PLoS Genetics (Apr 2011)

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
https://doi.org/10.1371/journal.pgen.1001378
Journal volume & issue
Vol. 7, no. 4
p. e1001378

Abstract

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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.