Keratins 8 and 18(K8/K18) protect the liver from various forms of injury.Studies of liver explants from a large cohort of U.S.patients showed that K8/K18 mutations confer a risk to developing end-stage liver diseases,though which diseases are preferentially involved is unknown.We tested the hypothesis that K8/K18 variants are associated with chronic hepatitis C(CHC) and that their presence correlates with progression of fibrosis.Genomic DNA was isolated from peripheral blood of a well-characterized German cohort of 329 patients with CHC infection.Exonic regions were PCR-amplified and analyzed using denaturing high-performance liquid chromatography and DNA sequencing.Our findings showed:(1) amino acid altering keratin heterozygous variants in 24 of 329 CHC patients(7.3%) and non-coding heterozygous variants in 26 patients(7.8%) ,and(2) 3 new exonic K8 variants(T26R/G55A/A359T) ;6 novel non-coding variants and one K18 coding variant(K18 S230T;2 patients) .The most common variants were K8 R341H(10 patients) ,K8 G62C(6 patients) and K8 I63V(4 patients) .A novel and exclusive association of an intronic KRT8 IVS7+ 10delC deletion in all 10 patients with K8 R341H was observed.Notably,there was a significant association of exonic,but not of intronic K8 variants with increased fibrosis.In conclusion,previously described and novel K8 variants are present in a German population and collectively associate with progression of fibrosis in CHC infection.The unique 100% segregation of the most common K8 variant,R341H,with an intronic deletion suggests that one of these two genetic changes might lead to the other. Keratins 8 and 18 (K8 / K18) protect the liver from various forms of injury. Studies of liver explants from a large cohort of USpatients showed that K8 / K18 mutations confer a risk to developing end-stage liver diseases, though which diseases are preferentially involved is unknown. We tested the hypothesis that K8 / K18 variants are associated with chronic hepatitis C (CHC) and that their presence correlates with progression of fibrosis. Genomic DNA was isolated from peripheral blood of a well-characterized German cohort of 329 patients with CHC infection. Exonic regions were PCR-amplified and analyzed using denaturing high-performance liquid chromatography and DNA sequencing. Our findings showed: (1) amino acid altering keratin heterozygous variants in 24 of 329 CHC patients (7.3%) and non-coding heterozygous variants in 26 patients (7.8%), and (2) 3 new exonic K8 variants (T26R / G55A / A359T); 6 novel non coding variants and one K18 coding variant (K18 S230T; were K8 R341H (10 patients), K8 G62C (6 patients) and K8 I63V (4 patients). A novel and exclusive association of an intronic KRT8 IVS7 + 10delC deletion in all 10 patients with K8 R341H was observed. Notably, there was a significant association of exonic, but not of intronic K8 variants with increased fibrosis. In conclusion, previously described and novel K8 variants are present in a German population and collectively associate with progression of fibrosis in CHC infection. The unique 100% segregation of the most common K8 variant, R341H, with an intronic deletion suggests that one of these two genetic changes might lead to the other.