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

Zhiwei Liu^#¹, Yang Luo^#^{2

3

4

5

6

7}, Samuel Kirimunda⁸, Murielle Verboom⁹, Olusegun O Onabajo¹, Mateus H Gouveia¹⁰, Martin D Ogwang^{11

12}, Patrick Kerchan^{12

13}, Steven J Reynolds¹⁴, Constance N Tenge^{12

15}, Pamela A Were^{12

16}, Robert T Kuremu^{12

15}, Walter N Wekesa^{12

15}, Nestory Masalu¹⁷, Esther Kawira^{12

18}, Tobias Kinyera^{11

12}, Isaac Otim^{11

12}, Ismail D Legason^{12

13}, Hadijah Nabalende^{11

12}, Herry Dhudha^{12

18}, Leona W Ayers¹⁹, Kishor Bhatia¹, James J Goedert¹, Nathan Cole²⁰, Wen Luo²⁰, Jia Liu²⁰, Michelle Manning²⁰, Belynda Hicks²⁰, Ludmila Prokunina-Olsson¹, George Chagaluka²¹, W Thomas Johnston²², Nora Mutalima^{22

23}, Eric Borgstein²¹, George N Liomba²¹, Steve Kamiza²¹, Nyengo Mkandawire²¹, Collins Mitambo²⁴, Elizabeth M Molyneux²¹, Robert Newton²², Ann W Hsing²⁵, James E Mensah²⁶, Anthony A Adjei²⁶, Amy Hutchinson²⁰, Mary Carrington^{27

28}, Meredith Yeager²⁰, Rainer Blasczyk⁹, Stephen J Chanock¹, Soumya Raychaudhuri^{3

4

5

6

7}, Sam M Mbulaiteye²⁹

Affiliations

¹ Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.
² Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK.
³ Center for Data Sciences, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
⁴ Division of Rheumatology, Immunology, and Immunity, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
⁵ Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
⁶ Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.
⁷ Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁸ College of Health Sciences, Makerere University, Kampala, Uganda.
⁹ Institute of Transfusion Medicine and Transplant Engineering, Hanover, Germany.
¹⁰ Center for Research on Genomics & Global Health, NHGRI, National Institutes of Health, Bethesda, MD, USA.
¹¹ St. Mary's Hospital, Lacor, Gulu, Uganda.
¹² EMBLEM Study, African Field Epidemiology Network, Kampala, Uganda.
¹³ Kuluva Hospital, Arua, Uganda.
¹⁴ Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
¹⁵ Moi University College of Health Sciences, Eldoret, Kenya.
¹⁶ Academic Model Providing Access To Healthcare (AMPATH), Eldoret, Kenya.
¹⁷ Bugando Medical Center, Mwanza, Tanzania.
¹⁸ Shirati Health, Education, and Development Foundation, Shirati, Tanzania.
¹⁹ Department of Pathology, The Ohio State University, Columbus, OH, USA.
²⁰ Cancer Genomics Research Laboratory, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
²¹ Departments of Pediatrics and Surgery, Kamuzu University of Health Sciences (formerly College of Medicine), University of Malawi, Blantyre, Malawi.
²² Epidemiology and Cancer Statistics Group, Department of Health Sciences, University of York, York, UK.
²³ Cancer Epidemiology Unit, University of Oxford, Oxford, UK.
²⁴ National Health Sciences Research Committee, Research Department, Ministry of Health, Lilongwe, Malawi.
²⁵ Stanford Cancer Institute, Stanford University, Stanford, CA, USA.
²⁶ University of Ghana Medical School, Accra, Ghana.
²⁷ Basic Science Program, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD, USA and Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
²⁸ Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA.
²⁹ Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA. mbulaits@mail.nih.gov.

^# Contributed equally.

PMID: 38182727
PMCID: PMC10770398
DOI: 10.1038/s42003-023-05701-5

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

Zhiwei Liu et al. Commun Biol. 2024.

. 2024 Jan 5;7(1):41.

doi: 10.1038/s42003-023-05701-5.

