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


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.

SUBMITTER: Smedby KE 

PROVIDER: S-EPMC3080853 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature

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

Smedby Karin E KE   Foo Jia Nee JN   Skibola Christine F CF   Darabi Hatef H   Conde Lucia L   Hjalgrim Henrik H   Kumar Vikrant V   Chang Ellen T ET   Rothman Nathaniel N   Cerhan James R JR   Brooks-Wilson Angela R AR   Rehnberg Emil E   Irwan Ishak D ID   Ryder Lars P LP   Brown Peter N PN   Bracci Paige M PM   Agana Luz L   Riby Jacques J   Cozen Wendy W   Davis Scott S   Hartge Patricia P   Morton Lindsay M LM   Severson Richard K RK   Wang Sophia S SS   Slager Susan L SL   Fredericksen Zachary S ZS   Novak Anne J AJ   Kay Neil E NE   Habermann Thomas M TM   Armstrong Bruce B   Kricker Anne A   Milliken Sam S   Purdue Mark P MP   Vajdic Claire M CM   Boyle Peter P   Lan Qing Q   Zahm Shelia H SH   Zhang Yawei Y   Zheng Tongzhang T   Leach Stephen S   Spinelli John J JJ   Smith Martyn T MT   Chanock Stephen J SJ   Padyukov Leonid L   Alfredsson Lars L   Klareskog Lars L   Glimelius Bengt B   Melbye Mads M   Liu Edison T ET   Adami Hans-Olov HO   Humphreys Keith K   Liu Jianjun J  

PLoS genetics 20110421 4


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  ...[more]

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