HLA class I and II diversity contributes to the etiologic heterogeneity of non-Hodgkin lymphoma subtypes

Sophia S. Wang, Mary Carrington, Sonja I. Berndt, Susan L Slager, Paige M. Bracci, Jenna Voutsinas, James R Cerhan, Karin E. Smedby, Henrik Hjalgrim, Joseph Vijai, Lindsay M. Morton, Roel Vermeulen, Ora Paltiel, Claire M. Vajdic, Martha S. Linet, Alexandra Nieters, Silvia de Sanjose, Wendy Cozen, Elizabeth E. Brown, Jennifer Turner & 63 others John J. Spinelli, Tongzhang Zheng, Brenda M. Birmann, Christopher R. Flowers, Nikolaus Becker, Elizabeth A. Holly, Eleanor Kane, Dennis Weisenburger, Marc Maynadie, Pierluigi Cocco, Demetrius Albanes, Stephanie J. Weinstein, Lauren R. Teras, W. Ryan Diver, Stephanie J. Lax, Ruth C. Travis, Rudolph Kaaks, Elio Riboli, Yolanda Benavente, Paul Brennan, James McKay, Marie Hélène Delfau-Larue, Brian K. Link, Corrado Magnani, Maria Grazia Ennas, Giancarlo Latte, Andrew L Feldman, Nicole Wong Doo, Graham G. Giles, Melissa C. Southey, Roger L. Milne, Kenneth Offit, Jacob Musinsky, Alan A. Arslan, Mark P. Purdue, Hans Olov Adami, Mads Melbye, Bengt Glimelius, Lucia Conde, Nicola J. Camp, Martha Glenn, Karen Curtin, Jacqueline Clavel, Alain Monnereau, David G. Cox, Hervé Ghesquières, Gilles Salles, Paulo Bofetta, Lenka Foretova, Anthony Staines, Scott Davis, Richard K. Severson, Qing Lan, Angela Brooks-Wilson, Martyn T. Smith, Eve Roman, Anne Kricker, Yawei Zhang, Peter Kraft, Stephen J. Chanock, Nathaniel Rothman, Patricia Hartge, Christine F. Skibola

Research output: Contribution to journalArticle

2 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)4086-4096
Number of pages11
JournalCancer Research
Volume78
Issue number14
DOIs
StatePublished - Jul 15 2018

Fingerprint

HLA Antigens
Non-Hodgkin's Lymphoma
Lymphoma, Large B-Cell, Diffuse
Lymphoma
Follicular Lymphoma
B-Cell Chronic Lymphocytic Leukemia
HLA-D Antigens
Marginal Zone B-Cell Lymphoma
Genome-Wide Association Study
Heterozygote
Alleles

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Wang, S. S., Carrington, M., Berndt, S. I., Slager, S. L., Bracci, P. M., Voutsinas, J., ... Skibola, C. F. (2018). HLA class I and II diversity contributes to the etiologic heterogeneity of non-Hodgkin lymphoma subtypes. Cancer Research, 78(14), 4086-4096. https://doi.org/10.1158/0008-5472.CAN-17-2900

