Human leukocyte antigen-DQA1*04:01 and rs2040406 variants are associated with elevated risk of childhood Burkitt lymphoma

Burkitt lymphoma (BL) is responsible for many childhood cancers in sub-Saharan Africa, where it is linked to recurrent or chronic infection by Epstein-Barr virus or Plasmodium falciparum. However, whether human leukocyte antigen (HLA) polymorphisms, which regulate immune response, are associated with BL has not been well investigated, which limits our understanding of BL etiology. Here we investigate this association among 4,645 children aged 0-15 years, 800 with BL, enrolled in Uganda, Tanzania, Kenya, and Malawi. HLA alleles are imputed with accuracy >90% for HLA class I and 85-89% for class II alleles. BL risk is elevated with HLA-DQA1*04:01 (adjusted odds ratio [OR] = 1.61, 95% confidence interval [CI] = 1.32-1.97, P = 3.71 × 10-6), with rs2040406(G) in HLA-DQA1 region (OR = 1.43, 95% CI = 1.26-1.63, P = 4.62 × 10-8), and with amino acid Gln at position 53 versus other variants in HLA-DQA1 (OR = 1.36, P = 2.06 × 10-6). The associations with HLA-DQA1*04:01 (OR = 1.29, P = 0.03) and rs2040406(G) (OR = 1.68, P = 0.019) persist in mutually adjusted models. The higher risk rs2040406(G) variant for BL is associated with decreased HLA-DQB1 expression in eQTLs in EBV transformed lymphocytes. Our results support the role of HLA variation in the etiology of BL and suggest that a promising area of research might be understanding the link between HLA variation and EBV control

Mosaic chromosomal alterations in peripheral blood leukocytes of children in sub-Saharan Africa

In high-income countries, mosaic chromosomal alterations in peripheral blood leukocytes are associated with an elevated risk of adverse health outcomes, including hematologic malignancies. We investigate mosaic chromosomal alterations in sub-Saharan Africa among 931 children with Burkitt lymphoma, an aggressive lymphoma commonly characterized by immunoglobulin-MYC chromosomal rearrangements, 3822 Burkitt lymphoma-free children, and 674 cancer-free men from Ghana. We find autosomal and X chromosome mosaic chromosomal alterations in 3.4% and 1.7% of Burkitt lymphoma-free children, and 8.4% and 3.7% of children with Burkitt lymphoma (P-values = 5.7×10-11 and 3.74×10-2, respectively). Autosomal mosaic chromosomal alterations are detected in 14.0% of Ghanaian men and increase with age. Mosaic chromosomal alterations in Burkitt lymphoma cases include gains on chromosomes 1q and 8, the latter spanning MYC, while mosaic chromosomal alterations in Burkitt lymphoma-free children include copy-neutral loss of heterozygosity on chromosomes 10, 14, and 16. Our results highlight mosaic chromosomal alterations in sub-Saharan African populations as a promising area of research

High prevalence of malaria in pregnancy among women attending antenatal care at a large referral hospital in northwestern Uganda: A cross-sectional study.

BackgroundMalaria in pregnancy contributes to substantial morbidity and mortality among women in Uganda. However, there is limited information on the prevalence and factors associated with malaria in pregnancy among women in Arua district, northwestern Uganda. We, therefore, assessed the prevalence and factors associated with malaria in pregnancy among women attending routine antenatal care (ANC) clinics at Arua regional referral hospital in north-western Uganda.MethodsWe conducted an analytic cross-sectional study between October and December 2021. We used a paper-based structured questionnaire to collect data on maternal socio-demographic and obstetric factors and malaria preventive measures. Malaria in pregnancy was defined as a positive rapid malarial antigen test during ANC visits. We performed a modified Poisson regression analysis with robust standard errors to determine factors independently associated with malaria in pregnancy, reported as adjusted prevalence ratios (aPR) and 95% confidence intervals (CI).ResultsWe studied 238 pregnant women with a mean age of 25.32±5.79 years that attended the ANC clinic, all without symptomatic malaria. Of the participants, 173 (72.7%) were in their second or third trimester, 117 (49.2%) were first or second-time pregnant women, and 212 (89.1%) reported sleeping under insecticide-treated bednets (ITNs) every day. The prevalence of malaria in pregnancy was 26.1% (62/238) by rapid diagnostic testing (RDT), with the independently associated factors being daily use of insecticide-treated bednets (aPR 0.41, 95% CI 0.28, 0.62), first ANC visit after 12 weeks of gestation (aPR1.78, 95% CI 1.05, 3.03), and being in the second or third trimester (aPR 0.45, 95% CI 0.26, 0.76).ConclusionThe prevalence of malaria in pregnancy among women attending ANC in this setting is high. We recommend the provision of insecticide-treated bednets to all pregnant women and early ANC attendance to enable access to malaria preventive therapy and related interventions

