Genome-wide Association Study Identifies Five Susceptibility Loci for Follicular Lymphoma outside the HLA Region

Abstract

Genome-wide association studies (GWASs) of follicular lymphoma (FL) have previously identified human leukocyte antigen (HLA) gene variants. To identify additional FL susceptibility loci, we conducted a large-scale two-stage GWAS in 4,523 case subjects and 13,344 control subjects of European ancestry. Five non-HLA loci were associated with FL risk: 11q23.3 (rs4938573, p = 5.79 × 10(-20)) near CXCR5; 11q24.3 (rs4937362, p = 6.76 × 10(-11)) near ETS1; 3q28 (rs6444305, p = 1.10 × 10(-10)) in LPP; 18q21.33 (rs17749561, p = 8.28 × 10(-10)) near BCL2; and 8q24.21 (rs13254990, p = 1.06 × 10(-8)) near PVT1. In an analysis of the HLA region, we identified four linked HLA-DRβ1 multiallelic amino acids at positions 11, 13, 28, and 30 that were associated with FL risk (pomnibus = 4.20 × 10(-67) to 2.67 × 10(-70)). Additional independent signals included rs17203612 in HLA class II (odds ratio [OR(per-allele)] = 1.44; p = 4.59 × 10(-16)) and rs3130437 in HLA class I (OR(per-allele) = 1.23; p = 8.23 × 10(-9)). Our findings further expand the number of loci associated with FL and provide evidence that multiple common variants outside the HLA region make a significant contribution to FL risk.

Familial predisposition and genetic risk factors for lymphoma

“…Outside of the HLA region, 5 novel loci have been identified including 11q23.3 (near CXCR5), 11q24.3 (near ETS1), 3q28 (in LPP), 18q21.33 (near BCL2), and 8q24 (near PVT1). 62 These genes are linked to B-cell biology making them plausible in the etiology of FL.…”

“…62 HLA alleles and amino acids (AA) were imputed and the top signal mapped to four-linked DRb1 multi-allelic AA at positions at 11, 13, 28, and 30, suggesting an important role for DRb1 peptide presentation in FL. 62 Additional independent signals were also identified in HLA class II (rs17203612) and class I (rs3130437, near HLA-C); after accounting for all of these signals, no other previously identified SNPs from the MHC achieved genome-wide significance. Outside of the HLA region, 5 novel loci have been identified including 11q23.3 (near CXCR5), 11q24.3 (near ETS1), 3q28 (in LPP), 18q21.33 (near BCL2), and 8q24 (near PVT1).…”

Association of Long Noncoding RNAs Polymorphisms With Ankylosing Spondylitis, Vogt-Koyanagi-Harada Disease, and Behcet's Disease

“…The SNP rs4937362 is located at 11q24.3 in lncRNA RP11-264E20.1 and has been shown to be strongly associated with follicular lymphoma (P ¼ 6.76 3 10 À11 ). 64 To further validate our findings, the other SNPs rs2156698 and rs73013527, which are in strong LD with rs4937362, were also genotyped and the results were consistent with the rs4937362 genotyping data. Intriguingly, rs4937362 locates at approximately 35 kb upstream of ETS1, which plays an important role in autoimmune diseases, such as SLE, psoriasis, RA, MS, pediatric uveitis, and hematopoietic tumors.…”

New developments in the pathology of malignant lymphoma. A review of the literature published from August 2014 to October 2014

“…As the associations with familial disease indicate, germ line alterations can be relevant. Skibola et al [15] found for instance five non-HLA loci related to susceptibility for FL (4523 case and 13,344 controls): 11q23.3 near CXCR5, 11q24.3 near ETS1, 3q28 in LPP, 18q21.33 near BCL2 and 8q24.21 near PVT1. These findings further expand the number of loci associated with FL.…”