HLA class I and II diversity contributes to the etiologic heterogeneity of non-Hodgkin lymphoma subtypes. / Wang, Sophia S.; Carrington, Mary; Berndt, Sonja I.; Slager, Susan L; Bracci, Paige M.; Voutsinas, Jenna; Cerhan, James R; Smedby, Karin E.; Hjalgrim, Henrik; Vijai, Joseph; Morton, Lindsay M.; Vermeulen, Roel; Paltiel, Ora; Vajdic, Claire M.; Linet, Martha S.; Nieters, Alexandra; de Sanjose, Silvia; Cozen, Wendy; Brown, Elizabeth E.; Turner, Jennifer; Spinelli, John J.; Zheng, Tongzhang; Birmann, Brenda M.; Flowers, Christopher R.; Becker, Nikolaus; Holly, Elizabeth A.; Kane, Eleanor; Weisenburger, Dennis; Maynadie, Marc; Cocco, Pierluigi; Albanes, Demetrius; Weinstein, Stephanie J.; Teras, Lauren R.; Diver, W. Ryan; Lax, Stephanie J.; Travis, Ruth C.; Kaaks, Rudolph; Riboli, Elio; Benavente, Yolanda; Brennan, Paul; McKay, James; Delfau-Larue, Marie Hélène; Link, Brian K.; Magnani, Corrado; Ennas, Maria Grazia; Latte, Giancarlo; Feldman, Andrew L; Doo, Nicole Wong; Giles, Graham G.; Southey, Melissa C.; Milne, Roger L.; Offit, Kenneth; Musinsky, Jacob; Arslan, Alan A.; Purdue, Mark P.; Adami, Hans Olov; Melbye, Mads; Glimelius, Bengt; Conde, Lucia; Camp, Nicola J.; Glenn, Martha; Curtin, Karen; Clavel, Jacqueline; Monnereau, Alain; Cox, David G.; Ghesquières, Hervé; Salles, Gilles; Bofetta, Paulo; Foretova, Lenka; Staines, Anthony; Davis, Scott; Severson, Richard K.; Lan, Qing; Brooks-Wilson, Angela; Smith, Martyn T.; Roman, Eve; Kricker, Anne; Zhang, Yawei; Kraft, Peter; Chanock, Stephen J.; Rothman, Nathaniel; Hartge, Patricia; Skibola, Christine F.

In: Cancer Research, Vol. 78, No. 14, 15.07.2018, p. 4086-4096.