Diagnostic validation of a portable whole slide imaging scanner for lymphoma diagnosis in resource-constrained setting: A cross-sectional study

Background: Telepathology utilizing high-throughput static whole slide image scanners is proposed to address the challenge of limited pathology services in resource-restricted settings. However, the prohibitive equipment costs and sophisticated technologies coupled with large amounts of space to set up the devices make it impractical for use in resource-limited settings. Herein, we aimed to address this challenge by validating a portable whole slide imaging (WSI) device against glass slide microscopy (GSM) using lymph node biopsies from suspected lymphoma cases from Sub-Saharan Africa. Material and methods: This was part of a multicenter prospective case–control head-to-head comparison study of liquid biopsy against conventional pathology. For the portable WSI scanner validation, the study pathologists evaluated 105 surgical lymph node specimens initially confirmed by gold-standard pathology between February and December 2021. The tissues were processed according to standard protocols for Hematoxylin and Eosin (H&E) and Immunohistochemistry (IHC) staining by well-trained histotechnicians, then digitalized the H& E and IHC slides at each center. The digital images were anonymized and uploaded to a HIPAA-compliant server by the histotechnicians. Three study pathologists independently accessed and reviewed the images after a 6-week washout. The agreement between diagnoses established on GSM and WSI across the pathologists was described and measured using Cohens’ kappa coefficient (κ). Results: On GSM, 65.5% (n=84) of specimens were lymphoma; 25% were classified as benign, while 9.5% were metastatic. Morphological quality assessment on GSM and WSI established that 79.8% and 53.6% of cases were of high quality, respectively. When diagnoses by GSM were compared to WSI, the overall concordance for various diagnostic categories was 93%, 100%, and 86% for lymphoma, metastases, and benign conditions respectively. The sensitivity and specificity of WSI for the detection of lymphoma were 95.2% and 85.7%, respectively, with an overall inter-observer agreement (κ) of 0.86; 95% CI (0.70–0.95). Conclusions: We demonstrate that mobile whole slide imaging (WSI) is non-inferior to conventional glass slide microscopy (GSM) for the primary diagnosis of malignant infiltration of lymph node specimens. Our results further provide proof of concept that mobile WSI can be adapted to resource-restricted settings for primary surgical pathology and would significantly improve patient outcomes

Associations between IgG reactivity to Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) antigens and Burkitt lymphoma in Ghana and Uganda case-control studiesResearch in context

