TY - JOUR
T1 - Inherited variants at 3q13.33 and 3p24.1 are associated with risk of diffuse large B-cell lymphoma and implicate immune pathways
AU - Kleinstern, Geffen
AU - Yan, Huihuang
AU - Hildebrandt, Michelle A.T.
AU - Vijai, Joseph
AU - Berndt, Sonja I.
AU - Ghesquières, Hervé
AU - McKay, James
AU - Wang, Sophia S.
AU - Nieters, Alexandra
AU - Ye, Yuanqing
AU - Monnereau, Alain
AU - Brooks-Wilson, Angela R.
AU - Lan, Qing
AU - Melbye, Mads
AU - Jackson, Rebecca D.
AU - Teras, Lauren R.
AU - Purdue, Mark P.
AU - Vajdic, Claire M.
AU - Vermeulen, Roel C.H.
AU - Giles, Graham G.
AU - Cocco, Pier Luigi
AU - Birmann, Brenda M.
AU - Kraft, Peter
AU - Albanes, Demetrius
AU - Zeleniuch-Jacquotte, Anne
AU - Crouch, Simon
AU - Zhang, Yawei
AU - Sarangi, Vivekananda
AU - Asmann, Yan
AU - Offit, Kenneth
AU - Salles, Gilles
AU - Wu, Xifeng
AU - Smedby, Karin E.
AU - Skibola, Christine F.
AU - Slager, Susan L.
AU - Rothman, Nathaniel
AU - Chanock, Stephen J.
AU - Cerhan, James R.
N1 - Funding Information: Dr G.K. was supported by the National Institutes of Health grant, R25 CA92049 (Mayo Cancer Genetic Epidemiology Training Program). Replication genotyping was supported by R01 CA200703 (to JRC), the Center for Translational and Public Health Genomics (to X.W.), MD Anderson’s Cancer Center Support Grant P30CA016672, MSKCC Core grant NIH P30CA008748, the Lymphoma Genetics Research Fund (KO), and the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH. The original GWAS was supported by the Intramural Research Program, Division of Cancer Epidemiology and Genetics, NCI, NHI. Individual study support is included in the Supplementary Materials. Publisher Copyright: © 2019 The Author(s). Published by Oxford University Press. All rights reserved.
PY - 2020/1/1
Y1 - 2020/1/1
N2 - We previously identified five single nucleotide polymorphisms (SNPs) at four susceptibility loci for diffuse large B-cell lymphoma (DLBCL) in individuals of European ancestry through a large genome-wide association study (GWAS). To further elucidate genetic susceptibility to DLBCL, we sought to validate two loci at 3q13.33 and 3p24.1 that were suggestive in the original GWAS with additional genotyping. In the meta-analysis (5662 cases and 9237 controls) of the four original GWAS discovery scans and three replication studies, the 3q13.33 locus (rs9831894; minor allele frequency [MAF] = 0.40) was associated with DLBCL risk [odds ratio (OR) = 0.83, P = 3.62 × 10-13]. rs9831894 is in linkage disequilibrium (LD) with additional variants that are part of a super-enhancer that physically interacts with promoters of CD86 and ILDR1. In the meta-analysis (5510 cases and 12 817 controls) of the four GWAS discovery scans and four replication studies, the 3p24.1 locus (rs6773363; MAF = 0.45) was also associated with DLBCL risk (OR = 1.20, P = 2.31 × 10-12). This SNP is 29 426-bp upstream of the nearest gene EOMES and in LD with additional SNPs that are part of a highly lineage-specific and tumor-acquired super-enhancer that shows long-range interaction with AZI2 promoter. These loci provide additional evidence for the role of immune function in the etiology of DLBCL, the most common lymphoma subtype.
AB - We previously identified five single nucleotide polymorphisms (SNPs) at four susceptibility loci for diffuse large B-cell lymphoma (DLBCL) in individuals of European ancestry through a large genome-wide association study (GWAS). To further elucidate genetic susceptibility to DLBCL, we sought to validate two loci at 3q13.33 and 3p24.1 that were suggestive in the original GWAS with additional genotyping. In the meta-analysis (5662 cases and 9237 controls) of the four original GWAS discovery scans and three replication studies, the 3q13.33 locus (rs9831894; minor allele frequency [MAF] = 0.40) was associated with DLBCL risk [odds ratio (OR) = 0.83, P = 3.62 × 10-13]. rs9831894 is in linkage disequilibrium (LD) with additional variants that are part of a super-enhancer that physically interacts with promoters of CD86 and ILDR1. In the meta-analysis (5510 cases and 12 817 controls) of the four GWAS discovery scans and four replication studies, the 3p24.1 locus (rs6773363; MAF = 0.45) was also associated with DLBCL risk (OR = 1.20, P = 2.31 × 10-12). This SNP is 29 426-bp upstream of the nearest gene EOMES and in LD with additional SNPs that are part of a highly lineage-specific and tumor-acquired super-enhancer that shows long-range interaction with AZI2 promoter. These loci provide additional evidence for the role of immune function in the etiology of DLBCL, the most common lymphoma subtype.
UR - http://www.scopus.com/inward/record.url?scp=85079019341&partnerID=8YFLogxK
U2 - https://doi.org/10.1093/hmg/ddz228
DO - https://doi.org/10.1093/hmg/ddz228
M3 - Article
C2 - 31600786
SN - 0964-6906
VL - 29
SP - 70
EP - 79
JO - Human Molecular Genetics
JF - Human Molecular Genetics
IS - 1
ER -