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

Abstract

BackgroundPlasmodium 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.MethodsMalaria-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.FindingsSCT 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.InterpretationOur results support a causal effect of malaria infection on eBL.

IFN-λ4 is associated with increased risk and earlier occurrence of gastrointestinal, respiratory and malarial infections in Malian children

“…DNA samples were genotyped for IFNL4 -rs368234815 and IFNL3 -rs4803217 by custom TaqMan genotyping assays as previously described (5, 12), ( Figure S1 ). HBB polymorphisms rs334-T/A, HBB -Glu7Val (HbS, encoding hemoglobin variants A/A, A/S, and S/S) and rs33930165, Glu7Lys (HbC, encoding hemoglobin variants A/A, A/C, and C/C) were genotyped by Sanger sequencing as previously described (13), ( Figure S2 ). Approximately 10% of samples were genotyped in technical duplicates, which were 100% concordant for all markers.…”

“…Representative Sanger sequencing chromatograms for genotyping of the HBB polymorphisms rs33930165-A/G (Glu7Lys) and rs334-A/T (Glu7Val) in the Mali birth cohort study samples, as has been previously described (13). …”

A population‐based study of the prevalence and risk factors of low‐grade Plasmodium falciparum malaria infection in children aged 0–15 years old in northern Tanzania

“…This is 5.6-to 88-fold higher than the incidence of sporadic BL in the United States [12], an elevation that is attributed to the impact of Plasmodium falciparum (Pf) malaria infection [11,13]. This association was recently confirmed by showing that the sickle cell trait, which is protective against severe malaria also protects against eBL [14]. Consistent with this, geographic patterns of eBL mirror those of malaria, with particularly high incidence in areas south and east of Lake Victoria [11,13].…”

“…[12][13][14][15] Age group, years n = 11 n = 31 n = 73 n = 41 n = 31 = 43 n = 194 n = 274 n = 178 n = 111Figure showingage-specific Plasmodium falciparum prevalence (pfPR) (a) and age-specific geometric mean parasite density (GMPD) (b) in children aged 0-15 years enrolled in northern Tanzania who were tested for malaria using the malaria rapid diagnostic test (RDT) or thick film microscopy (TFM) examination. The horizontal bars connected by a vertical line represent the 95% confidence intervals for each estimate.…”

Variation in the Human Leukocyte Antigen system and risk for endemic Burkitt lymphoma in northern Uganda

“…To investigate these hypotheses, we leveraged data from the Epidemiology of Burkitt lymphoma in East African children and minors (EMBLEM) study (Legason et al , ; Peprah et al , ) to assess HLA associations with eBL risk in northern Uganda based on high‐resolution HLA sequencing.…”