Association of polymorphisms of the transforming growth factor-beta1 gene with the rate of progression of HCV-induced liver fibrosis.
BACKGROUND
The objective of the present study was to elucidate possible relationships between four polymorphisms of the TGF-beta1 gene (-800G>A; -509C>T; Leu10Pro; Arg25Pro) and stage, histological activity grade and progression rate of liver fibrosis, classified according to the METAVIR-score.


METHODS
Three study groups, i.e. 48 patients with hepatic fibrosis (26 with known duration of hepatitis C virus infection), 47 patients with non-fibrotic diseases and 50 healthy blood donors, were analyzed for TGF-beta1 polymorphisms using ARMS-PCR and sequence analysis. The concentrations of total TGF-beta1 in plasma and of hyaluronan, P-III-NP and activities of transminases in serum were measured.


RESULTS
The presence of proline at codons 10 and/or 25 was associated with a faster progression of fibrosis than other polymorphisms. Patients with the genotype (25)ArgPro developed fibrosis significantly faster (0.23 units/year) than those having (25)ArgArg (0.08 units/year). Similarly, the fibrosis progression rate of patients with genotypes (10)LeuPro and (10)ProPro was almost three times as fast as of those having genotype (10)LeuLeu. Stage and histological activity grade of fibrosis in (25)ArgPro in comparison to (25)ArgArg were higher. Also (10)LeuPro showed a higher average stage of fibrosis than (10)LeuLeu. The TGF-beta1 plasma concentrations of patients with hepatic fibrosis were not significantly different between carriers of (25)ArgArg and (25)ArgPro genotypes. The frequency of the genotype (25)ArgPro in liver fibrotic patients was about three times that of the control group whereas the frequency distribution of the genotype (25)ArgArg tended to lower frequency in the fibrosis group. TGF-beta1-promoter polymorphisms did not show any correlation with stage, grade or progression of liver fibrosis.


CONCLUSIONS
Our results indicate that the heterozygous ArgPro of codon 25 predicts significantly faster fibrotic progression of chronic hepatitis C than the homozygous (25)ArgArg genotype. The homozygous LeuLeu genotype of codon 10 showed a slow progression of fibrosis.
Gewaltig
Jan
J
Institute of Clinical Chemistry and Pathobiochemistry, Central Laboratory, RWTH-University Hospital Aachen, Pauwelsstr. 30, 52074 Aachen, Germany.
Mangasser-Stephan
Kerstin
K
Gartung
Carsten
C
Biesterfeld
Stefan
S
Gressner
Axel M
AM
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D004252:DNA Mutational Analysis; D018450:Disease Progression; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006526:Hepatitis C / Q000150:complications* / Q000453:epidemiology / Q000473:pathology; D006801:Humans; D008103:Liver Cirrhosis / Q000453:epidemiology / Q000235:genetics* / Q000821:virology; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D012720:Severity of Illness Index; D016212:Transforming Growth Factor beta / Q000097:blood / Q000235:genetics*; D053773:Transforming Growth Factor beta1
D015415:Biomarkers; C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1