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||A frame-shift variant in the novel IFNL4 gene is associated with impaired HCV clearance.
||O'Brien T, Pfeiffer R M, Kuniholm M H, Muchmore B, Aka P, Tang W, Chen S, Wang A, Astemborski J, Bonkovsky H L, Edlin B R, Howell C D, Morgan T R, Sharp G B, Strickler H D, Thomas D L, Prokunina-Olsson L
||Background and Aims: We recently discovered that dinucleotide frame-shift variant ss469415590 (TT/DG) generates the novel interferon lambda 4 protein (IFN-l4, alias IFNAN) in individuals who carry the IFNL4 ss469415590-DG allele (Nature Genetics, in press). IFNL4 is found near IFNL3 (formerly IL28B) on chromosome 19; GWAS marker rs12979860 lies within intron 1 of IFNL4. Linkagedisequilibrium between the favorable rs12979860-C variant and IFNL4 ss469415590-TT is strong in Europeans (r2=0.92), but more modest in Africans (r2=0.71). Here we report associations of IFNL4 ss469415590 genotype with spontaneous HCV clearance and early response to treatment of chronic hepatitis C.Methods: Subjects are African American and European American participants in studies of spontaneous HCV clearance (UHS, ALIVE and WIHS) or response to treatment with egylatedinterferon/ribavirin (Virahep-C and HALT-C). Genotyping for rs12979860 and IFNL4 ss469415590 was performed with custom Taqman assays. Statistical analyses were stratified by racial ancestry.Results: Compared to individuals with two copies of the gene that produces IFN-l4 (ss469415590-DG/DG genotype), those who did not produce IFN-l4 (ss469415590-TT/TT genotype) were much more likely to clear HCV spontaneously (range of odds ratios [ORs], 3.5 to 4.7; p-values, <10−4 for all comparisons) or in response to treatment (range of ORs for response at week 20 or 24, 3.8to 10.6; p-values, 0.02 to 10−16). As predicted by the linkage disequilibrium data, ss469415590 and rs12979860 provided similarinformation for European Americans (data not shown). Among African American individuals, however, associations with HCV clearance were generally stronger for ss469415590 genotype than for rs12979860 genotype (Figure 1).Conclusions: IFNL4 ss469415590 genotype appears to explain previous associations between genetic variants in the interferon lambda region and impaired HCV clearance. For individuals consequence of viral inhibition not requiring exogenous immune stimulation.