No Association of IFNL4 Genotype with Opportunistic Infections and Cancers among Men with Human Immunodeficiency Virus 1 Infection

Michelle Z. Fang; Sarah S. Jackson; Ruth M. Pfeiffer; Eun Young Kim; Sabrina Chen; Shehnaz K. Hussain; Lisa P. Jacobson; Jeremy Martinson; Ludmila Prokunina-Olsson; Chloe L. Thio; Priya Duggal; Steven Wolinsky; Thomas R. O'Brien

doi:10.1093/cid/ciac447

No Association of IFNL4 Genotype with Opportunistic Infections and Cancers among Men with Human Immunodeficiency Virus 1 Infection

Michelle Z. Fang, Sarah S. Jackson, Ruth M. Pfeiffer, Eun Young Kim, Sabrina Chen, Shehnaz K. Hussain, Lisa P. Jacobson, Jeremy Martinson, Ludmila Prokunina-Olsson, Chloe L. Thio, Priya Duggal, Steven Wolinsky, Thomas R. O'Brien

Medicine, Infectious Diseases Division

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

1 Scopus citations

Abstract

Background: IFNL4 genetic variants that are strongly associated with clearance of hepatitis C virus have been linked to risk of certain opportunistic infections (OIs) and cancers, including Kaposi sarcoma, cytomegalovirus infection, and herpes simplex virus infection. As the interferon (IFN) λ family plays a role in response to viral, bacterial, and fungal infections, IFNL4 genotype might affect risk for a wide range of OIs/cancers. Methods: We examined associations between genotype for the functional IFNL4 rs368234815 polymorphism and incidence of 16 OIs/cancers among 2310 men with human immunodeficiency virus (2038 white; 272 black) enrolled in the Multicenter AIDS Cohort Study during 1984-1990. Our primary analyses used Cox proportional hazards models adjusted for self-reported racial ancestry to estimate hazard ratios with 95% confidence intervals, comparing participants with the genotypes that generate IFN-λ4 and those with the genotype that abrogates IFN-λ4. We censored follow-up at the introduction of highly effective antiretroviral therapies. Results: We found no statistically significant association between IFNL4 genotype and the incidence of Kaposi sarcoma (hazard ratio, 0.92 [95% confidence interval,. 76-1.11]), cytomegalovirus infection (0.94 [.71-1.24]), herpes simplex virus infection (1.37 [.68-2.93]), or any other OI/cancer. We observed consistent results using additive genetic models and after controlling for CD4 cell count through time-dependent adjustment or restriction to participants with a low CD4 cell count. Conclusions: The absence of associations between IFNL4 genotype and these OIs/cancers provides evidence that this gene does not affect the risk of disease from opportunistic pathogens.

Original language	English (US)
Pages (from-to)	521-527
Number of pages	7
Journal	Clinical Infectious Diseases
Volume	76
Issue number	3
DOIs	https://doi.org/10.1093/cid/ciac447
State	Published - Feb 1 2023

Funding

Potential conflicts of interest. L. P. J. reports a grant from the NIH, paid to the institution and unrelated to the current work. L. P. O. and T. R. O. are coinventors on patents for the interferon λ4 protein that are held by the National Cancer Institute. P. D. reports grants or contracts from the NIH, paid to the institution and unrelated to the current work. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

Keywords

Kaposi sarcoma
cytomegalovirus
genetics
herpes simplex virus
interferon λ

ASJC Scopus subject areas

Microbiology (medical)
Infectious Diseases

UN SDGs

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

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10.1093/cid/ciac447

Cite this

Fang, M. Z., Jackson, S. S., Pfeiffer, R. M., Kim, E. Y., Chen, S., Hussain, S. K., Jacobson, L. P., Martinson, J., Prokunina-Olsson, L., Thio, C. L., Duggal, P., Wolinsky, S., & O'Brien, T. R. (2023). No Association of IFNL4 Genotype with Opportunistic Infections and Cancers among Men with Human Immunodeficiency Virus 1 Infection. Clinical Infectious Diseases, 76(3), 521-527. https://doi.org/10.1093/cid/ciac447

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title = "No Association of IFNL4 Genotype with Opportunistic Infections and Cancers among Men with Human Immunodeficiency Virus 1 Infection",

abstract = "Background: IFNL4 genetic variants that are strongly associated with clearance of hepatitis C virus have been linked to risk of certain opportunistic infections (OIs) and cancers, including Kaposi sarcoma, cytomegalovirus infection, and herpes simplex virus infection. As the interferon (IFN) λ family plays a role in response to viral, bacterial, and fungal infections, IFNL4 genotype might affect risk for a wide range of OIs/cancers. Methods: We examined associations between genotype for the functional IFNL4 rs368234815 polymorphism and incidence of 16 OIs/cancers among 2310 men with human immunodeficiency virus (2038 white; 272 black) enrolled in the Multicenter AIDS Cohort Study during 1984-1990. Our primary analyses used Cox proportional hazards models adjusted for self-reported racial ancestry to estimate hazard ratios with 95% confidence intervals, comparing participants with the genotypes that generate IFN-λ4 and those with the genotype that abrogates IFN-λ4. We censored follow-up at the introduction of highly effective antiretroviral therapies. Results: We found no statistically significant association between IFNL4 genotype and the incidence of Kaposi sarcoma (hazard ratio, 0.92 [95% confidence interval,. 76-1.11]), cytomegalovirus infection (0.94 [.71-1.24]), herpes simplex virus infection (1.37 [.68-2.93]), or any other OI/cancer. We observed consistent results using additive genetic models and after controlling for CD4 cell count through time-dependent adjustment or restriction to participants with a low CD4 cell count. Conclusions: The absence of associations between IFNL4 genotype and these OIs/cancers provides evidence that this gene does not affect the risk of disease from opportunistic pathogens.",

