title: Keratin variants associate with progression of fibrosis during chronic hepatitis C infection.
abstract: 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.
authors.affiliation: Department of Medicine, Palo Alto VA Medical Center, Palo Alto, CA 94304, USA.
authors.forename: Pavel
authors.initials: P
authors.lastname: Strnad
authors.forename: Tim C
authors.initials: TC
authors.lastname: Lienau
authors.forename: Guo-Zhong
authors.initials: GZ
authors.lastname: Tao
authors.forename: Laura C
authors.initials: LC
authors.lastname: Lazzeroni
authors.forename: Felix
authors.initials: F
authors.lastname: Stickel
authors.forename: Detlef
authors.initials: D
authors.lastname: Schuppan
authors.forename: M Bishr
authors.initials: MB
authors.lastname: Omary
mesh_terms: D000328:Adult; D000367:Age Factors; D000704:Analysis of Variance; D015331:Cohort Studies; D018450:Disease Progression; D005260:Female; D005786:Gene Expression Regulation; D005819:Genetic Markers; D014644:Genetic Variation; D019698:Hepatitis C, Chronic / Q000235:genetics* / Q000503:physiopathology; D006801:Humans; D007633:Keratins / Q000235:genetics / Q000378:metabolism*; D008103:Liver Cirrhosis / Q000235:genetics* / Q000503:physiopathology; D008111:Liver Function Tests; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D011336:Probability; D011379:Prognosis; D012189:Retrospective Studies; D018570:Risk Assessment; D012720:Severity of Illness Index; D012737:Sex Factors
chemical_list: D005819:Genetic Markers; D007633:Keratins