Genome-wide association study of classical Hodgkin lymphoma and Epstein-Barr virus status-defined subgroups

Kevin Y. Urayama, Ruth F. Jarrett, Henrik Hjalgrim, Arjan Diepstra, Yoichiro Kamatani, Amelie Chabrier, Valerie Gaborieau, Anne Boland, Alexandra Nieters, Nikolaus Becker, Lenka Foretova, Yolanda Benavente, Marc Maynadie, Anthony Staines, Lesley Shield, Annette Lake, Dorothy Montgomery, Malcolm Taylor, Karin Ekstrom Smedby, Rose-Marie AminiHans-Olov Adami, Bengt Glimelius, Bjarke Feenstra, Ilja M. Nolte, Lydia Visser, Gustaaf W. van Imhoff, Tracy Lightfoot, Pierluigi Cocco, Lambertus Kiemeney, Sita H. Vermeulen, Ivana Holcatova, Lars Vatten, Gary J. Macfarlane, Peter Thomson, David I. Conway, Simone Benhamou, Antonio Agudo, Claire M. Healy, Kim Overvad, Anne Tjonneland, Beatrice Melin, Federico Canzian, Kay-Tee Khaw, Ruth C. Travis, Petra H. M. Peeters, Carlos A. Gonzalez, Jose Ramon Quiros, Maria-Jose Sanchez, Jose Maria Huerta, Eva Ardanaz, Miren Dorronsoro, Francoise Clavel-Chapelon, H. Bas Bueno-de-Mesquita, Elio Riboli, Eve Roman, Paolo Boffetta, Silvia de Sanjose, Diana Zelenika, Mads Melbye, Anke van den Berg, Mark Lathrop, Paul Brennan*, James D. McKay

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

108 Citations (Scopus)

Abstract

BACKGROUND: Accumulating evidence suggests that risk factors for classical Hodgkin lymphoma (cHL) differ by tumor Epstein-Barr virus (EBV) status. This potential etiological heterogeneity is not recognized in current disease classification.

METHODS: We conducted a genome-wide association study of 1200 cHL patients and 6417 control subjects, with validation in an independent replication series, to identify common genetic variants associated with total cHL and subtypes defined by tumor EBV status. Multiple logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) assuming a log-additive genetic model for the variants. All statistical tests were two-sided.

RESULTS: Two novel loci associated with total cHL irrespective of EBV status were identified in the major histocompatibility complex region; one resides adjacent to MICB (rs2248462: OR = 0.61, 95% CI = 0.53 to 0.69, P = 1.3 × 10(-13)) and the other at HLA-DRA (rs2395185: OR = 0.56, 95% CI = 0.50 to 0.62, P = 8.3 × 10(-25)) with both results confirmed in an independent replication series. Consistent with previous reports, associations were found between EBV-positive cHL and genetic variants within the class I region (rs2734986, HLA-A: OR = 2.45, 95% CI = 2.00 to 3.00, P = 1.2 × 10(-15); rs6904029, HCG9: OR = 0.46, 95% CI = 0.36 to 0.59, P = 5.5 × 10(-10)) and between EBV-negative cHL and rs6903608 within the class II region (rs6903608, HLA-DRA: OR = 2.08, 95% CI = 1.84 to 2.35, P = 6.1 × 10(-31)). The association between rs6903608 and EBV-negative cHL was confined to the nodular sclerosis histological subtype. Evidence for an association between EBV-negative cHL and rs20541 (5q31, IL13: OR = 1.53, 95% CI = 1.32 to 1.76, P = 5.4 x 10(-9)), a variant previously linked to psoriasis and asthma, was observed; however, the evidence for replication was less clear. Notably, one additional psoriasis-associated variant, rs27524 (5q15, ERAP1), showed evidence of an association with cHL in the genome-wide association study (OR = 1.21, 95% CI = 1.10 to 1.33, P = 1.5 × 10(-4)) and replication series (P = .03).

CONCLUSION: Overall, these results provide strong evidence that EBV status is an etiologically important classification of cHL and also suggest that some components of the pathological process are common to both EBV-positive and EBV-negative patients.

Original languageEnglish
Pages (from-to)240-253
Number of pages14
JournalJnci-Journal of the national cancer institute
Volume104
Issue number3
DOIs
Publication statusPublished - 8-Feb-2012

Keywords

  • REED-STERNBERG CELLS
  • INFECTIOUS-MONONUCLEOSIS
  • SUSCEPTIBILITY LOCI
  • ENDOPLASMIC-RETICULUM
  • DISEASE HD
  • CLASS-I
  • RISK
  • GENES
  • POPULATION
  • PSORIASIS

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