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

Urayama, K. Y. et al. (2012) Genome-wide association study of classical Hodgkin lymphoma and Epstein-Barr virus status-defined subgroups. Journal of the National Cancer Institute, 104(3), pp. 240-253. (doi:10.1093/jnci/djr516)

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Publisher's URL: http://dx.doi.org/10.1093/jnci/djr516

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.<p></p> 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.<p></p> 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).<p></p> 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.<p></p>

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Lake, Ms Annette and Jarrett, Professor Ruth and Shield, Ms Lesley and Conway, Professor David and Montgomery, Mrs Dorothy
Authors: Urayama, K. Y., Jarrett, R. F., Hjalgrim, H., Diepstra, A., Kamatani, Y., Chabrier, A., Gaborieau, V., Boland, A., Nieters, A., Becker, N., Foretova, L., Benavente, Y., Maynadie, M., Staines, A., Shield, L., Lake, A., Montgomery, D., Taylor, M., Smedby, K. E., Amini, R.-M., Adami, H.-O., Glimelius, B., Feenstra, B., Nolte, I. M., Visser, L., van Imhoff, G. W., Lightfoot, T., Cocco, P., Kiemeney, L., Vermeulen, S. H., Holcatova, I., Vatten, L., Macfarlane, G. J., Thomson, P., Conway, D. I., Benhamou, S., Agudo, A., Healy, C. M., Overvad, K., Tjonneland, A., Melin, B., Canzian, F., Khaw, K.-T., Travis, R. C., Peeters, P. H. M., Gonzalez, C. A., Quiros, J. R., Sanchez, M.-J., Huerta, J. M., Ardanaz, E., Dorronsoro, M., Clavel-Chapelon, F., Bueno-de-Mesquita, H. B., Riboli, E., Roman, E., Boffetta, P., de Sanjose, S., Zelenika, D., Melbye, M., van den Berg, A., Lathrop, M., Brennan, P., and McKay, J. D.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing > Dental School
Journal Name:Journal of the National Cancer Institute
Journal Abbr.:JNCI
Publisher:Oxford University Press
ISSN:0027-8874
ISSN (Online):1460-2105
Published Online:27 January 2012
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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
409571Investigation of the pathogenesis of Hodgkin lymphomaRuth JarrettLeukaemia & Lymphoma Research (LRF)05045Centre for Virus Research
409572Investigation of the pathogenesis of Hodgkin lymphomaRuth JarrettLeukaemia & Lymphoma Research (LRF)08031Centre for Virus Research