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

Research output: Contribution to journalArticle

73 Scopus citations

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.

Original languageEnglish (US)
Article numbere1001378
JournalPLoS genetics
Volume7
Issue number4
DOIs
StatePublished - Apr 1 2011

ASJC Scopus subject areas

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

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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), [e1001378]. https://doi.org/10.1371/journal.pgen.1001378