Keratin 8 and 18 variants are overrepresented in chronic hepatitis C and associate with adverse disease outcome

Backround and Aims: Keratins (K) 8/18 are the major intermediate filaments (IFs) of single layered/glandular epithelia. K8/18 are established hepatoprotective proteins and K8/K18 variants associate with liver fibrosis progression in patients with chronic hepatitis C (CHC) and primary biliary cirrhosis. To further characterize the role of K8/K18 in CHC, we analyzed US cohort of 1222 patients enrolled in the Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) trial for presence of K8/K18 variants. Methods: Genomic DNA was isolated from peripheral blood. Exonic regions carrying K8/K18 mutational hot-spots were PCR-amplified and analyzed using denaturing high-performance liquid chromatography and DNA sequencing. The biological significance of novel K8/K18 variants was assessed in transfected cell lines. Results: 128 out of 1222 CHC patients (10.5%) harbored likely biologically significant, amino-acid altering K8/K18 variants including six novel variants (K8 A345S/A447V/G471E and K18 R45P/Y94Y/T410T). Among Caucasians, R341H and G62C were the most common ones and their frequency were 6.1% (55/905) and 1.4% (14/905). In African-Americans, K8 A333A and K8 G434S variants were found in 6.4% (12/187) and 9.1% (17/187) of patients, respectively. Both K8 A333A and K8 G434S were significantly overrepresented in African-Americans compared to Caucasians (p<0.0001 for each). The K8 R341H variant was significantly overrepresented in CHC Caucasians compared to previously analyzed Caucasian controls (6.1% vs. 3.2%, p=0.01). Biologically significant variants associate with adverse disease outcome and the novel K18 R45P variant increased keratin solubility in vitro. Conclusions: KRT8 and KRT18 are important susceptibility genes for CHC disease progression and some variants segregate with unique ethnic and race backgrounds.