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

• Main Authors: 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
• Format: Article
• Language: English
• Published: Public Library of Science (PLoS) 2011-04-01
• Series: PLoS Genetics
• Online Access: http://europepmc.org/articles/PMC3080853?pdf=render
• ISSN: 1553-7390; 1553-7404

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.