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 D. Strickler; David L. Thomas; Ludmila Prokunina-Olsson

doi:10.1016/j.jhep.2015.06.035

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 D. Strickler, David L. Thomas, Ludmila Prokunina-Olsson

Research output: Contribution to journal › Article › peer-review

59 Scopus citations

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 language	English
Pages (from-to)	1103-1110
Number of pages	8
Journal	Journal of Hepatology
Volume	63
Issue number	5
DOIs	https://doi.org/10.1016/j.jhep.2015.06.035
State	Published - Nov 2015

Bibliographical note

Publisher Copyright:
©.

Funding

This research was supported by the Intramural Research Program of the US National Institutes of Health (National Cancer Institute, Division of Cancer Epidemiology and Genetics), as well as the following grants: DA R01 013324 (D.L.T.); ALIVE cohort (G.D.K), U01-DA-036297 , R01-DA-04334 and R01-DA-12568 , and US National Institutes of Health grants R15 HL117199 , U01 DK 065201 , U54 DK 083909 (H.L.B.); R01-DA09532 , R01-DA12109 , R01-DA13245 , and R01-DA16159 (B.R.E.); National Cancer Institute contracts N02-CP-91027 and N01-CO-12400 (B.R.E.); Substance Abuse and Mental Health Services Administration grant H79-TI12103 (B.R.E.). The VIRAHEP-C and HALT-C studies were conducted, respectively, by the VIRAHEP-C and HALT-C Investigators and supported by the National Institute of Diabetes and Digestive and Kidney Diseases. The data and samples from the VIRAHEP-C and HALT-C studies reported here were supplied by the National Institute of Diabetes and Digestive and Kidney Diseases Central Repositories. This manuscript was not prepared in collaboration with the VIRAHEP-C study group or the HALT-C study group and does not necessarily reflect the opinions or views of the VIRAHEP-C Trial and HALT-C Trial, the National Institute of Diabetes and Digestive and Kidney Diseases Central Repositories or the National Institute of Diabetes and Digestive and Kidney Diseases. Data in this manuscript were collected by the Women’s Interagency HIV Study (WIHS) Collaborative Study Group with centers (principal investigators) located at: New York City/Bronx Consortium (Kathryn Anastos); Brooklyn, NY (Howard Minkoff); Washington DC Metropolitan Consortium (Mary Young); The Connie Wofsy Study Consortium of Northern California (Ruth Greenblatt); Los Angeles County/Southern California Consortium (Alexandra Levine); Chicago Consortium (Mardge Cohen); and Data Analysis Center (Stephen Gange). The WIHS is funded by the National Institute of Allergy and Infectious Diseases ( U01-AI-35004 , UO1-AI-31834 , UO1-AI-34994 , UO1-AI-34989 , UO1-AI-34993 , and UO1-AI-42590 ) and by the Eunice Kennedy Shriver National Institute of Child Health and Human Development ( UO1-HD-32632 ). The WIHS is co-funded by the National Cancer Institute, the National Institute on Drug Abuse, and the National Institute on Deafness and Other Communication Disorders. Funding is also provided by the National Center for Research Resources (UCSF-CTSI grant UL1 RR024131 ). The content of this publication does not necessarily reflect the views or policies of the US Department of Health and Human Services nor does mention of trade names, commercial products or organizations imply endorsement by the US government.

Funders	Funder number
UCSF-CTSI	UL1 RR024131
National Institutes of Health (NIH)
National Institute on Drug Abuse	R01DA012109
National Institute on Drug Abuse
National Childhood Cancer Registry – National Cancer Institute
Substance Abuse and Mental Health Services Administration	H79-TI12103
Substance Abuse and Mental Health Services Administration
National Institute of Allergy and Infectious Diseases	U01AI034993, UO1-AI-34989, K24AI118591, U01AI031834, UO1-AI-42590, U01-AI-35004, UO1-AI-34994
National Institute of Allergy and Infectious Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
National Center for Research Resources
Eunice Kennedy Shriver National Institute of Child Health and Human Development	UO1-HD-32632
Eunice Kennedy Shriver National Institute of Child Health and Human Development
National Cancer Institute Division of Cancer Epidemiology and Genetics	R01-DA-04334, R01-DA09532, U01DA036297, N01-CO-12400, R01-DA-12568, U01 DK 065201, U54 DK 083909, R01-DA16159, R01-DA13245, DA R01 013324, N02-CP-91027, R15 HL117199
National Cancer Institute Division of Cancer Epidemiology and Genetics

Keywords

Genetics
IFNL3
IFNL4
IL28B
Innate immunity
Interferon lambda
Treatment
Viral clearance

ASJC Scopus subject areas

Hepatology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.jhep.2015.06.035

Cite this

O'Brien, T. R., Pfeiffer, R. M., Paquin, A., Lang Kuhs, K. A., Chen, S., Bonkovsky, H. L., Edlin, B. R., Howell, C. D., Kirk, G. D., Kuniholm, M. H., Morgan, T. R., Strickler, H. D., Thomas, D. 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

@article{376d6e2cbe3045d794f5d35f7959f1f7,

title = "Comparison of functional variants in IFNL4 and IFNL3 for association with HCV clearance",

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.",

keywords = "Genetics, IFNL3, IFNL4, IL28B, Innate immunity, Interferon lambda, Treatment, Viral clearance",

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

note = "Publisher Copyright: {\textcopyright}.",

year = "2015",

month = nov,

doi = "10.1016/j.jhep.2015.06.035",

language = "English",

volume = "63",

pages = "1103--1110",

number = "5",

}

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, HD, 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

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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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 -

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

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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