GWAS of follicular lymphoma reveals allelic heterogeneity at 6p21.32 and suggests shared genetic susceptibility with diffuse large B-cell lymphoma

Karin E. Smedby; Jia Nee Foo; Christine F. Skibola; Hatef Darabi; Lucia Conde; Henrik Hjalgrim; Vikrant Kumar; Ellen T. Chang; Nathaniel Rothman; James R. Cerhan; Angela R. Brooks-Wilson; Emil Rehnberg; Ishak D. Irwan; Lars P. Ryder; Peter N. Brown; Paige M. Bracci; Luz Agana; Jacques Riby; Wendy Cozen; Scott Davis; Patricia Hartge; Lindsay M. Morton; Richard K. Severson; Sophia S. Wang; Susan L. Slager; Zachary S. Fredericksen; Anne J. Novak; Neil E. Kay; Thomas M. Habermann; Bruce Armstrong; Anne Kricker; Sam Milliken; Mark P. Purdue; Claire M. Vajdic; Peter Boyle; Qing Lan; Shelia H. Zahm; Yawei Zhang; Tongzhang Zheng; Stephen Leach; John J. Spinelli; Martyn T. Smith; Stephen J. Chanock; Leonid Padyukov; Lars Alfredsson; Lars Klareskog; Bengt Glimelius; Mads Melbye; Edison T. Liu; Hans Olov Adami; Keith Humphreys; Jianjun Liu

doi:10.1371/journal.pgen.1001378

GWAS of follicular lymphoma reveals allelic heterogeneity at 6p21.32 and suggests shared genetic susceptibility with diffuse large B-cell lymphoma

Karin E. Smedby, Jia Nee Foo, Christine F. Skibola, Hatef Darabi, Lucia Conde, Henrik Hjalgrim, Vikrant Kumar, Ellen T. Chang, Nathaniel Rothman, James R. Cerhan, Angela R. Brooks-Wilson, Emil Rehnberg, Ishak D. Irwan, Lars P. Ryder, Peter N. Brown, Paige M. Bracci, Luz Agana, Jacques Riby, Wendy Cozen, Scott DavisPatricia Hartge, Lindsay M. Morton, Richard K. Severson, Sophia S. Wang, Susan L. Slager, Zachary S. Fredericksen, Anne J. Novak, Neil E. Kay, Thomas M. Habermann, Bruce Armstrong, Anne Kricker, Sam Milliken, Mark P. Purdue, Claire M. Vajdic, Peter Boyle, Qing Lan, Shelia H. Zahm, Yawei Zhang, Tongzhang Zheng, Stephen Leach, John J. Spinelli, Martyn T. Smith, Stephen J. Chanock, Leonid Padyukov, Lars Alfredsson, Lars Klareskog, Bengt Glimelius, Mads Melbye, Edison T. Liu, Hans Olov Adami, Keith Humphreys, Jianjun Liu^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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Abstract

Non-Hodgkin lymphoma (NHL) represents a diverse group of hematological malignancies, of which follicular lymphoma (FL) is a prevalent subtype. A previous genome-wide association study has established a marker, rs10484561 in the human leukocyte antigen (HLA) class II region on 6p21.32 associated with increased FL risk. Here, in a three-stage genome-wide association study, starting with a genome-wide scan of 379 FL cases and 791 controls followed by validation in 1,049 cases and 5,790 controls, we identified a second independent FL-associated locus on 6p21.32, rs2647012 (OR_combined = 0.64, P_combined = 2×10^-21) located 962 bp away from rs10484561 (r²<0.1 in controls). After mutual adjustment, the associations at the two SNPs remained genome-wide significant (rs2647012:OR_adjusted = 0.70, P_adjusted = 4×10^-12; rs10484561:OR_adjusted = 1.64, P_adjusted = 5×10^-15). Haplotype and coalescence analyses indicated that rs2647012 arose on an evolutionarily distinct haplotype from that of rs10484561 and tags a novel allele with an opposite (protective) effect on FL risk. Moreover, in a follow-up analysis of the top 6 FL-associated SNPs in 4,449 cases of other NHL subtypes, rs10484561 was associated with risk of diffuse large B-cell lymphoma (OR_combined = 1.36, P_combined = 1.4×10^-7). Our results reveal the presence of allelic heterogeneity within the HLA class II region influencing FL susceptibility and indicate a possible shared genetic etiology with diffuse large B-cell lymphoma. These findings suggest that the HLA class II region plays a complex yet important role in NHL.

