No role of matrixmetalloproteinase-3 genetic promoter polymorphism 1171 as a risk factor for cirrhosis in alcoholic liver disease.
BACKGROUND
As only a minority of alcoholics develop cirrhosis, polymorphic genes, whose products are involved in fibrosis development were suggested to confer individual susceptibility. We tested whether a functional promoter polymorphism in the gene encoding matrix metalloproteinase-3 (MMP-3; 1171 5A/6A) was associated liver cirrhosis in alcoholics.


METHODS
Independent cohorts from the UK and Germany were studied. (i) UK cohort: 320 alcoholic cirrhotics and 183 heavy drinkers without liver damage and (ii) German cohort: 149 alcoholic cirrhotics, 220 alcoholic cirrhotics who underwent liver transplantation and 151 alcoholics without liver disease. Patients were genotyped for MMP-3 variants by restriction fragment length polymorphism, single strand confirmation polymorphism, and direct sequencing. In addition, MMP-3 transcript levels were correlated with MMP-3 genotype in normal liver tissues.


RESULTS
Matrix metalloproteinase-3 genotype and allele distribution in all 1023 alcoholic patients were in Hardy-Weinberg equilibrium. No significant differences in MMP-3 genotype and allele frequencies were observed either between alcoholics with or without cirrhosis. There were no differences in hepatic mRNA transcription levels according to MMP-3 genotype.


CONCLUSIONS
Matrix metalloproteinase-3 1171 promoter polymorphism plays no role in the genetic predisposition for liver cirrhosis in alcoholics. Stringently designed candidate gene association studies are required to exclude chance observations.
Stickel
Felix
F
Institute of Clinical Pharmacology, University of Berne, Switzerland. felix.stickel@ikp.unibe.ch
Osterreicher
Christoph H
CH
Halangk
Juliane
J
Berg
Thomas
T
Homann
Nils
N
Hellerbrand
Claus
C
Patsenker
Eleonora
E
Schneider
Vreni
V
Kolb
Armin
A
Friess
Helmut
H
Schuppan
Detlef
D
Puhl
Gero
G
Seitz
Helmut K
HK
Leathart
Julian L B
JL
Day
Christopher P
CP
D000328:Adult; D000704:Analysis of Variance; D015331:Cohort Studies; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D005858:Germany; D006801:Humans; D008099:Liver / Q000201:enzymology; D008104:Liver Cirrhosis, Alcoholic / Q000235:genetics*; D016015:Logistic Models; D008297:Male; D019278:Matrix Metalloproteinase 3 / Q000235:genetics*; D008875:Middle Aged; D011110:Polymorphism, Genetic / Q000235:genetics*; D012150:Polymorphism, Restriction Fragment Length; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D006113:United Kingdom
D012333:RNA, Messenger; D019278:Matrix Metalloproteinase 3