GWAS of Follicular Lymphoma Reveals Allelic Heterogeneity at 6p21.32 and Suggests Shared Genetic Susceptibility with Diffuse Large B-cell Lymphoma

Department of Medicine, Clinical Epidemiology Unit, Karolinska Institutet, Stockholm, Sweden.
PLoS Genetics (Impact Factor: 7.53). 04/2011; 7(4):e1001378. DOI: 10.1371/journal.pgen.1001378
Source: PubMed


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.

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    • "The identification of the type of compound or industry possibly implicated in this effect could be very interesting, but it is beyond the scope of this study. Recent genome-wide association studies (GWAS) have identified polymorphisms associated with lymphoma risk such as rs10484561 [39], rs2647012 [40] and rs6457327 [41] in the human leukocyte antigen (HLA) region on 6p21.32 and 6p21.33. Very recently, a novel region on 11q12.1 showed also association with lymphoma susceptibility [42]. "
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    • "Full details of the study design and methods, genotyping, quality control and statistical analyses have been published [3]. The final analysis included 298,680 genetic variants available for 379 cases and 791 controls. "
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