Comparison of functional variants in IFNL4 and IFNL3 for association with HCV clearance

Thomas R. O'Brien, Ruth M. Pfeiffer, Ashley Paquin, Krystle A. Lang Kuhs, Sabrina Chen, Herbert L. Bonkovsky, Brian R. Edlin, Charles D. Howell, Gregory D. Kirk, Mark H. Kuniholm, Timothy R. Morgan, Howard Strickler, David L. Thomas, Ludmila Prokunina-Olsson

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1103-1110
Number of pages8
JournalJournal of Hepatology
Volume63
Issue number5
DOIs
StatePublished - Nov 1 2015

Fingerprint

Hepacivirus
Interferons
Haplotypes
RNA
African Americans
Genotype
Ribavirin
Linkage Disequilibrium
RNA Stability
3' Untranslated Regions
Genetic Polymorphisms
Alleles

Keywords

  • Genetics
  • IFNL3
  • IFNL4
  • IL28B
  • Innate immunity
  • Interferon lambda
  • Treatment
  • Viral clearance

ASJC Scopus subject areas

  • Hepatology

Cite this

O'Brien, T. R., Pfeiffer, R. M., Paquin, A., Lang Kuhs, K. A., Chen, S., Bonkovsky, H. L., ... Prokunina-Olsson, L. (2015). Comparison of functional variants in IFNL4 and IFNL3 for association with HCV clearance. Journal of Hepatology, 63(5), 1103-1110. https://doi.org/10.1016/j.jhep.2015.06.035

Comparison of functional variants in IFNL4 and IFNL3 for association with HCV clearance. / O'Brien, Thomas R.; Pfeiffer, Ruth M.; Paquin, Ashley; Lang Kuhs, Krystle A.; Chen, Sabrina; Bonkovsky, Herbert L.; Edlin, Brian R.; Howell, Charles D.; Kirk, Gregory D.; Kuniholm, Mark H.; Morgan, Timothy R.; Strickler, Howard; Thomas, David L.; Prokunina-Olsson, Ludmila.

In: Journal of Hepatology, Vol. 63, No. 5, 01.11.2015, p. 1103-1110.

Research output: Contribution to journalArticle

O'Brien, TR, Pfeiffer, RM, Paquin, A, Lang Kuhs, KA, Chen, S, Bonkovsky, HL, Edlin, BR, Howell, CD, Kirk, GD, Kuniholm, MH, Morgan, TR, Strickler, H, Thomas, DL & Prokunina-Olsson, L 2015, 'Comparison of functional variants in IFNL4 and IFNL3 for association with HCV clearance', Journal of Hepatology, vol. 63, no. 5, pp. 1103-1110. https://doi.org/10.1016/j.jhep.2015.06.035
O'Brien TR, Pfeiffer RM, Paquin A, Lang Kuhs KA, Chen S, Bonkovsky HL et al. Comparison of functional variants in IFNL4 and IFNL3 for association with HCV clearance. Journal of Hepatology. 2015 Nov 1;63(5):1103-1110. https://doi.org/10.1016/j.jhep.2015.06.035
O'Brien, Thomas R. ; Pfeiffer, Ruth M. ; Paquin, Ashley ; Lang Kuhs, Krystle A. ; Chen, Sabrina ; Bonkovsky, Herbert L. ; Edlin, Brian R. ; Howell, Charles D. ; Kirk, Gregory D. ; Kuniholm, Mark H. ; Morgan, Timothy R. ; Strickler, Howard ; Thomas, David L. ; Prokunina-Olsson, Ludmila. / Comparison of functional variants in IFNL4 and IFNL3 for association with HCV clearance. In: Journal of Hepatology. 2015 ; Vol. 63, No. 5. pp. 1103-1110.
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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

AU - Thomas, David L.

AU - Prokunina-Olsson, Ludmila

PY - 2015/11/1

Y1 - 2015/11/1

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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