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Analysis of Common Infections in Malian Children Under Five: IFNL4-dG Allele Is Associated with Higher Risk and Earlier Episodes of Gastrointestinal Infections

25 Pages Posted: 26 Jun 2020

See all articles by Ludmila Prokunina-Olsson

Ludmila Prokunina-Olsson

Government of the United States of America - Laboratory of Translational Genomics

Robert D. Morrison

Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health

Adeola Obajemu

Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health

Almahamoudou Mahamar

Radboud University Nijmegen - Department of Pharmacy and Radboud Center for Infectious Diseases; University of Sciences Techniques and Technologies of Bamako - Malaria Research & Training Center

Sungduk Kim

Biostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health

Oumar Attaher

University of Sciences, Technique and Technologies of Bamako (USTTB) - Malaria Research and Training Centre

Oscar Florez-Vargas

Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health

Youssoufa Sidibe

Malaria Research & Training Center, Faculty of Medicine, Pharmacy and Dentistry, University of Sciences Techniques and Technologies of Bamako

Olusegun O. Onabajo

Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health

Amy A. Hutchinson

Cancer Genomics Research Laboratory, Frederick National Laboratory for Cancer Research

Michelle Manning

Cancer Genomics Research Laboratory, Frederick National Laboratory for Cancer Research

Jennifer Kwan

Laboratory of Clinical Immunology and Microbiology

Nathan Brand

Department of Surgery, University of California San Francisco

Alassane Dicko

Radboud University Nijmegen - Department of Medical Microbiology

Michal Fried

Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health

Paul S. Albert

Biostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health

Sam M. Mbulaiteye

Government of the United States of America - Division of Cancer Epidemiology and Genetics

Patrick E. Duffy

Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health

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Abstract

Background: Genetic polymorphisms within the IFNL3 / IFNL4 genomic region, which encodes type III interferons, have been strongly associated with impaired clearance of hepatitis C virus (HCV) infection. We hypothesized that type III interferons might be important for the immune response to other pathogens as well.

Methods: In a cohort of 914 Malian children, we analyzed episodes of malaria, gastrointestinal and respiratory infections using information for 30,626 clinic visits from birth through 1-5 years of follow-up. Genetic polymorphisms IFNL4 -rs368234815 and IFNL3-rs4803217 that functionally affect type III interferons were genotyped with TaqMan assays. For both genetic variants and each infection, we evaluated time-to-first episode and calculated odds ratios (ORs) for the risk of an infection episode during follow-up.

Results: Compared to children with the rs368234815-TT/TT genotype (IFN-λ4-Null), each copy of the rs368234815-dG allele was associated with an earlier first episode of a gastrointestinal infection (p=0.003) and respiratory infection (p=0.045). The risk of experiencing an infection episode during the follow-up was also significantly increased with each copy of the rs368234815-dG allele – for gastrointestinal infections (OR=1.53, 95%CI (1.13-2.07), p=0.005) and malaria (OR=1.30, 95%CI (1.02-1.65), p=0.033). IFNL4 -rs368234815 and IFNL3 -rs4803217 were in moderate linkage disequilibrium in this population (r2 =0.78), and all the associations for rs4803217 were weaker and lost significance after adjusting for rs368234815, implicating IFN-λ4 and not IFN-λ3 as the primary cause of these associations.

Interpretation: Our results provide support for the role of IFN-λ4 in common gastrointestinal infections, and possibly in other infections as well.

Trial Registration: NCT01168271

Funding Statement: The study was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute (NCI), the Intramural Research Program, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, US Department of Health and Human Services.

Declaration of Interests: L.P.-O. is a co-inventor on IFN-λ4-related patents issued to NCI/NIH, and receives royalties for monoclonal antibodies for IFN-λ4 detection. Other authors have no conflict of interest to declare.

Ethics Approval Statement: The protocol and study procedures were approved by the institutional review board of the National Institute of Allergy and Infectious Diseases (NIAID) at the US National Institutes of Health (ClinicalTrials.gov ID NCT01168271), and the Ethics Committee of the Faculty of Medicine, Pharmacy and Dentistry at the University of Bamako, Mali.

Keywords: IFNL4, IFN-λ4, interferon, immune response, infections

Suggested Citation

Prokunina-Olsson, Ludmila and Morrison, Robert D. and Obajemu, Adeola and Mahamar, Almahamoudou and Mahamar, Almahamoudou and Kim, Sungduk and Attaher, Oumar and Florez-Vargas, Oscar and Sidibe, Youssoufa and Onabajo, Olusegun O. and Hutchinson, Amy A. and Manning, Michelle and Kwan, Jennifer and Brand, Nathan and Dicko, Alassane and Fried, Michal and Albert, Paul S. and Mbulaiteye, Sam M. and Duffy, Patrick E., Analysis of Common Infections in Malian Children Under Five: IFNL4-dG Allele Is Associated with Higher Risk and Earlier Episodes of Gastrointestinal Infections (4/3/2020). Available at SSRN: https://ssrn.com/abstract=3571512 or http://dx.doi.org/10.2139/ssrn.3571512

Ludmila Prokunina-Olsson (Contact Author)

Government of the United States of America - Laboratory of Translational Genomics

Bethesda, MD 20892
United States

Robert D. Morrison

Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health

Adeola Obajemu

Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health

Almahamoudou Mahamar

University of Sciences Techniques and Technologies of Bamako - Malaria Research & Training Center

Radboud University Nijmegen - Department of Pharmacy and Radboud Center for Infectious Diseases

Nijmegen
Netherlands

Sungduk Kim

Biostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health

Oumar Attaher

University of Sciences, Technique and Technologies of Bamako (USTTB) - Malaria Research and Training Centre

Bamako
Mali

Oscar Florez-Vargas

Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health

Youssoufa Sidibe

Malaria Research & Training Center, Faculty of Medicine, Pharmacy and Dentistry, University of Sciences Techniques and Technologies of Bamako

Olusegun O. Onabajo

Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health

Amy A. Hutchinson

Cancer Genomics Research Laboratory, Frederick National Laboratory for Cancer Research

Michelle Manning

Cancer Genomics Research Laboratory, Frederick National Laboratory for Cancer Research

Jennifer Kwan

Laboratory of Clinical Immunology and Microbiology

Bethesda, MD 20892
United States

Nathan Brand

Department of Surgery, University of California San Francisco

Alassane Dicko

Radboud University Nijmegen - Department of Medical Microbiology

Netherlands

Michal Fried

Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health

Paul S. Albert

Biostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health

Sam M. Mbulaiteye

Government of the United States of America - Division of Cancer Epidemiology and Genetics

9609 Medical Center Drive
Rockville, MD 20850
United States

Patrick E. Duffy

Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health

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