||Smedby KE, Foo JN, Skibola CF, Darabi H, Conde L, Hjalgrim H, Kumar V, Chang ET, Rothman N, Cerhan JR, Brooks-Wilson AR, Rehnberg E, Irwan ID, Ryder LP, Brown PN, Bracci PM, Agana L, Riby J, Cozen W, Davis S, Hartge P, Morton LM, Severson RK, Wang SS, Slager SL, Fredericksen ZS, Novak AJ, Kay NE, Habermann TM, Armstrong B, Kricker A, Milliken S, Purdue MP, Vajdic CM, Boyle P, Lan Q, Zahm SH, Zhang Y, Zheng T, Leach S, Spinelli JJ, Smith MT, Chanock SJ, Padyukov L, Alfredsson L, Klareskog L, Glimelius B, Melbye M, Liu ET, Adami HO, Humphreys K, Liu J
||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.