Original language	English
Article number	e1001378
Journal	PLoS Genetics
Volume	7
Issue number	4
DOIs	https://doi.org/10.1371/journal.pgen.1001378
Publication status	Published - Apr 2011
Externally published	Yes

ASJC Scopus Subject Areas

Ecology, Evolution, Behavior and Systematics
Molecular Biology
Genetics
Genetics(clinical)
Cancer Research

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1371/journal.pgen.1001378

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Smedby, K. E., Foo, J. N., Skibola, C. F., Darabi, H., Conde, L., Hjalgrim, H., Kumar, V., Chang, E. T., Rothman, N., Cerhan, J. R., Brooks-Wilson, A. R., Rehnberg, E., Irwan, I. D., Ryder, L. P., Brown, P. N., Bracci, P. M., Agana, L., Riby, J., Cozen, W., ... Liu, J. (2011). GWAS of follicular lymphoma reveals allelic heterogeneity at 6p21.32 and suggests shared genetic susceptibility with diffuse large B-cell lymphoma. PLoS Genetics, 7(4), Article e1001378. https://doi.org/10.1371/journal.pgen.1001378

@article{5039794be2a940f4a94f48ba9119bbbc,

title = "GWAS of follicular lymphoma reveals allelic heterogeneity at 6p21.32 and suggests shared genetic susceptibility with diffuse large B-cell lymphoma",

abstract = "Non-Hodgkin lymphoma (NHL) represents a diverse group of hematological malignancies, of which follicular lymphoma (FL) is a prevalent subtype. A previous genome-wide association study has established a marker, rs10484561 in the human leukocyte antigen (HLA) class II region on 6p21.32 associated with increased FL risk. Here, in a three-stage genome-wide association study, starting with a genome-wide scan of 379 FL cases and 791 controls followed by validation in 1,049 cases and 5,790 controls, we identified a second independent FL-associated locus on 6p21.32, rs2647012 (ORcombined = 0.64, Pcombined = 2×10-21) located 962 bp away from rs10484561 (r2<0.1 in controls). After mutual adjustment, the associations at the two SNPs remained genome-wide significant (rs2647012:ORadjusted = 0.70, Padjusted = 4×10-12; rs10484561:ORadjusted = 1.64, Padjusted = 5×10-15). Haplotype and coalescence analyses indicated that rs2647012 arose on an evolutionarily distinct haplotype from that of rs10484561 and tags a novel allele with an opposite (protective) effect on FL risk. Moreover, in a follow-up analysis of the top 6 FL-associated SNPs in 4,449 cases of other NHL subtypes, rs10484561 was associated with risk of diffuse large B-cell lymphoma (ORcombined = 1.36, Pcombined = 1.4×10-7). Our results reveal the presence of allelic heterogeneity within the HLA class II region influencing FL susceptibility and indicate a possible shared genetic etiology with diffuse large B-cell lymphoma. These findings suggest that the HLA class II region plays a complex yet important role in NHL.",