Research output: Contribution to journalArticle

Wang, SS, Carrington, M, Berndt, SI, Slager, SL, Bracci, PM, Voutsinas, J, Cerhan, JR, Smedby, KE, Hjalgrim, H, Vijai, J, Morton, LM, Vermeulen, R, Paltiel, O, Vajdic, CM, Linet, MS, Nieters, A, de Sanjose, S, Cozen, W, Brown, EE, Turner, J, Spinelli, JJ, Zheng, T, Birmann, BM, Flowers, CR, Becker, N, Holly, EA, Kane, E, Weisenburger, D, Maynadie, M, Cocco, P, Albanes, D, Weinstein, SJ, Teras, LR, Diver, WR, Lax, SJ, Travis, RC, Kaaks, R, Riboli, E, Benavente, Y, Brennan, P, McKay, J, Delfau-Larue, MH, Link, BK, Magnani, C, Ennas, MG, Latte, G, Feldman, AL, Doo, NW, Giles, GG, Southey, MC, Milne, RL, Offit, K, Musinsky, J, Arslan, AA, Purdue, MP, Adami, HO, Melbye, M, Glimelius, B, Conde, L, Camp, NJ, Glenn, M, Curtin, K, Clavel, J, Monnereau, A, Cox, DG, Ghesquières, H, Salles, G, Bofetta, P, Foretova, L, Staines, A, Davis, S, Severson, RK, Lan, Q, Brooks-Wilson, A, Smith, MT, Roman, E, Kricker, A, Zhang, Y, Kraft, P, Chanock, SJ, Rothman, N, Hartge, P & Skibola, CF 2018, 'HLA class I and II diversity contributes to the etiologic heterogeneity of non-Hodgkin lymphoma subtypes', Cancer Research, vol. 78, no. 14, pp. 4086-4096. https://doi.org/10.1158/0008-5472.CAN-17-2900
Wang, Sophia S. ; Carrington, Mary ; Berndt, Sonja I. ; Slager, Susan L ; Bracci, Paige M. ; Voutsinas, Jenna ; Cerhan, James R ; Smedby, Karin E. ; Hjalgrim, Henrik ; Vijai, Joseph ; Morton, Lindsay M. ; Vermeulen, Roel ; Paltiel, Ora ; Vajdic, Claire M. ; Linet, Martha S. ; Nieters, Alexandra ; de Sanjose, Silvia ; Cozen, Wendy ; Brown, Elizabeth E. ; Turner, Jennifer ; Spinelli, John J. ; Zheng, Tongzhang ; Birmann, Brenda M. ; Flowers, Christopher R. ; Becker, Nikolaus ; Holly, Elizabeth A. ; Kane, Eleanor ; Weisenburger, Dennis ; Maynadie, Marc ; Cocco, Pierluigi ; Albanes, Demetrius ; Weinstein, Stephanie J. ; Teras, Lauren R. ; Diver, W. Ryan ; Lax, Stephanie J. ; Travis, Ruth C. ; Kaaks, Rudolph ; Riboli, Elio ; Benavente, Yolanda ; Brennan, Paul ; McKay, James ; Delfau-Larue, Marie Hélène ; Link, Brian K. ; Magnani, Corrado ; Ennas, Maria Grazia ; Latte, Giancarlo ; Feldman, Andrew L ; Doo, Nicole Wong ; Giles, Graham G. ; Southey, Melissa C. ; Milne, Roger L. ; Offit, Kenneth ; Musinsky, Jacob ; Arslan, Alan A. ; Purdue, Mark P. ; Adami, Hans Olov ; Melbye, Mads ; Glimelius, Bengt ; Conde, Lucia ; Camp, Nicola J. ; Glenn, Martha ; Curtin, Karen ; Clavel, Jacqueline ; Monnereau, Alain ; Cox, David G. ; Ghesquières, Hervé ; Salles, Gilles ; Bofetta, Paulo ; Foretova, Lenka ; Staines, Anthony ; Davis, Scott ; Severson, Richard K. ; Lan, Qing ; Brooks-Wilson, Angela ; Smith, Martyn T. ; Roman, Eve ; Kricker, Anne ; Zhang, Yawei ; Kraft, Peter ; Chanock, Stephen J. ; Rothman, Nathaniel ; Hartge, Patricia ; Skibola, Christine F. / HLA class I and II diversity contributes to the etiologic heterogeneity of non-Hodgkin lymphoma subtypes. In: Cancer Research. 2018 ; Vol. 78, No. 14. pp. 4086-4096.
@article{184a965e83dd4f17ab4c73ea853f825b,
title = "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.",
author = "Wang, {Sophia S.} and Mary Carrington and Berndt, {Sonja I.} and Slager, {Susan L} and Bracci, {Paige M.} and Jenna Voutsinas and Cerhan, {James R} and Smedby, {Karin E.} and Henrik Hjalgrim and Joseph Vijai and Morton, {Lindsay M.} and Roel Vermeulen and Ora Paltiel and Vajdic, {Claire M.} and Linet, {Martha S.} and Alexandra Nieters and {de Sanjose}, Silvia and Wendy Cozen and Brown, {Elizabeth E.} and Jennifer Turner and Spinelli, {John J.} and Tongzhang Zheng and Birmann, {Brenda M.} and Flowers, {Christopher R.} and Nikolaus Becker and Holly, {Elizabeth A.} and Eleanor Kane and Dennis Weisenburger and Marc Maynadie and Pierluigi Cocco and Demetrius Albanes and Weinstein, {Stephanie J.} and Teras, {Lauren R.} and Diver, {W. Ryan} and Lax, {Stephanie J.} and Travis, {Ruth C.} and Rudolph Kaaks and Elio Riboli and Yolanda Benavente and Paul Brennan and James McKay and Delfau-Larue, {Marie H{\'e}l{\`e}ne} and Link, {Brian K.} and Corrado Magnani and Ennas, {Maria Grazia} and Giancarlo Latte and Feldman, {Andrew L} and Doo, {Nicole Wong} and Giles, {Graham G.} and Southey, {Melissa C.} and Milne, {Roger L.} and Kenneth Offit and Jacob Musinsky and Arslan, {Alan A.} and Purdue, {Mark P.} and Adami, {Hans Olov} and Mads Melbye and Bengt Glimelius and Lucia Conde and Camp, {Nicola J.} and Martha Glenn and Karen Curtin and Jacqueline Clavel and Alain Monnereau and Cox, {David G.} and Herv{\'e} Ghesqui{\`e}res and Gilles Salles and Paulo Bofetta and Lenka Foretova and Anthony Staines and Scott Davis and Severson, {Richard K.} and Qing Lan and Angela Brooks-Wilson and Smith, {Martyn T.} and Eve Roman and Anne Kricker and Yawei Zhang and Peter Kraft and Chanock, {Stephen J.} and Nathaniel Rothman and Patricia Hartge and Skibola, {Christine F.}",
year = "2018",
month = "7",
day = "15",
doi = "10.1158/0008-5472.CAN-17-2900",
language = "English (US)",
volume = "78",
pages = "4086--4096",
journal = "Journal of Cancer Research",
issn = "0099-7013",
publisher = "American Association for Cancer Research Inc.",
number = "14",

