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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Date
2011
Author(s)
Smedby, Karin E.
Foo, Jia Nee
Skibola, Christine F.
Darabi, Hatef
Conde, Lucia
Hjalgrim, Henrik
Kumar, Vikrant
Chang, Ellen T.
Rothman, Nathaniel
Cerhan, James R.
Brooks-Wilson, Angela R.
Rehnberg, Emil
Irwan, Ishak D.
Ryder, Lars P.
Bracci, Paige M.
Agana, Luz
Riby, Jacques
Cozen, Wendy
Hartge, Patricia
Morton, Lindsay M.
Severson, Richard K.
Slager, Susan L.
Fredericksen, Zachary S.
Novak, Anne J.
Kay, Neil E.
Habermann, Thomas M.
Armstrong, Bruce
Kricker, Anne
Milliken, Sam
Purdue, Mark P.
Vajdic, Claire M.
Boyle, Peter
Lan, Qing
Zahm, Shelia H.
Zhang, Yawei
Zheng, Tongzhang
Leach, Stephen
Spinelli, John J.
Smith, Martyn T.
Chanock, Stephen J.
Padyukov, Leonid
Alfredsson, Lars
Klareskog, Lars
Glimelius, Bengt
Melbye, Mads
Liu, Edison T.
Humphreys, Keith
Liu, Jianjun
Gibson, Greg
Brown, Peter N.
Davis, Scott
Publisher
Public Library of Science
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Citation
Smedby, Karin E., Jia Nee Foo, Christine F. Skibola, Hatef Darabi, Lucia Conde, Henrik Hjalgrim, Vikrant Kumar, et al. 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): e1001378.
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 \((r^2 <0.1 in controls)\). 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.
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