Authors

Affiliations

¹ Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.
² Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK.
³ Center for Data Sciences, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
⁴ Division of Rheumatology, Immunology, and Immunity, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
⁵ Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
⁶ Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.
⁷ Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁸ College of Health Sciences, Makerere University, Kampala, Uganda.
⁹ Institute of Transfusion Medicine and Transplant Engineering, Hanover, Germany.
¹⁰ Center for Research on Genomics & Global Health, NHGRI, National Institutes of Health, Bethesda, MD, USA.
¹¹ St. Mary's Hospital, Lacor, Gulu, Uganda.
¹² EMBLEM Study, African Field Epidemiology Network, Kampala, Uganda.
¹³ Kuluva Hospital, Arua, Uganda.
¹⁴ Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
¹⁵ Moi University College of Health Sciences, Eldoret, Kenya.
¹⁶ Academic Model Providing Access To Healthcare (AMPATH), Eldoret, Kenya.
¹⁷ Bugando Medical Center, Mwanza, Tanzania.
¹⁸ Shirati Health, Education, and Development Foundation, Shirati, Tanzania.
¹⁹ Department of Pathology, The Ohio State University, Columbus, OH, USA.
²⁰ Cancer Genomics Research Laboratory, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
²¹ Departments of Pediatrics and Surgery, Kamuzu University of Health Sciences (formerly College of Medicine), University of Malawi, Blantyre, Malawi.
²² Epidemiology and Cancer Statistics Group, Department of Health Sciences, University of York, York, UK.
²³ Cancer Epidemiology Unit, University of Oxford, Oxford, UK.
²⁴ National Health Sciences Research Committee, Research Department, Ministry of Health, Lilongwe, Malawi.
²⁵ Stanford Cancer Institute, Stanford University, Stanford, CA, USA.
²⁶ University of Ghana Medical School, Accra, Ghana.
²⁷ Basic Science Program, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD, USA and Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
²⁸ Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA.
²⁹ Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA. mbulaits@mail.nih.gov.

^# Contributed equally.

PMID: 38182727
PMCID: PMC10770398
DOI: 10.1038/s42003-023-05701-5

Abstract

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.

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Conflict of interest statement

The authors declare no competing interests.

Figures

**Fig. 1. Map of study area and flow chard of study procedures.**
a Map showing geographical areas shaded green where Burkitt lymphoma cases and controls were enrolled. Participating hospitals are marked with a red cross, while the capital cities where major tertiary care centers are located are marked with white star on a green background. The map was drawn using ESRI ArcGIS Pro software. No portions of this figure were imported as image components from a database. b The Study workflow components.

**Fig. 2. Region association plots of variants in the human leukocyte antigen region and Burkitt lymphoma based on 800 BL cases and 3,845 controls.**
a Shows results from unconditional analyses; b Shows analyses conditional on DQA1*04:01; c Shows results conditional on rs2040406. The color of the dots indicates different polymorphisms: grey dots indicate imputed SNPs; magenta dots indicate genotyped SNPs; turquoise dots indicate amino acids (AA); light blue dots indicate indels; and orange dots indicate classical HLA alleles at 1- or 2-field resolution.

See this image and copyright information in PMC

References

1. López C, et al. Burkitt lymphoma. Nat. Rev. Dis. Primers. 2022;8:78. doi: 10.1038/s41572-022-00404-3. - DOI - PubMed
1. Burkitt D. A sarcoma involving the jaws in African children. Br. J. Surg. 1958;46:218–223. doi: 10.1002/bjs.18004619704. - DOI - PubMed
1. Aka P, et al. Incidence and trends in Burkitt lymphoma in northern Tanzania from 2000 to 2009. Pediatr Blood Cancer. 2012;59:1234–1238. doi: 10.1002/pbc.24194. - DOI - PMC - PubMed
1. Ogwang MD, Bhatia K, Biggar RJ, Mbulaiteye SM. Incidence and geographic distribution of endemic Burkitt lymphoma in northern Uganda revisited. Int. J. Cancer. 2008;123:2658–2663. doi: 10.1002/ijc.23800. - DOI - PMC - PubMed
1. Epstein MA, Achong BG, Barr YM. Virus particles in cultured lymphoblasts from Burkitt’s lymphoma. Lancet. 1964;1:702–703. doi: 10.1016/S0140-6736(64)91524-7. - DOI - PubMed

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

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