author = "Smedby, {Karin E.} and Foo, {Jia Nee} and Skibola, {Christine F.} and Hatef Darabi and Lucia Conde and Henrik Hjalgrim and Vikrant Kumar and Chang, {Ellen T.} and Nathaniel Rothman and Cerhan, {James R.} and Brooks-Wilson, {Angela R.} and Emil Rehnberg and Irwan, {Ishak D.} and Ryder, {Lars P.} and Brown, {Peter N.} and Bracci, {Paige M.} and Luz Agana and Jacques Riby and Wendy Cozen and Scott Davis and Patricia Hartge and Morton, {Lindsay M.} and Severson, {Richard K.} and Wang, {Sophia S.} and Slager, {Susan L.} and Fredericksen, {Zachary S.} and Novak, {Anne J.} and Kay, {Neil E.} and Habermann, {Thomas M.} and Bruce Armstrong and Anne Kricker and Sam Milliken and Purdue, {Mark P.} and Vajdic, {Claire M.} and Peter Boyle and Qing Lan and Zahm, {Shelia H.} and Yawei Zhang and Tongzhang Zheng and Stephen Leach and Spinelli, {John J.} and Smith, {Martyn T.} and Chanock, {Stephen J.} and Leonid Padyukov and Lars Alfredsson and Lars Klareskog and Bengt Glimelius and Mads Melbye and Liu, {Edison T.} and Adami, {Hans Olov} and Keith Humphreys and Jianjun Liu",

year = "2011",

month = apr,

doi = "10.1371/journal.pgen.1001378",

language = "English",

volume = "7",

journal = "PLoS Genetics",

issn = "1553-7390",

publisher = "Public Library of Science",

number = "4",

}

Smedby, KE, Foo, JN, Skibola, CF, Darabi, H, Conde, L, Hjalgrim, H, Kumar, V, Chang, ET, Rothman, N, Cerhan, JR, Brooks-Wilson, AR, Rehnberg, E, Irwan, ID, Ryder, LP, Brown, PN, Bracci, PM, Agana, L, Riby, J, Cozen, W, Davis, S, Hartge, P, Morton, LM, Severson, RK, Wang, SS, Slager, SL, Fredericksen, ZS, Novak, AJ, Kay, NE, Habermann, TM, Armstrong, B, Kricker, A, Milliken, S, Purdue, MP, Vajdic, CM, Boyle, P, Lan, Q, Zahm, SH, Zhang, Y, Zheng, T, Leach, S, Spinelli, JJ, Smith, MT, Chanock, SJ, Padyukov, L, Alfredsson, L, Klareskog, L, Glimelius, B, Melbye, M, Liu, ET, Adami, HO, Humphreys, K & Liu, J 2011, 'GWAS of follicular lymphoma reveals allelic heterogeneity at 6p21.32 and suggests shared genetic susceptibility with diffuse large B-cell lymphoma', PLoS Genetics, vol. 7, no. 4, e1001378. https://doi.org/10.1371/journal.pgen.1001378

TY - JOUR

T1 - GWAS of follicular lymphoma reveals allelic heterogeneity at 6p21.32 and suggests shared genetic susceptibility with diffuse large B-cell lymphoma

AU - Smedby, Karin E.

AU - Foo, Jia Nee

AU - Skibola, Christine F.

AU - Darabi, Hatef

AU - Conde, Lucia

AU - Hjalgrim, Henrik

AU - Kumar, Vikrant

AU - Chang, Ellen T.

AU - Rothman, Nathaniel

AU - Cerhan, James R.

AU - Brooks-Wilson, Angela R.

AU - Rehnberg, Emil

AU - Irwan, Ishak D.

AU - Ryder, Lars P.

AU - Brown, Peter N.

AU - Bracci, Paige M.

AU - Agana, Luz

AU - Riby, Jacques

AU - Cozen, Wendy

AU - Davis, Scott

AU - Hartge, Patricia

AU - Morton, Lindsay M.

AU - Severson, Richard K.

AU - Wang, Sophia S.

AU - Slager, Susan L.

AU - Fredericksen, Zachary S.

AU - Novak, Anne J.

AU - Kay, Neil E.

AU - Habermann, Thomas M.

AU - Armstrong, Bruce

AU - Kricker, Anne

AU - Milliken, Sam

AU - Purdue, Mark P.

AU - Vajdic, Claire M.

AU - Boyle, Peter

AU - Lan, Qing

AU - Zahm, Shelia H.

