title: 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.
authors.affiliation: Department of Medicine, Clinical Epidemiology Unit, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Karin E
authors.initials: KE
authors.lastname: Smedby
authors.forename: Jia Nee
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authors.lastname: Severson
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authors.lastname: Fredericksen
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authors.lastname: Purdue
authors.forename: Claire M
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authors.lastname: Vajdic
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authors.lastname: Boyle
authors.forename: Qing
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authors.forename: Shelia H
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authors.lastname: Zahm
authors.forename: Yawei
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authors.lastname: Zhang
authors.forename: Tongzhang
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authors.lastname: Zheng
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authors.lastname: Leach
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authors.lastname: Chanock
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authors.lastname: Padyukov
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authors.lastname: Alfredsson
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authors.lastname: Klareskog
authors.forename: Bengt
authors.initials: B
authors.lastname: Glimelius
authors.forename: Mads
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authors.lastname: Melbye
authors.forename: Edison T
authors.initials: ET
authors.lastname: Liu
authors.forename: Hans-Olov
authors.initials: HO
authors.lastname: Adami
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mesh_terms: D002896:Chromosomes, Human, Pair 6 / Q000235:genetics*; D003718:Denmark; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D015894:Genome, Human; D055106:Genome-Wide Association Study; D006239:Haplotypes; D000949:Histocompatibility Antigens Class II / Q000235:genetics*; D006801:Humans; D008224:Lymphoma, Follicular / Q000235:genetics*; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D013548:Sweden
chemical_list: D000949:Histocompatibility Antigens Class II