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Genome-wide association study of classical Hodgkin lymphoma and Epstein-Barr virus status-defined subgroups
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Urayama, Kevin Y Jarrett, Ruth F Hjalgrim, Henrik Diepstra, Arjan Kamatani, Yoichiro Chabrier, Amelie Gaborieau, Valerie Boland, Anne Nieters, Alexandra Becker, Nikolaus Foretova, Lenka Benavente, Yolanda Maynadie, Marc Staines, Anthony Shield, Lesley Lake, Annette Montgomery, Dorothy Taylor, Malcolm Smedby, Karin Ekstrom Amini, Rose-Marie Adami, Hans-Olov Glimelius, Bengt Feenstra, Bjarke Nolte, Ilja M Visser, Lydia van Imhoff, Gustaaf W Lightfoot, Tracy Cocco, Pierluigi Kiemeney, Lambertus Vermeulen, Sita H Holcatova, Ivana Vatten, Lars Macfarlane, Gary J Thomson, Peter Conway, David I Benhamou, Simone Agudo, Antonio Healy, Claire M Overvad, Kim Tjonneland, Anne Melin, Beatrice Canzian, Federico Khaw, Kay-Tee Travis, Ruth C Peeters, Petra H M Gonzalez, Carlos A Quiros, Jose Ramon Sanchez, Maria-Jose Huerta, Jose Maria Ardanaz, Eva Dorronsoro, Miren Clavel-Chapelon, Francoise Bueno-de-Mesquita, H Bas Riboli, Elio Roman, Eve Boffetta, Paolo de Sanjose, Silvia Zelenika, Diana Melbye, Mads van den Berg, Anke Lathrop, Mark Brennan, Paul McKay, James D eng 11692/Cancer Research UK/United Kingdom G0401527/Medical Research Council/United Kingdom G1000143/Medical Research Council/United Kingdom Research Support, Non-U.S. Gov't 2012/01/31 06:00 J Natl Cancer Inst. 2012 Feb 8;104(3):240-53. doi: 10.1093/jnci/djr516. Epub 2012 Jan 27.. International audience. 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 x 10(-13)) and the other at HLA-DRA (rs2395185: OR = 0.56, 95% CI = 0.50 to 0.62, P = 8.3 x 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 x 10(-15); rs6904029, HCG9: OR = 0.46, 95% CI = 0.36 to 0.59, P = 5.5 x 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 x 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 x 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.
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