Evaluating the Causal Link Between Malaria Infection and Endemic Burkitt Lymphoma in Northern Uganda: A Mendelian Randomization Study

Ismail D. Legason; Ruth M. Pfeiffer; Krizia-Ivana Udquim; Andrew W. Bergen; Mateus H. Gouveia; Samuel Kirimunda; Isaac Otim; Eric Karlins; Patrick Kerchan; Hadijah Nabalende; Ariunaa Bayanjargal; Benjamin Emmanuel; Paul Kagwa; Ambrose O. Talisuna; Kishor Bhatia; Meredith Yeager; Robert J. Biggar; Leona W. Ayers; Steven J. Reynolds; James J. Goedert; Martin D. Ogwang; Joseph F. Fraumeni, Jr; Ludmila Prokunina-Olsson; Sam M. Mbulaiteye

doi:10.1016/j.ebiom.2017.09.037

EBioMedicine (Nov 2017)

Evaluating the Causal Link Between Malaria Infection and Endemic Burkitt Lymphoma in Northern Uganda: A Mendelian Randomization Study

Ismail D. Legason,
Ruth M. Pfeiffer,
Krizia-Ivana Udquim,
Andrew W. Bergen,
Mateus H. Gouveia,
Samuel Kirimunda,
Isaac Otim,
Eric Karlins,
Patrick Kerchan,
Hadijah Nabalende,
Ariunaa Bayanjargal,
Benjamin Emmanuel,
Paul Kagwa,
Ambrose O. Talisuna,
Kishor Bhatia,
Meredith Yeager,
Robert J. Biggar,
Leona W. Ayers,
Steven J. Reynolds,
James J. Goedert,
Martin D. Ogwang,
Joseph F. Fraumeni, Jr,
Ludmila Prokunina-Olsson,
Sam M. Mbulaiteye

Affiliations

Ismail D. Legason: EMBLEM Study, African Field Epidemiology Network, P.O. Box 12874, Kampala, Uganda
Ruth M. Pfeiffer: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 9609 Medical Ctr Dr, Bethesda 20892, MD, USA
Krizia-Ivana Udquim: Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
Andrew W. Bergen: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 9609 Medical Ctr Dr, Bethesda 20892, MD, USA
Mateus H. Gouveia: Instituto de Pesquisa Rene Rachou, Fundação Oswaldo Cruz, 30190-002 Belo Horizonte, Minas Gerais, Brazil
Samuel Kirimunda: Department of Medical Microbiology, College of Health Sciences, Makerere University, P.O. Box 7072, Kampala, Uganda
Isaac Otim: EMBLEM Study, African Field Epidemiology Network, P.O. Box 12874, Kampala, Uganda
Eric Karlins: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 9609 Medical Ctr Dr, Bethesda 20892, MD, USA
Patrick Kerchan: EMBLEM Study, African Field Epidemiology Network, P.O. Box 12874, Kampala, Uganda
Hadijah Nabalende: EMBLEM Study, African Field Epidemiology Network, P.O. Box 12874, Kampala, Uganda
Ariunaa Bayanjargal: Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
Benjamin Emmanuel: EMBLEM Study, African Field Epidemiology Network, P.O. Box 12874, Kampala, Uganda
Paul Kagwa: EMBLEM Study, African Field Epidemiology Network, P.O. Box 12874, Kampala, Uganda
Ambrose O. Talisuna: World Health Organization, Regional Office for Africa, Brazzaville, Congo
Kishor Bhatia: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 9609 Medical Ctr Dr, Bethesda 20892, MD, USA
Meredith Yeager: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 9609 Medical Ctr Dr, Bethesda 20892, MD, USA
Robert J. Biggar: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 9609 Medical Ctr Dr, Bethesda 20892, MD, USA
Leona W. Ayers: Department of Pathology, The Ohio State University, Columbus, OH, USA
Steven J. Reynolds: Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
James J. Goedert: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 9609 Medical Ctr Dr, Bethesda 20892, MD, USA
Martin D. Ogwang: EMBLEM Study, St. Mary's Hospital, Lacor, P.O. Box 180, Gulu, Uganda
Joseph F. Fraumeni, Jr: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 9609 Medical Ctr Dr, Bethesda 20892, MD, USA
Ludmila Prokunina-Olsson: Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
Sam M. Mbulaiteye: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 9609 Medical Ctr Dr, Bethesda 20892, MD, USA

DOI: https://doi.org/10.1016/j.ebiom.2017.09.037
Journal volume & issue: Vol. 25, no. C
pp. 58 – 65

Abstract

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Background: Plasmodium falciparum (Pf) malaria infection is suspected to cause endemic Burkitt Lymphoma (eBL), but the evidence remains unsettled. An inverse relationship between sickle cell trait (SCT) and eBL, which supports that between malaria and eBL, has been reported before, but in small studies with low power. We investigated this hypothesis in children in a population-based study in northern Uganda using Mendelian Randomization. Methods: Malaria-related polymorphisms (SCT, IL10, IL1A, CD36, SEMA3C, and IFNAR1) were genotyped in 202 eBL cases and 624 controls enrolled during 2010–2015. We modeled associations between genotypes and eBL or malaria using logistic regression. Findings: SCT was associated with decreased risk of eBL (adjusted odds ratio [OR] 0·37, 95% CI 0·21–0·66; p = 0·0003). Decreased risk of eBL was associated with IL10 rs1800896-CT (OR 0·73, 95% CI 0·50–1·07) and -CC genotypes (OR 0·53, 95% CI 0·29–0·95, ptrend = 0·019); IL1A rs2856838-AG (OR 0·56, 95% CI 0·39–0·81) and -AA genotype (OR 0·50, 95% CI 0·28–1·01, ptrend = 0·0016); and SEMA3C rs4461841-CT or -CC genotypes (OR 0·57, 95% CI 0·35–0·93, p = 0·0193). SCT and IL10 rs1800896, IL1A rs2856838, but not SEMA3C rs4461841, polymorphisms were associated with decreased risk of malaria in the controls. Interpretation: Our results support a causal effect of malaria infection on eBL.

Published in EBioMedicine

ISSN: 2352-3964 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Medicine (General)
Website: http://www.journals.elsevier.com/ebiomedicine/

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