keywords = "Kaposi sarcoma, cytomegalovirus, genetics, herpes simplex virus, interferon λ",

author = "Fang, {Michelle Z.} and Jackson, {Sarah S.} and Pfeiffer, {Ruth M.} and Kim, {Eun Young} and Sabrina Chen and Hussain, {Shehnaz K.} and Jacobson, {Lisa P.} and Jeremy Martinson and Ludmila Prokunina-Olsson and Thio, {Chloe L.} and Priya Duggal and Steven Wolinsky and O'Brien, {Thomas R.}",

note = "Publisher Copyright: {\textcopyright} 2022 Published by Oxford University Press on behalf of Infectious Diseases Society of America.",

year = "2023",

month = feb,

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doi = "10.1093/cid/ciac447",

language = "English (US)",

volume = "76",

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Fang, MZ, Jackson, SS, Pfeiffer, RM, Kim, EY, Chen, S, Hussain, SK, Jacobson, LP, Martinson, J, Prokunina-Olsson, L, Thio, CL, Duggal, P, Wolinsky, S & O'Brien, TR 2023, 'No Association of IFNL4 Genotype with Opportunistic Infections and Cancers among Men with Human Immunodeficiency Virus 1 Infection', Clinical Infectious Diseases, vol. 76, no. 3, pp. 521-527. https://doi.org/10.1093/cid/ciac447

TY - JOUR

T1 - No Association of IFNL4 Genotype with Opportunistic Infections and Cancers among Men with Human Immunodeficiency Virus 1 Infection

AU - Fang, Michelle Z.

AU - Jackson, Sarah S.

AU - Pfeiffer, Ruth M.

AU - Kim, Eun Young

AU - Chen, Sabrina

AU - Hussain, Shehnaz K.

AU - Jacobson, Lisa P.

AU - Martinson, Jeremy

AU - Prokunina-Olsson, Ludmila

AU - Thio, Chloe L.

AU - Duggal, Priya

AU - Wolinsky, Steven

AU - O'Brien, Thomas R.

PY - 2023/2/1

Y1 - 2023/2/1

N2 - Background: IFNL4 genetic variants that are strongly associated with clearance of hepatitis C virus have been linked to risk of certain opportunistic infections (OIs) and cancers, including Kaposi sarcoma, cytomegalovirus infection, and herpes simplex virus infection. As the interferon (IFN) λ family plays a role in response to viral, bacterial, and fungal infections, IFNL4 genotype might affect risk for a wide range of OIs/cancers. Methods: We examined associations between genotype for the functional IFNL4 rs368234815 polymorphism and incidence of 16 OIs/cancers among 2310 men with human immunodeficiency virus (2038 white; 272 black) enrolled in the Multicenter AIDS Cohort Study during 1984-1990. Our primary analyses used Cox proportional hazards models adjusted for self-reported racial ancestry to estimate hazard ratios with 95% confidence intervals, comparing participants with the genotypes that generate IFN-λ4 and those with the genotype that abrogates IFN-λ4. We censored follow-up at the introduction of highly effective antiretroviral therapies. Results: We found no statistically significant association between IFNL4 genotype and the incidence of Kaposi sarcoma (hazard ratio, 0.92 [95% confidence interval,. 76-1.11]), cytomegalovirus infection (0.94 [.71-1.24]), herpes simplex virus infection (1.37 [.68-2.93]), or any other OI/cancer. We observed consistent results using additive genetic models and after controlling for CD4 cell count through time-dependent adjustment or restriction to participants with a low CD4 cell count. Conclusions: The absence of associations between IFNL4 genotype and these OIs/cancers provides evidence that this gene does not affect the risk of disease from opportunistic pathogens.

AB - Background: IFNL4 genetic variants that are strongly associated with clearance of hepatitis C virus have been linked to risk of certain opportunistic infections (OIs) and cancers, including Kaposi sarcoma, cytomegalovirus infection, and herpes simplex virus infection. As the interferon (IFN) λ family plays a role in response to viral, bacterial, and fungal infections, IFNL4 genotype might affect risk for a wide range of OIs/cancers. Methods: We examined associations between genotype for the functional IFNL4 rs368234815 polymorphism and incidence of 16 OIs/cancers among 2310 men with human immunodeficiency virus (2038 white; 272 black) enrolled in the Multicenter AIDS Cohort Study during 1984-1990. Our primary analyses used Cox proportional hazards models adjusted for self-reported racial ancestry to estimate hazard ratios with 95% confidence intervals, comparing participants with the genotypes that generate IFN-λ4 and those with the genotype that abrogates IFN-λ4. We censored follow-up at the introduction of highly effective antiretroviral therapies. Results: We found no statistically significant association between IFNL4 genotype and the incidence of Kaposi sarcoma (hazard ratio, 0.92 [95% confidence interval,. 76-1.11]), cytomegalovirus infection (0.94 [.71-1.24]), herpes simplex virus infection (1.37 [.68-2.93]), or any other OI/cancer. We observed consistent results using additive genetic models and after controlling for CD4 cell count through time-dependent adjustment or restriction to participants with a low CD4 cell count. Conclusions: The absence of associations between IFNL4 genotype and these OIs/cancers provides evidence that this gene does not affect the risk of disease from opportunistic pathogens.

KW - Kaposi sarcoma

KW - cytomegalovirus

KW - genetics

KW - herpes simplex virus

KW - interferon λ

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ER -

No Association of IFNL4 Genotype with Opportunistic Infections and Cancers among Men with Human Immunodeficiency Virus 1 Infection

Abstract

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ASJC Scopus subject areas

UN SDGs

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