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HLA Class I and II Diversity Contributes to the Etiologic Heterogeneity of Non-Hodgkin Lymphoma Subtypes.

ABSTRACT: 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. Cancer Res; 78(14); 4086-96. ©2018 AACR.

SUBMITTER: Wang SS

PROVIDER: S-EPMC6065509 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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HLA Class I and II Diversity Contributes to the Etiologic Heterogeneity of Non-Hodgkin Lymphoma Subtypes.

Wang Sophia S SS Carrington Mary M Berndt Sonja I SI Slager Susan L SL Bracci Paige M PM Voutsinas Jenna J Cerhan James R JR Smedby Karin E KE Hjalgrim Henrik H Vijai Joseph J Morton Lindsay M LM Vermeulen Roel R Paltiel Ora O Vajdic Claire M CM Linet Martha S MS Nieters Alexandra A de Sanjose Silvia S Cozen Wendy W Brown Elizabeth E EE Turner Jennifer J Spinelli John J JJ Zheng Tongzhang T Birmann Brenda M BM Flowers Christopher R CR Becker Nikolaus N Holly Elizabeth A EA Kane Eleanor E Weisenburger Dennis D Maynadie Marc M Cocco Pierluigi P Albanes Demetrius D Weinstein Stephanie J SJ Teras Lauren R LR Diver W Ryan WR Lax Stephanie J SJ Travis Ruth C RC Kaaks Rudolph R Riboli Elio E Benavente Yolanda Y Brennan Paul P McKay James J Delfau-Larue Marie-Hélène MH Link Brian K BK Magnani Corrado C Ennas Maria Grazia MG Latte Giancarlo G Feldman Andrew L AL Doo Nicole Wong NW Giles Graham G GG Southey Melissa C MC Milne Roger L RL Offit Kenneth K Musinsky Jacob J Arslan Alan A AA Purdue Mark P MP Adami Hans-Olov HO Melbye Mads M Glimelius Bengt B Conde Lucia L Camp Nicola J NJ Glenn Martha M Curtin Karen K Clavel Jacqueline J Monnereau Alain A Cox David G DG Ghesquières Hervé H Salles Gilles G Bofetta Paulo P Foretova Lenka L Staines Anthony A Davis Scott S Severson Richard K RK Lan Qing Q Brooks-Wilson Angela A Smith Martyn T MT Roman Eve E Kricker Anne A Zhang Yawei Y Kraft Peter P Chanock Stephen J SJ Rothman Nathaniel N Hartge Patricia P Skibola Christine F CF

Cancer research 20180507 14

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, ...[more]

PMID: 29735552

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Project description:BackgroundNon-Hodgkin lymphoma (NHL) comprises biologically and clinically heterogeneous subtypes. Previously, study size has limited the ability to compare and contrast the risk factor profiles among these heterogeneous subtypes.MethodsWe pooled individual-level data from 17 471 NHL cases and 23 096 controls in 20 case-control studies from the International Lymphoma Epidemiology Consortium (InterLymph). We estimated the associations, measured as odds ratios, between each of 11 NHL subtypes and self-reported medical history, family history of hematologic malignancy, lifestyle factors, and occupation. We then assessed the heterogeneity of associations by evaluating the variability (Q value) of the estimated odds ratios for a given exposure among subtypes. Finally, we organized the subtypes into a hierarchical tree to identify groups that had similar risk factor profiles. Statistical significance of tree partitions was estimated by permutation-based P values (P NODE).ResultsRisks differed statistically significantly among NHL subtypes for medical history factors (autoimmune diseases, hepatitis C virus seropositivity, eczema, and blood transfusion), family history of leukemia and multiple myeloma, alcohol consumption, cigarette smoking, and certain occupations, whereas generally homogeneous risks among subtypes were observed for family history of NHL, recreational sun exposure, hay fever, allergy, and socioeconomic status. Overall, the greatest difference in risk factors occurred between T-cell and B-cell lymphomas (P NODE < 1.0×10(-4)), with increased risks generally restricted to T-cell lymphomas for eczema, T-cell-activating autoimmune diseases, family history of multiple myeloma, and occupation as a painter. We further observed substantial heterogeneity among B-cell lymphomas (P NODE < 1.0×10(-4)). Increased risks for B-cell-activating autoimmune disease and hepatitis C virus seropositivity and decreased risks for alcohol consumption and occupation as a teacher generally were restricted to marginal zone lymphoma, Burkitt/Burkitt-like lymphoma/leukemia, diffuse large B-cell lymphoma, and/or lymphoplasmacytic lymphoma/Waldenström macroglobulinemia.ConclusionsUsing a novel approach to investigate etiologic heterogeneity among NHL subtypes, we identified risk factors that were common among subtypes as well as risk factors that appeared to be distinct among individual or a few subtypes, suggesting both subtype-specific and shared underlying mechanisms. Further research is needed to test putative mechanisms, investigate other risk factors (eg, other infections, environmental exposures, and diet), and evaluate potential joint effects with genetic susceptibility.

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HLA Class I and II Diversity Contributes to the Etiologic Heterogeneity of Non-Hodgkin Lymphoma Subtypes.

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HLA Class I and II Diversity Contributes to the Etiologic Heterogeneity of Non-Hodgkin Lymphoma Subtypes.

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