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2020-01-01
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EVALUATING THE CAUSAL LINK BETWEEN MALARIA INFECTION AND ENDEMIC BURKITT LYMPHOMA IN NORTHERN UGANDA: A MENDELIAN RANDOMIZATION STUDY
Malaria
Plasmodium falciparum
Mendelian randomization
Sickle cell trait
Malaria resistance genes
Author
Legason, Ismail D.
Pfeiffer, Ruth M.
Udquim, Krizia-Ivana
Bergen, Andrew W.
Gouveia, Mateus Henrique
Kirimunda, Samuel
Otim, Isaac
Karlins, Eric
Kerchan, Patrick
Nabalende, Hadijah
Bayanjargal, Ariunaa
Emmanuel, Benjamin
Kagwa, Paul
Talisuna, Ambrose O.
Bhatia, Kishor
Yeager, Meredith
Biggar, Robert J.
Ayers, Leona W.
Reynolds, Steven J.
Goedert, James J.
Ogwang, Martin D.
Fraumeni Junior, Joseph F.
Prokunina-Olsson, Ludmila
Mbulaiteye, Sam M.
Pfeiffer, Ruth M.
Udquim, Krizia-Ivana
Bergen, Andrew W.
Gouveia, Mateus Henrique
Kirimunda, Samuel
Otim, Isaac
Karlins, Eric
Kerchan, Patrick
Nabalende, Hadijah
Bayanjargal, Ariunaa
Emmanuel, Benjamin
Kagwa, Paul
Talisuna, Ambrose O.
Bhatia, Kishor
Yeager, Meredith
Biggar, Robert J.
Ayers, Leona W.
Reynolds, Steven J.
Goedert, James J.
Ogwang, Martin D.
Fraumeni Junior, Joseph F.
Prokunina-Olsson, Ludmila
Mbulaiteye, Sam M.
Affilliation
African Field Epidemiology Network. EMBLEM Study. Kampala, Uganda
National Institutes of Health. National Cancer Institute. Division of Cancer Epidemiology and Genetics. Bethesda, MD, USA
National Institutes of Health. National Cancer Institute. Division of Cancer Epidemiology and Genetics. Laboratory of Translational Genomics. Bethesda, MD, USA
National Institutes of Health. National Cancer Institute. Division of Cancer Epidemiology and Genetics. Bethesda, MD, USA
Fundação Oswaldo Cruz. Instituto Rene Rachou. Belo Horizonte, MG, Brazil
Makerere University. College of Health Sciences. Department of Medical Microbiology. Kampala, Uganda
African Field Epidemiology Network. EMBLEM Study. Kampala, Uganda
National Institutes of Health. National Cancer Institute. Division of Cancer Epidemiology and Genetics. Bethesda, MD, USA
African Field Epidemiology Network. EMBLEM Study. Kampala, Uganda
African Field Epidemiology Network. EMBLEM Study. Kampala, Uganda
National Institutes of Health. National Cancer Institute. Division of Cancer Epidemiology and Genetics. Laboratory of Translational Genomics. Bethesda, MD, USA
African Field Epidemiology Network. EMBLEM Study. Kampala, Uganda/ University of Maryland School of Medicine. Institute of Human Virology Benjamin Emmanuel. Baltimore, MD, USA
African Field Epidemiology Network. EMBLEM Study. Kampala, Uganda
World Health Organization. Regional Office for Africa. Brazzaville, Congo
National Institutes of Health. National Cancer Institute. Division of Cancer Epidemiology and Genetics. Bethesda, MD, USA
National Institutes of Health. National Cancer Institute. Division of Cancer Epidemiology and Genetics. Bethesda, MD, USA
National Institutes of Health. National Cancer Institute. Division of Cancer Epidemiology and Genetics. Bethesda, MD, USA
Ohio State University. Department of Pathology. Columbus, OH, USA
National Institutes of Health. National Institute of Allergy and Infectious Diseases. Division of Intramural Research. Bethesda, MD, USA
National Institutes of Health. National Cancer Institute. Division of Cancer Epidemiology and Genetics. Bethesda, MD, USA
St. Mary's Hospital. EMBLEM Study. Lacor, Gulu, Uganda
National Institutes of Health. National Cancer Institute. Division of Cancer Epidemiology and Genetics. Bethesda, MD, USA
National Institutes of Health. National Cancer Institute. Division of Cancer Epidemiology and Genetics. Laboratory of Translational Genomics. Bethesda, MD, USA
National Institutes of Health. National Cancer Institute. Division of Cancer Epidemiology and Genetics. Bethesda, MD, USA
National Institutes of Health. National Cancer Institute. Division of Cancer Epidemiology and Genetics. Bethesda, MD, USA
National Institutes of Health. National Cancer Institute. Division of Cancer Epidemiology and Genetics. Laboratory of Translational Genomics. Bethesda, MD, USA
National Institutes of Health. National Cancer Institute. Division of Cancer Epidemiology and Genetics. Bethesda, MD, USA
Fundação Oswaldo Cruz. Instituto Rene Rachou. Belo Horizonte, MG, Brazil
Makerere University. College of Health Sciences. Department of Medical Microbiology. Kampala, Uganda
African Field Epidemiology Network. EMBLEM Study. Kampala, Uganda
National Institutes of Health. National Cancer Institute. Division of Cancer Epidemiology and Genetics. Bethesda, MD, USA
African Field Epidemiology Network. EMBLEM Study. Kampala, Uganda
African Field Epidemiology Network. EMBLEM Study. Kampala, Uganda
National Institutes of Health. National Cancer Institute. Division of Cancer Epidemiology and Genetics. Laboratory of Translational Genomics. Bethesda, MD, USA
African Field Epidemiology Network. EMBLEM Study. Kampala, Uganda/ University of Maryland School of Medicine. Institute of Human Virology Benjamin Emmanuel. Baltimore, MD, USA
African Field Epidemiology Network. EMBLEM Study. Kampala, Uganda
World Health Organization. Regional Office for Africa. Brazzaville, Congo
National Institutes of Health. National Cancer Institute. Division of Cancer Epidemiology and Genetics. Bethesda, MD, USA
National Institutes of Health. National Cancer Institute. Division of Cancer Epidemiology and Genetics. Bethesda, MD, USA
National Institutes of Health. National Cancer Institute. Division of Cancer Epidemiology and Genetics. Bethesda, MD, USA
Ohio State University. Department of Pathology. Columbus, OH, USA
National Institutes of Health. National Institute of Allergy and Infectious Diseases. Division of Intramural Research. Bethesda, MD, USA
National Institutes of Health. National Cancer Institute. Division of Cancer Epidemiology and Genetics. Bethesda, MD, USA
St. Mary's Hospital. EMBLEM Study. Lacor, Gulu, Uganda
National Institutes of Health. National Cancer Institute. Division of Cancer Epidemiology and Genetics. Bethesda, MD, USA
National Institutes of Health. National Cancer Institute. Division of Cancer Epidemiology and Genetics. Laboratory of Translational Genomics. Bethesda, MD, USA
National Institutes of Health. National Cancer Institute. Division of Cancer Epidemiology and Genetics. Bethesda, MD, USA
Abstract
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
Keywords
Burkitt LymphomaMalaria
Plasmodium falciparum
Mendelian randomization
Sickle cell trait
Malaria resistance genes
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