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

Zhiwei Liu; Yang Luo; Samuel Kirimunda; Murielle Verboom; Olusegun O Onabajo; Mateus H Gouveia; Martin D Ogwang; Patrick Kerchan; Steven J Reynolds; Constance N Tenge; Pamela A Were; Robert T Kuremu; Walter N Wekesa; Nestory Masalu; Esther Kawira; Tobias Kinyera; Isaac Otim; Ismail D Legason; Hadijah Nabalende; Herry Dhudha; Leona W Ayers; Kishor Bhatia; James J Goedert; Nathan Cole; Wen Luo; Jia Liu; Michelle Manning; Belynda Hicks; Ludmila Prokunina-Olsson; George Chagaluka; W Thomas Johnston; Nora Mutalima; Eric Borgstein; George N Liomba; Steve Kamiza; Nyengo Mkandawire; Collins Mitambo; Elizabeth M Molyneux; Robert Newton; Ann W Hsing; James E Mensah; Anthony A Adjei; Amy Hutchinson; Mary Carrington; Meredith Yeager; Rainer Blasczyk; Stephen J Chanock; Soumya Raychaudhuri; Sam M Mbulaiteye

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, Yang Luo, Samuel Kirimunda, Murielle Verboom, Olusegun O Onabajo, Mateus H Gouveia, Martin D Ogwang, Patrick Kerchan, Steven J Reynolds, Constance N Tenge, Pamela A Were, Robert T Kuremu, Walter N Wekesa, Nestory Masalu, Esther Kawira, Tobias Kinyera, Isaac Otim, Ismail D Legason, Hadijah Nabalende, Herry DhudhaLeona W Ayers, Kishor Bhatia, James J Goedert, Nathan Cole, Wen Luo, Jia Liu, Michelle Manning, Belynda Hicks, Ludmila Prokunina-Olsson, George Chagaluka, W Thomas Johnston, Nora Mutalima, Eric Borgstein, George N Liomba, Steve Kamiza, Nyengo Mkandawire, Collins Mitambo, Elizabeth M Molyneux, Robert Newton, Ann W Hsing, James E Mensah, Anthony A Adjei, Amy Hutchinson, Mary Carrington, Meredith Yeager, Rainer Blasczyk, Stephen J Chanock, Soumya Raychaudhuri, Sam M Mbulaiteye

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Article number	41
Number of pages	9
Journal	Communications Biology
Volume	7
Issue number	1
DOIs	https://doi.org/10.1038/s42003-023-05701-5
Publication status	Published - 5 Jan 2024

Bibliographical note

Keywords

Child
Humans
Burkitt Lymphoma/genetics
Epstein-Barr Virus Infections/complications
Herpesvirus 4, Human/genetics
HLA-DQ alpha-Chains/genetics

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Human leukocyte antigen-DQA1*04:01 and rs2040406 variants are associated with elevated risk of childhood Burkitt lymphomaFinal published version, 3.51 MBLicence: CC BY

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Liu, Z., Luo, Y., Kirimunda, S., Verboom, M., Onabajo, O. O., Gouveia, M. H., Ogwang, M. D., Kerchan, P., Reynolds, S. J., Tenge, C. N., Were, P. A., Kuremu, R. T., Wekesa, W. N., Masalu, N., Kawira, E., Kinyera, T., Otim, I., Legason, I. D., Nabalende, H., ... Mbulaiteye, S. M. (2024). Human leukocyte antigen-DQA1*04:01 and rs2040406 variants are associated with elevated risk of childhood Burkitt lymphoma. Communications Biology, 7(1), Article 41. https://doi.org/10.1038/s42003-023-05701-5

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

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.",

keywords = "Child, Humans, Burkitt Lymphoma/genetics, Epstein-Barr Virus Infections/complications, Herpesvirus 4, Human/genetics, HLA-DQ alpha-Chains/genetics",

