Person: Wang, Sophia
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Publication GWAS of Follicular Lymphoma Reveals Allelic Heterogeneity at 6p21.32 and Suggests Shared Genetic Susceptibility with Diffuse Large B-Cell Lymphoma
(Public Library of Science, 2011) 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; Wang, Sophia; Adami, Hans-OlovNon-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.