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 Amini; Hans-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

doi:10.1093/jnci/djr516

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 voor dit werk

Onderzoeksoutput › Academic › peer review

133 Citaten (Scopus)

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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.

Originele taal-2	English
Pagina's (van-tot)	240-253
Aantal pagina's	14
Tijdschrift	Journal of the National Cancer Institute
Volume	104
Nummer van het tijdschrift	3
DOI's	https://doi.org/10.1093/jnci/djr516
Status	Published - 8-feb.-2012

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Genome-wide association study of classical Hodgkin lymphoma and Epstein-Barr virus status-defined subgroups
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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., ... McKay, J. D. (2012). Genome-wide association study of classical Hodgkin lymphoma and Epstein-Barr virus status-defined subgroups. Journal of the National Cancer Institute , 104(3), 240-253. https://doi.org/10.1093/jnci/djr516

@article{f2d36b3f5d654963891696b21833ecb9,

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

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.",

keywords = "REED-STERNBERG CELLS, INFECTIOUS-MONONUCLEOSIS, SUSCEPTIBILITY LOCI, ENDOPLASMIC-RETICULUM, DISEASE HD, CLASS-I, RISK, GENES, POPULATION, PSORIASIS",

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

year = "2012",

month = feb,

day = "8",

doi = "10.1093/jnci/djr516",

language = "English",

volume = "104",

pages = "240--253",

journal = "Journal of the National Cancer Institute ",

issn = "0027-8874",

publisher = "Oxford University Press",

number = "3",

}

Urayama, KY, Jarrett, RF, 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, KE, Amini, R-M, Adami, H-O, Glimelius, B, Feenstra, B, Nolte, IM , Visser, L , van Imhoff, GW, Lightfoot, T, Cocco, P, Kiemeney, L, Vermeulen, SH, Holcatova, I, Vatten, L, Macfarlane, GJ, Thomson, P, Conway, DI, Benhamou, S, Agudo, A, Healy, CM, Overvad, K, Tjonneland, A, Melin, B, Canzian, F, Khaw, K-T, Travis, RC, Peeters, PHM, Gonzalez, CA, Quiros, JR, Sanchez, M-J, Maria Huerta, J, Ardanaz, E, Dorronsoro, M, Clavel-Chapelon, F, Bueno-de-Mesquita, HB, Riboli, E, Roman, E, Boffetta, P, de Sanjose, S, Zelenika, D, Melbye, M, van den Berg, A, Lathrop, M, Brennan, P & McKay, JD 2012, 'Genome-wide association study of classical Hodgkin lymphoma and Epstein-Barr virus status-defined subgroups', Journal of the National Cancer Institute , vol. 104, nr. 3, blz. 240-253. https://doi.org/10.1093/jnci/djr516

TY - JOUR

T1 - Genome-wide association study of classical Hodgkin lymphoma and Epstein-Barr virus status-defined subgroups

AU - Urayama, Kevin Y.

AU - Jarrett, Ruth F.

AU - Hjalgrim, Henrik

AU - Diepstra, Arjan

AU - Kamatani, Yoichiro

AU - Chabrier, Amelie

AU - Gaborieau, Valerie

AU - Boland, Anne

AU - Nieters, Alexandra

AU - Becker, Nikolaus

AU - Foretova, Lenka

AU - Benavente, Yolanda

AU - Maynadie, Marc

AU - Staines, Anthony

AU - Shield, Lesley

AU - Lake, Annette

AU - Montgomery, Dorothy

AU - Taylor, Malcolm

AU - Smedby, Karin Ekstrom

AU - Amini, Rose-Marie

AU - Adami, Hans-Olov

AU - Glimelius, Bengt

AU - Feenstra, Bjarke

AU - Nolte, Ilja M.

AU - Visser, Lydia

AU - van Imhoff, Gustaaf W.

AU - Lightfoot, Tracy

AU - Cocco, Pierluigi

AU - Kiemeney, Lambertus

AU - Vermeulen, Sita H.

AU - Holcatova, Ivana

AU - Vatten, Lars

AU - Macfarlane, Gary J.

AU - Thomson, Peter

AU - Conway, David I.

AU - Benhamou, Simone

AU - Agudo, Antonio

AU - Healy, Claire M.

AU - Overvad, Kim

AU - Tjonneland, Anne

AU - Melin, Beatrice

AU - Canzian, Federico

AU - Khaw, Kay-Tee

AU - Travis, Ruth C.

AU - Peeters, Petra H. M.

AU - Gonzalez, Carlos A.

AU - Quiros, Jose Ramon

AU - Sanchez, Maria-Jose

AU - Maria Huerta, Jose

AU - Ardanaz, Eva

AU - Dorronsoro, Miren

AU - Clavel-Chapelon, Francoise

AU - Bueno-de-Mesquita, H. Bas

AU - Riboli, Elio

AU - Roman, Eve

AU - Boffetta, Paolo

AU - de Sanjose, Silvia

AU - Zelenika, Diana

AU - Melbye, Mads

AU - van den Berg, Anke

AU - Lathrop, Mark

AU - Brennan, Paul

AU - McKay, James D.

PY - 2012/2/8

Y1 - 2012/2/8

N2 - 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.

AB - 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.

KW - REED-STERNBERG CELLS

KW - INFECTIOUS-MONONUCLEOSIS

KW - SUSCEPTIBILITY LOCI

KW - ENDOPLASMIC-RETICULUM

KW - DISEASE HD

KW - CLASS-I

KW - RISK

KW - GENES

KW - POPULATION

KW - PSORIASIS

U2 - 10.1093/jnci/djr516

DO - 10.1093/jnci/djr516

M3 - Article

C2 - 22286212

SN - 0027-8874

VL - 104

SP - 240

EP - 253

JO - Journal of the National Cancer Institute

JF - Journal of the National Cancer Institute

IS - 3

ER -

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

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