Background: Endemic Burkitt lymphoma (eBL) is an aggressive childhood B-cell lymphoma linked to Plasmodium falciparum (Pf) malaria in sub-Saharan Africa. We investigated antibody reactivity to several human receptor-binding domains of the Pf erythrocyte membrane protein 1 (PfEMP1) that play a key role in malaria pathogenesis and are targets of acquired immunity to malaria. Methods: Serum/plasma IgG antibody reactivity was measured to 22 Pf antigens, including 18 to PfEMP1 CIDR domains between cases and controls from two populations (149 eBL cases and 150 controls from Ghana and 194 eBL cases and 600 controls from Uganda). Adjusted odds ratios (aORs) for case-control associations were estimated by logistic regression. Findings: There was stronger reactivity to the severe malaria associated CIDRα1 domains than other CIDR domains both in cases and controls. eBL cases reacted to fewer antigens than controls (Ghana: p = 0·001; Uganda: p = 0·03), with statistically significant lower ORs associated with reactivity to 13+ antigens in Ghana (aOR 0·39, 95% CI 0·24–0·63; pheterogeneity = 0·00011) and Uganda (aOR 0·60, 95% CI 0.41–0·88; pheterogeneity = 0·008). eBL was inversely associated with reactivity, coded as quartiles, to group A variant CIDRδ1 (ptrend = 0·035) in Ghana and group B CD36-binding variants CIDRα2·2 (ptrend = 0·006) and CIDRα2·4 (ptrend = 0·033) in Uganda, and positively associated with reactivity to SERA5 in Ghana (ptrend = 0·017) and Uganda (ptrend = 0·007) and group A CIDRα1·5 variant in Uganda only (ptrend = 0·034). Interpretation: eBL cases reacted to fewer antigens than controls using samples from two populations, Ghana and Uganda. Attenuated humoral immunity to Pf EMP1 may contribute to susceptibility to low-grade malaria and eBL risk. Funding: Intramural Research Program, National Cancer Institute and National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services. Keywords: Non-Hodgkin lymphoma, Plasmodium falciparum malaria, PfEMP1, Epstein-Barr virus, Burkitt lymphoma, Afric

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

Submitted by Nuzia Santos ([email protected]) on 2018-03-14T17:44:37Z No. of bitstreams: 1 Evaluating the Causal Link Between Malaria.pdf: 271793 bytes, checksum: 2844c8378094216bfb4d102d6677dd91 (MD5)Approved for entry into archive by Nuzia Santos ([email protected]) on 2018-03-14T18:01:40Z (GMT) No. of bitstreams: 1 Evaluating the Causal Link Between Malaria.pdf: 271793 bytes, checksum: 2844c8378094216bfb4d102d6677dd91 (MD5)Made available in DSpace on 2018-03-14T18:01:40Z (GMT). No. of bitstreams: 1 Evaluating the Causal Link Between Malaria.pdf: 271793 bytes, checksum: 2844c8378094216bfb4d102d6677dd91 (MD5) Previous issue date: 2017African Field Epidemiology Network. EMBLEM Study. Kampala, UgandaNational Institutes of Health. National Cancer Institute. Division of Cancer Epidemiology and Genetics. Bethesda, MD, USANational Institutes of Health. National Cancer Institute. Division of Cancer Epidemiology and Genetics. Laboratory of Translational Genomics. Bethesda, MD, USANational Institutes of Health. National Cancer Institute. Division of Cancer Epidemiology and Genetics. Bethesda, MD, USAFundação Oswaldo Cruz. Instituto Rene Rachou. Belo Horizonte, MG, BrazilMakerere University. College of Health Sciences. Department of Medical Microbiology. Kampala, UgandaAfrican Field Epidemiology Network. EMBLEM Study. Kampala, UgandaNational Institutes of Health. National Cancer Institute. Division of Cancer Epidemiology and Genetics. Bethesda, MD, USAAfrican Field Epidemiology Network. EMBLEM Study. Kampala, UgandaAfrican Field Epidemiology Network. EMBLEM Study. Kampala, UgandaNational Institutes of Health. National Cancer Institute. Division of Cancer Epidemiology and Genetics. Laboratory of Translational Genomics. Bethesda, MD, USAAfrican Field Epidemiology Network. EMBLEM Study. Kampala, Uganda/ University of Maryland School of Medicine. Institute of Human Virology Benjamin Emmanuel. Baltimore, MD, USAAfrican Field Epidemiology Network. EMBLEM Study. Kampala, UgandaWorld Health Organization. Regional Office for Africa. Brazzaville, CongoNational Institutes of Health. National Cancer Institute. Division of Cancer Epidemiology and Genetics. Bethesda, MD, USANational Institutes of Health. National Cancer Institute. Division of Cancer Epidemiology and Genetics. Bethesda, MD, USANational Institutes of Health. National Cancer Institute. Division of Cancer Epidemiology and Genetics. Bethesda, MD, USAOhio State University. Department of Pathology. Columbus, OH, USANational Institutes of Health. National Institute of Allergy and Infectious Diseases. Division of Intramural Research. Bethesda, MD, USANational Institutes of Health. National Cancer Institute. Division of Cancer Epidemiology and Genetics. Bethesda, MD, USASt. Mary's Hospital. EMBLEM Study. Lacor, Gulu, UgandaNational Institutes of Health. National Cancer Institute. Division of Cancer Epidemiology and Genetics. Bethesda, MD, USANational Institutes of Health. National Cancer Institute. Division of Cancer Epidemiology and Genetics. Laboratory of Translational Genomics. Bethesda, MD, USANational Institutes of Health. National Cancer Institute. Division of Cancer Epidemiology and Genetics. Bethesda, MD, USABackground: 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 eB