AU - Zhang, Yawei

AU - Zheng, Tongzhang

AU - Leach, Stephen

AU - Spinelli, John J.

AU - Smith, Martyn T.

AU - Chanock, Stephen J.

AU - Padyukov, Leonid

AU - Alfredsson, Lars

AU - Klareskog, Lars

AU - Glimelius, Bengt

AU - Melbye, Mads

AU - Liu, Edison T.

AU - Adami, Hans Olov

AU - Humphreys, Keith

AU - Liu, Jianjun

PY - 2011/4

Y1 - 2011/4

N2 - Non-Hodgkin lymphoma (NHL) represents a diverse group of hematological malignancies, of which follicular lymphoma (FL) is a prevalent subtype. A previous genome-wide association study has established a marker, rs10484561 in the human leukocyte antigen (HLA) class II region on 6p21.32 associated with increased FL risk. Here, in a three-stage genome-wide association study, starting with a genome-wide scan of 379 FL cases and 791 controls followed by validation in 1,049 cases and 5,790 controls, we identified a second independent FL-associated locus on 6p21.32, rs2647012 (ORcombined = 0.64, Pcombined = 2×10-21) located 962 bp away from rs10484561 (r2<0.1 in controls). After mutual adjustment, the associations at the two SNPs remained genome-wide significant (rs2647012:ORadjusted = 0.70, Padjusted = 4×10-12; rs10484561:ORadjusted = 1.64, Padjusted = 5×10-15). Haplotype and coalescence analyses indicated that rs2647012 arose on an evolutionarily distinct haplotype from that of rs10484561 and tags a novel allele with an opposite (protective) effect on FL risk. Moreover, in a follow-up analysis of the top 6 FL-associated SNPs in 4,449 cases of other NHL subtypes, rs10484561 was associated with risk of diffuse large B-cell lymphoma (ORcombined = 1.36, Pcombined = 1.4×10-7). Our results reveal the presence of allelic heterogeneity within the HLA class II region influencing FL susceptibility and indicate a possible shared genetic etiology with diffuse large B-cell lymphoma. These findings suggest that the HLA class II region plays a complex yet important role in NHL.

AB - Non-Hodgkin lymphoma (NHL) represents a diverse group of hematological malignancies, of which follicular lymphoma (FL) is a prevalent subtype. A previous genome-wide association study has established a marker, rs10484561 in the human leukocyte antigen (HLA) class II region on 6p21.32 associated with increased FL risk. Here, in a three-stage genome-wide association study, starting with a genome-wide scan of 379 FL cases and 791 controls followed by validation in 1,049 cases and 5,790 controls, we identified a second independent FL-associated locus on 6p21.32, rs2647012 (ORcombined = 0.64, Pcombined = 2×10-21) located 962 bp away from rs10484561 (r2<0.1 in controls). After mutual adjustment, the associations at the two SNPs remained genome-wide significant (rs2647012:ORadjusted = 0.70, Padjusted = 4×10-12; rs10484561:ORadjusted = 1.64, Padjusted = 5×10-15). Haplotype and coalescence analyses indicated that rs2647012 arose on an evolutionarily distinct haplotype from that of rs10484561 and tags a novel allele with an opposite (protective) effect on FL risk. Moreover, in a follow-up analysis of the top 6 FL-associated SNPs in 4,449 cases of other NHL subtypes, rs10484561 was associated with risk of diffuse large B-cell lymphoma (ORcombined = 1.36, Pcombined = 1.4×10-7). Our results reveal the presence of allelic heterogeneity within the HLA class II region influencing FL susceptibility and indicate a possible shared genetic etiology with diffuse large B-cell lymphoma. These findings suggest that the HLA class II region plays a complex yet important role in NHL.

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DO - 10.1371/journal.pgen.1001378

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JO - PLoS Genetics

JF - PLoS Genetics

IS - 4

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ER -

GWAS of follicular lymphoma reveals allelic heterogeneity at 6p21.32 and suggests shared genetic susceptibility with diffuse large B-cell lymphoma

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