author = "Zhiwei Liu and Yang Luo and Samuel Kirimunda and Murielle Verboom and Onabajo, {Olusegun O} and Gouveia, {Mateus H} and Ogwang, {Martin D} and Patrick Kerchan and Reynolds, {Steven J} and Tenge, {Constance N} and Were, {Pamela A} and Kuremu, {Robert T} and Wekesa, {Walter N} and Nestory Masalu and Esther Kawira and Tobias Kinyera and Isaac Otim and Legason, {Ismail D} and Hadijah Nabalende and Herry Dhudha and Ayers, {Leona W} and Kishor Bhatia and Goedert, {James J} and Nathan Cole and Wen Luo and Jia Liu and Michelle Manning and Belynda Hicks and Ludmila Prokunina-Olsson and George Chagaluka and Johnston, {W Thomas} and Nora Mutalima and Eric Borgstein and Liomba, {George N} and Steve Kamiza and Nyengo Mkandawire and Collins Mitambo and Molyneux, {Elizabeth M} and Robert Newton and Hsing, {Ann W} and Mensah, {James E} and Adjei, {Anthony A} and Amy Hutchinson and Mary Carrington and Meredith Yeager and Rainer Blasczyk and Chanock, {Stephen J} and Soumya Raychaudhuri and Mbulaiteye, {Sam M}",

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Liu, Z, Luo, Y, Kirimunda, S, Verboom, M, Onabajo, OO, Gouveia, MH, Ogwang, MD, Kerchan, P, Reynolds, SJ, Tenge, CN, Were, PA, Kuremu, RT, Wekesa, WN, Masalu, N, Kawira, E, Kinyera, T, Otim, I, Legason, ID, Nabalende, H, Dhudha, H, Ayers, LW, Bhatia, K, Goedert, JJ, Cole, N, Luo, W, Liu, J, Manning, M, Hicks, B, Prokunina-Olsson, L, Chagaluka, G, Johnston, WT , Mutalima, N, Borgstein, E, Liomba, GN, Kamiza, S, Mkandawire, N, Mitambo, C, Molyneux, EM, Newton, R, Hsing, AW, Mensah, JE, Adjei, AA, Hutchinson, A, Carrington, M, Yeager, M, Blasczyk, R, Chanock, SJ, Raychaudhuri, S & Mbulaiteye, SM 2024, 'Human leukocyte antigen-DQA1*04:01 and rs2040406 variants are associated with elevated risk of childhood Burkitt lymphoma', Communications Biology, vol. 7, no. 1, 41. https://doi.org/10.1038/s42003-023-05701-5

TY - JOUR

T1 - Human leukocyte antigen-DQA1*04:01 and rs2040406 variants are associated with elevated risk of childhood Burkitt lymphoma

AU - Liu, Zhiwei

AU - Luo, Yang

AU - Kirimunda, Samuel

AU - Verboom, Murielle

AU - Onabajo, Olusegun O

AU - Gouveia, Mateus H

AU - Ogwang, Martin D

AU - Kerchan, Patrick

AU - Reynolds, Steven J

AU - Tenge, Constance N

AU - Were, Pamela A

AU - Kuremu, Robert T

AU - Wekesa, Walter N

AU - Masalu, Nestory

AU - Kawira, Esther

AU - Kinyera, Tobias

AU - Otim, Isaac

AU - Legason, Ismail D

AU - Nabalende, Hadijah

AU - Dhudha, Herry

AU - Ayers, Leona W

AU - Bhatia, Kishor

AU - Goedert, James J

AU - Cole, Nathan

AU - Luo, Wen

AU - Liu, Jia

AU - Manning, Michelle

AU - Hicks, Belynda

AU - Prokunina-Olsson, Ludmila

AU - Chagaluka, George

AU - Johnston, W Thomas

AU - Mutalima, Nora

AU - Borgstein, Eric

AU - Liomba, George N

AU - Kamiza, Steve

AU - Mkandawire, Nyengo

AU - Mitambo, Collins

AU - Molyneux, Elizabeth M

AU - Newton, Robert

AU - Hsing, Ann W

AU - Mensah, James E

AU - Adjei, Anthony A

AU - Hutchinson, Amy

AU - Carrington, Mary

AU - Yeager, Meredith

AU - Blasczyk, Rainer

AU - Chanock, Stephen J

AU - Raychaudhuri, Soumya

AU - Mbulaiteye, Sam M

PY - 2024/1/5

Y1 - 2024/1/5

N2 - 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.

AB - 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.

KW - Child

KW - Humans

KW - Burkitt Lymphoma/genetics

KW - Epstein-Barr Virus Infections/complications

KW - Herpesvirus 4, Human/genetics

KW - HLA-DQ alpha-Chains/genetics

U2 - 10.1038/s42003-023-05701-5

DO - 10.1038/s42003-023-05701-5

M3 - Article

C2 - 38182727

SN - 2399-3642

VL - 7

JO - Communications Biology

JF - Communications Biology

IS - 1

M1 - 41

ER -