Keratin variants associate with progression of fibrosis during chronic hepatitis C infection

Hepatology. 2006 Jun;43(6):1354-63. doi: 10.1002/hep.21211.


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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adult
  • Age Factors
  • Analysis of Variance
  • Cohort Studies
  • Disease Progression
  • Female
  • Gene Expression Regulation
  • Genetic Markers
  • Genetic Variation
  • Hepatitis C, Chronic / genetics*
  • Hepatitis C, Chronic / physiopathology
  • Humans
  • Keratins / genetics
  • Keratins / metabolism*
  • Liver Cirrhosis / genetics*
  • Liver Cirrhosis / physiopathology
  • Liver Function Tests
  • Logistic Models
  • Male
  • Middle Aged
  • Probability
  • Prognosis
  • Retrospective Studies
  • Risk Assessment
  • Severity of Illness Index
  • Sex Factors


  • Genetic Markers
  • Keratins