HLA class I and II diversity contributes to the etiologic heterogeneity of non-Hodgkin lymphoma subtypes

Sophia S. Wang*, Mary Carrington, Sonja I. Berndt, Susan L. Slager, Paige M. Bracci, Jenna Voutsinas, James R. Cerhan, Karin E. Smedby, Henrik Hjalgrim, Joseph Vijai, Lindsay M. Morton, Roel Vermeulen, Ora Paltiel, Claire M. Vajdic, Martha S. Linet, Alexandra Nieters, Silvia de Sanjose, Wendy Cozen, Elizabeth E. Brown, Jennifer TurnerJohn J. Spinelli, Tongzhang Zheng, Brenda M. Birmann, Christopher R. Flowers, Nikolaus Becker, Elizabeth A. Holly, Eleanor Kane, Dennis Weisenburger, Marc Maynadie, Pierluigi Cocco, Demetrius Albanes, Stephanie J. Weinstein, Lauren R. Teras, W. Ryan Diver, Stephanie J. Lax, Ruth C. Travis, Rudolph Kaaks, Elio Riboli, Yolanda Benavente, Paul Brennan, James McKay, Marie Hélène Delfau-Larue, Brian K. Link, Corrado Magnani, Maria Grazia Ennas, Giancarlo Latte, Andrew L. Feldman, Nicole Wong Doo, Graham G. Giles, Melissa C. Southey, Roger L. Milne, Kenneth Offit, Jacob Musinsky, Alan A. Arslan, Mark P. Purdue, Hans Olov Adami, Mads Melbye, Bengt Glimelius, Lucia Conde, Nicola J. Camp, Martha Glenn, Karen Curtin, Jacqueline Clavel, Alain Monnereau, David G. Cox, Hervé Ghesquières, Gilles Salles, Paulo Bofetta, Lenka Foretova, Anthony Staines, Scott Davis, Richard K. Severson, Qing Lan, Angela Brooks-Wilson, Martyn T. Smith, Eve Roman, Anne Kricker, Yawei Zhang, Peter Kraft, Stephen J. Chanock, Nathaniel Rothman, Patricia Hartge, Christine F. Skibola

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

27 Scopus citations


A growing number of loci within the human leukocyte antigen (HLA) region have been implicated in non-Hodgkin lymphoma (NHL) etiology. Here, we test a complementary hypothesis of "heterozygote advantage" regarding the role of HLA and NHL, whereby HLA diversity is beneficial and homozygous HLA loci are associated with increased disease risk. HLA alleles at class I and II loci were imputed from genome-wide association studies (GWAS) using SNP2HLA for 3,617 diffuse large B-cell lymphomas (DLBCL), 2,686 follicular lymphomas (FL), 2,878 chronic lymphocytic leukemia/small lymphocytic lymphomas (CLL/SLL), 741 marginal zone lymphomas (MZL), and 8,753 controls of European descent. Both DLBCL and MZL risk were elevated with homozygosity at class I HLA-B and -C loci (OR DLBCL = 1.31, 95% CI = 1.06–1.60; OR MZL = 1.45, 95% CI = 1.12–1.89) and class II HLA-DRB1 locus (OR DLBCL = 2.10, 95% CI = 1.24–3.55; OR MZL = 2.10, 95% CI = 0.99–4.45). Increased FL risk was observed with the overall increase in number of homozygous HLA class II loci (P trend < 0.0001, FDR = 0.0005). These results support a role for HLA zygosity in NHL etiology and suggests that distinct immune pathways may underly the etiology of the different NHL subtypes. Significance: HLA gene diversity reduces risk for non-Hodgkin lymphoma.

Original languageAmerican English
Pages (from-to)4086-4096
Number of pages11
JournalCancer Research
Issue number14
StatePublished - 15 Jul 2018
Externally publishedYes

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Publisher Copyright:
© 2018 American Association for Cancer Research.


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