Genetic signatures of gene flow and malaria-driven natural selection in sub-Saharan populations of the "endemic Burkitt Lymphoma belt"

Submitted by Nuzia Santos ([email protected]) on 2020-02-04T14:35:16Z No. of bitstreams: 1 Genetic signatures of gene flow and malaria-driven.pdf: 11801795 bytes, checksum: fd87b07ab4fac498d62a72df070e920d (MD5)Approved for entry into archive by Nuzia Santos ([email protected]) on 2020-02-04T16:03:51Z (GMT) No. of bitstreams: 1 Genetic signatures of gene flow and malaria-driven.pdf: 11801795 bytes, checksum: fd87b07ab4fac498d62a72df070e920d (MD5)Made available in DSpace on 2020-02-04T16:03:51Z (GMT). No. of bitstreams: 1 Genetic signatures of gene flow and malaria-driven.pdf: 11801795 bytes, checksum: fd87b07ab4fac498d62a72df070e920d (MD5) Previous issue date: 2019Fundação Oswaldo Cruz. Instituto René Rachou. Belo Horizonte, MG, Brasil / Universidade Federal de Minas Gerais. Instituto de Ciências Biológicas. Departamento de Biologia. Belo Horizonte, MG, Brasil /Center for Research on Genomics & Global Health, National Institutes of Health. US Department of Health and Human Services. Bethesda, Maryland, USA.Division of Cancer Epidemiology and Genetics. National Cancer Institute. National Institutes of Health. US Department of Health and Human Services. Bethesda, Maryland, USA.Universidade Federal de Minas Gerais. Instituto de Ciências Biológicas. Departamento de Biologia. Belo Horizonte, MG, Brasil.Universidade de São Paulo. Instituto de Biociências. Departamento de Genética e Biologia Evolutiva. São Paulo, SP, Brasil.Universidade Federal de Minas Gerais. Instituto de Ciências Biológicas. Departamento de Biologia. Belo Horizonte, MG, Brasil / Universidade Federal de Minas Gerais. Departamento de Estatística. Belo Horizonte, MG, Brasil.EMBLEM Study. African Field Epidemiology Network. Kampala, Uganda.University of Ghana Medical School, Accra, Ghana.University of Ghana Medical School, Accra, Ghana.EMBLEM Study. African Field Epidemiology Network. Kampala, Uganda.EMBLEM Study. African Field Epidemiology Network. Kampala, Uganda.EMBLEM Study. African Field Epidemiology Network. Kampala, Uganda.EMBLEM Study. African Field Epidemiology Network. Kampala, Uganda.Department of Biological Sciences. University of Botswana. Gaborone, Botswana.Department of Biomedical Sciences. University of Botswana School of Medicine. Gaborone, Botswana.EMBLEM Study. African Field Epidemiology Network. Kampala, Uganda.Division of Cancer Epidemiology and Genetics. National Cancer Institute. National Institutes of Health. US Department of Health and Human Services. Bethesda, Maryland, USA.Division of Intramural Research. National Institute of Allergy and Infectious Diseases. National Institutes of Health. US Department of Health and Human Services. Bethesda, Maryland, USA.University of Ghana Medical School. Accra, Ghana.University of Ghana Medical School. Accra, Ghana.University of Ghana Medical School. Accra, Ghana.University of Ghana Medical School. Accra, Ghana.Division of Cancer Epidemiology and Genetics. National Cancer Institute. National Institutes of Health. US Department of Health and Human Services. Bethesda, Maryland, USA.Division of Cancer Epidemiology and Genetics. National Cancer Institute. National Institutes of Health. US Department of Health and Human Services. Bethesda, Maryland, USA.Division of Cancer Epidemiology and Genetics. National