TGF-β1 codon 25 gene polymorphism is associated with cirrhosis in patients with hereditary hemochromatosis

Abstract Hereditary hemochromatosis (HHC) is an autosomal recessive disorder of iron metabolism with variable penetrance. Only a minority of C282Y homozygotes develop clinical overt disease and cirrhosis. The phenotypic heterogeneity of HHC may be due to host genetic factors influencing fibrogenesis such as cytokine gene polymorphisms. In this respect, we investigated the impact of functional genetic polymorphisms of TGF-β1 (codon 10 Leu/Pro, codon 25 Arg/Pro), TNF-α (−308 G/A, −238 G/A) and angiotensinogen (−6 G/A) on the development of cirrhosis in HHC. One hundred and forty-nine (111 male, mean age: 51.0 ± 12.9) C282Y homozygotes who underwent liver biopsy were studied. Genotyping was performed by RFLP analysis. TGF-β1 codon 25 genotypes Arg/Pro and Pro/Pro were more common in patients with cirrhosis than in those without (23.6% vs. 7.4%, p  = 0.005). In contrast, the distribution of TGF-β1 codon 10, TNF-α and angiotensinogen genotypes was not different. Logistic regression analysis identified male sex, age, serum ferritin and TGF-β1 codon 25 Arg/Pro and Pro/Pro as independent predictors for the presence of cirrhosis. The adjusted odds ratio for TGF-β1 codon 25 Arg/Pro and Pro/Pro was 2.8 (95% CI 1.4–5.7, p  = 0.004). In conclusion, C282Y homozygotes carrying TGF-β1 genotypes Arg/Pro and Pro/Pro are more likely to develop cirrhosis than those with genotype Arg/Arg.