Genetic polymorphisms of matrix metalloproteinase 3 in primary sclerosing cholangitis.
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.


OBJECTIVE
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.
Center for Basic Research in Digestive Diseases, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
Brian D
BD
Juran
Elizabeth J
EJ
Atkinson
Erik M
EM
Schlicht
Joseph J
JJ
Larson
David
D
Ellinghaus
Andre
A
Franke
Konstantinos N
KN
Lazaridis
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D002648:Child; D015209:Cholangitis, Sclerosing / Q000201:enzymology / Q000235:genetics* / Q000401:mortality; D003093:Colitis, Ulcerative / Q000453:epidemiology; D015897:Comorbidity; D018450:Disease Progression; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D053208:Kaplan-Meier Estimate; D015810:Linkage Disequilibrium; D016015:Logistic Models; D008297:Male; D019278:Matrix Metalloproteinase 3 / Q000235:genetics*; D008875:Middle Aged; D008910:Minnesota; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D018570:Risk Assessment; D012307:Risk Factors; D055815:Young Adult
C511768:MMP3 protein, human; D019278:Matrix Metalloproteinase 3