Cancer Institute. National Institutes of Health. US Department of Health and Human Services. Bethesda, Maryland, USA.Division of Cancer Epidemiology and Genetics. National Cancer Institute. National Institutes of Health. US Department of Health and Human Services. Bethesda, Maryland, USA.Laboratory of Translational Genomics. Division of Cancer Epidemiology and Genetics. National Cancer Institute. National Institutes of Health. USDepartment of Health and Human Services. Bethesda, Maryland, USA.Laboratory of Translational Genomics. Division of Cancer Epidemiology and Genetics. National Cancer Institute. National Institutes of Health. US Department of Health and Human Services. Bethesda, Maryland, USA.Cancer Genomics Research Laboratory. Leidos Biomedical Research. Frederick National Laboratory for Cancer Research. US Department of Health and Human Services. Frederick, Maryland, USA.Fundação Oswaldo Cruz. Instituto René Rachou. Belo Horizonte, MG, Brasil.Stanford Cancer Institute. Stanford University. Stanford, California, USA.Department of Genetics and Biology, University of Pennsylvania, Philadelphia, USA.Division of Cancer Epidemiology and Genetics. National Cancer Institute. National Institutes of Health. US Department of Health and Human Services. Bethesda, Maryland, USA.Universidade Federal de Minas Gerais. Instituto de Ciências Biológicas. Departamento de Biologia Geral. Belo Horizonte, MG, Brasil.Division of Cancer Epidemiology and Genetics. National Cancer Institute. National Institutes of Health. US Department of Health and Human Services. Bethesda, Maryland, USA.Populations in sub-Saharan Africa have historically been exposed to intense selection from chronic infection with falciparum malaria. Interestingly, populations with the highest malaria intensity can be identified by the increased occurrence of endemic Burkitt Lymphoma (eBL), a pediatric cancer that affects populations with intense malaria exposure, in the so called “eBL belt” in sub-Saharan Africa. However, the effects of intense malaria exposure and sub-Saharan populations’ genetic histories remain poorly explored. To determine if historical migrations and intense malaria exposure have shaped the genetic composition of the eBL belt populations, we genotyped ~4.3 million SNPs in 1,708 individuals from Ghana and Northern Uganda, located on opposite sides of eBL belt and with ≥ 7 months/year of intense malaria exposure and published evidence of high incidence of BL. Among 35 Ghanaian tribes, we showed a predominantly West-Central African ancestry and genomic footprints of gene flow from Gambian and East African populations. In Uganda, the North West population showed a predominantly Nilotic ancestry, and the North Central population was a mixture of Nilotic and Southern Bantu ancestry, while the Southwest Ugandan population showed a predominant Southern Bantu ancestry. Our results support the hypothesis of diverse ancestral origins of the Ugandan, Kenyan and Tanzanian Great Lakes African populations, reflecting a confluence of Nilotic, Cushitic and Bantu migrations in the last 3000 years. Natural selection analyses suggest, for the first time, a strong positive selection signal in the ATP2B4 gene (rs10900588) in Northern Ugandan populations. These findings provide important baseline genomic data to facilitate disease association studies, including of eBL, in eBL belt populations