}

TY - JOUR

T1 - HLA class I and II diversity contributes to the etiologic heterogeneity of non-Hodgkin lymphoma subtypes

AU - Wang, Sophia S.

AU - Carrington, Mary

AU - Berndt, Sonja I.

AU - Slager, Susan L

AU - Bracci, Paige M.

AU - Voutsinas, Jenna

AU - Cerhan, James R

AU - Smedby, Karin E.

AU - Hjalgrim, Henrik

AU - Vijai, Joseph

AU - Morton, Lindsay M.

AU - Vermeulen, Roel

AU - Paltiel, Ora

AU - Vajdic, Claire M.

AU - Linet, Martha S.

AU - Nieters, Alexandra

AU - de Sanjose, Silvia

AU - Cozen, Wendy

AU - Brown, Elizabeth E.

AU - Turner, Jennifer

AU - Spinelli, John J.

AU - Zheng, Tongzhang

AU - Birmann, Brenda M.

AU - Flowers, Christopher R.

AU - Becker, Nikolaus

AU - Holly, Elizabeth A.

AU - Kane, Eleanor

AU - Weisenburger, Dennis

AU - Maynadie, Marc

AU - Cocco, Pierluigi

AU - Albanes, Demetrius

AU - Weinstein, Stephanie J.

AU - Teras, Lauren R.

AU - Diver, W. Ryan

AU - Lax, Stephanie J.

AU - Travis, Ruth C.

AU - Kaaks, Rudolph

AU - Riboli, Elio

AU - Benavente, Yolanda

AU - Brennan, Paul

AU - McKay, James

AU - Delfau-Larue, Marie Hélène

AU - Link, Brian K.

AU - Magnani, Corrado

AU - Ennas, Maria Grazia

AU - Latte, Giancarlo

AU - Feldman, Andrew L

AU - Doo, Nicole Wong

AU - Giles, Graham G.

AU - Southey, Melissa C.

AU - Milne, Roger L.

AU - Offit, Kenneth

AU - Musinsky, Jacob

AU - Arslan, Alan A.

AU - Purdue, Mark P.

AU - Adami, Hans Olov

AU - Melbye, Mads

AU - Glimelius, Bengt

AU - Conde, Lucia

AU - Camp, Nicola J.

AU - Glenn, Martha

AU - Curtin, Karen

AU - Clavel, Jacqueline

AU - Monnereau, Alain

AU - Cox, David G.

AU - Ghesquières, Hervé

AU - Salles, Gilles

AU - Bofetta, Paulo

AU - Foretova, Lenka

AU - Staines, Anthony

AU - Davis, Scott

AU - Severson, Richard K.

AU - Lan, Qing

AU - Brooks-Wilson, Angela

AU - Smith, Martyn T.

AU - Roman, Eve

AU - Kricker, Anne

AU - Zhang, Yawei

AU - Kraft, Peter

AU - Chanock, Stephen J.

AU - Rothman, Nathaniel

AU - Hartge, Patricia

AU - Skibola, Christine F.

PY - 2018/7/15

Y1 - 2018/7/15

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85050829279&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85050829279&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-17-2900

DO - 10.1158/0008-5472.CAN-17-2900

M3 - Article

VL - 78

SP - 4086

EP - 4096

JO - Journal of Cancer Research

JF - Journal of Cancer Research

SN - 0099-7013

IS - 14

ER -