TY - JOUR
T1 - Comparison of functional variants in IFNL4 and IFNL3 for association with HCV clearance
AU - O'Brien, Thomas R.
AU - Pfeiffer, Ruth M.
AU - Paquin, Ashley
AU - Lang Kuhs, Krystle A.
AU - Chen, Sabrina
AU - Bonkovsky, Herbert L.
AU - Edlin, Brian R.
AU - Howell, Charles D.
AU - Kirk, Gregory D.
AU - Kuniholm, Mark H.
AU - Morgan, Timothy R.
AU - Strickler, Howard D.
AU - Thomas, David L.
AU - Prokunina-Olsson, Ludmila
N1 - Publisher Copyright:
©.
PY - 2015/11
Y1 - 2015/11
N2 - Background & Aims Genetic polymorphisms within the interferon lambda (IFN-λ) region are strongly associated with hepatitis C virus (HCV) clearance; the IFNL4-ΔG/TT (rs368234815) polymorphism, which controls the generation of IFN-λ4 protein, is more strongly associated with HCV clearance than rs12979860 (the 'IL28B variant'). An IFNL3 3′ untranslated region polymorphism (rs4803217) has been proposed as a causal variant that may affect HCV clearance by altering IFNL3 mRNA stability. Methods We compared IFNL4-ΔG/TT and rs4803217 for association with response to pegylated-IFN-α/ribavirin in the VIRAHEP-C and HALT-C trials, and spontaneous HCV clearance in the ALIVE, UHS and WIHS studies. Genotyping was performed with TaqMan assays. We compared differences in mean reduction in HCV RNA levels by genotype and haplotype. For HCV clearance, we calculated p-values comparing c-statistics for IFNL4-ΔG/TT and rs4803217 genotypes by a bootstrap approach. Results Among European Americans, linkage disequilibrium between IFNL4-ΔG/TT and rs4803217 was strong (r2 = 0.89-0.99) and there were no significant differences between the variants. In African American (AA) individuals enrolled in VIRAHEP-C, HCV RNA at treatment day 28 was more strongly associated with IFNL4-ΔG/TT than rs4803217 (p = 0.003); the IFNL4-ΔG:rs4803217-G haplotype, which includes the putatively favorable IFNL3 allele, was actually associated with the poorest day 28 response (p = 0.03, comparison to IFNL4-ΔG:rs4803217-T haplotype). Among AA participants, associations were stronger for IFNL4-ΔG/TT than rs4803217 for undetectable HCV RNA at week 24 in Virahep-C (p = 0.03) and week 20 in HALT-C (p = 0.03), as well as for spontaneous HCV clearance (p = 0.048). Conclusion IFNL4-ΔG/TT is the primary IFN-λ region polymorphism for impaired HCV clearance.
AB - Background & Aims Genetic polymorphisms within the interferon lambda (IFN-λ) region are strongly associated with hepatitis C virus (HCV) clearance; the IFNL4-ΔG/TT (rs368234815) polymorphism, which controls the generation of IFN-λ4 protein, is more strongly associated with HCV clearance than rs12979860 (the 'IL28B variant'). An IFNL3 3′ untranslated region polymorphism (rs4803217) has been proposed as a causal variant that may affect HCV clearance by altering IFNL3 mRNA stability. Methods We compared IFNL4-ΔG/TT and rs4803217 for association with response to pegylated-IFN-α/ribavirin in the VIRAHEP-C and HALT-C trials, and spontaneous HCV clearance in the ALIVE, UHS and WIHS studies. Genotyping was performed with TaqMan assays. We compared differences in mean reduction in HCV RNA levels by genotype and haplotype. For HCV clearance, we calculated p-values comparing c-statistics for IFNL4-ΔG/TT and rs4803217 genotypes by a bootstrap approach. Results Among European Americans, linkage disequilibrium between IFNL4-ΔG/TT and rs4803217 was strong (r2 = 0.89-0.99) and there were no significant differences between the variants. In African American (AA) individuals enrolled in VIRAHEP-C, HCV RNA at treatment day 28 was more strongly associated with IFNL4-ΔG/TT than rs4803217 (p = 0.003); the IFNL4-ΔG:rs4803217-G haplotype, which includes the putatively favorable IFNL3 allele, was actually associated with the poorest day 28 response (p = 0.03, comparison to IFNL4-ΔG:rs4803217-T haplotype). Among AA participants, associations were stronger for IFNL4-ΔG/TT than rs4803217 for undetectable HCV RNA at week 24 in Virahep-C (p = 0.03) and week 20 in HALT-C (p = 0.03), as well as for spontaneous HCV clearance (p = 0.048). Conclusion IFNL4-ΔG/TT is the primary IFN-λ region polymorphism for impaired HCV clearance.
KW - Genetics
KW - IFNL3
KW - IFNL4
KW - IL28B
KW - Innate immunity
KW - Interferon lambda
KW - Treatment
KW - Viral clearance
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U2 - 10.1016/j.jhep.2015.06.035
DO - 10.1016/j.jhep.2015.06.035
M3 - Article
C2 - 26186989
AN - SCOPUS:84943650678
SN - 0168-8278
VL - 63
SP - 1103
EP - 1110
JO - Journal of Hepatology
JF - Journal of Hepatology
IS - 5
ER -