaridis; Lewis R Roberts Journal: Cancer Med Date: 2015-08-15 Impact factor: 4.452