Abstract
Background and aims:
Primary sclerosing cholangitis (PSC) is characterised by progressive fibrosis of the intra- and extrahepatic bile ducts leading to bile duct strictures and liver cirrhosis. In animal models of
PSC, there is upregulation of transforming growth factor beta (TGFβ) and other genes involved in fibrogenesis. In cystic fibrosis, a more severe disease course was recently documented for individuals homozygous for variants of the TGFβ gene that lead to higher
expression levels. We aimed to investigate whether TGFβ gene variants may be important for disease susceptibility or disease progression in patients with PSC.
Methods:
Five singe nucleotide polymorphisms (SNPs) covering the TGFβ gene were genotyped (rs1800469, rs1982073, rs1800471, rs8179181 and rs6957) in 365 Scandinavian PSC patients and 368 healthy controls. Genotype frequencies were compared using the Chi-squared test.
Influence on survival, defined as the time from diagnostic cholangiography until death or liver transplantation, was assessed by Kaplan-Meier analysis and Cox regressions.
Results:
We found no association between any of the TGFβ polymorphisms and PSC susceptibility. Furthermore, when evaluating the 325 patients for whom complete follow-up data were available, we found no statistically significant influence on survival for genotypes of any
SNP. Interestingly, median survival for individuals homozygous for the CC genotype at rs1982073, the genotype that was found to influence disease severity in cystic fibrosis, was 10.9 years (95% confidence interval; CI [6.6, 15.3]) versus 15.5 years (95% CI [12.8, 18.2]) for the CT and TT genotypes. In age adjusted Cox regressions, the non-significant trend for reduced survival for the CC genotype was also evident (hazard ratio 1.47, 95% CI [0.96, 2.5], p=0.074).
Conclusions:
Genetic variants of TGFβ were not found to be associated with the development of PSC. Furthermore, none of the variants were found to significantly affect survival in the present material. It should be noted that the tendency towards a decrease in survival among PSC
patients homozygous for the CC genotype at rs1982073 is in line with the effect observed in cystic fibrosis. Re-evaluation of the influence from this particular variant on disease progression may need to be performed in larger cohorts of PSC patients when available.