A functional TNFRSF5 gene variant is associated with risk of lymphoma

Abstract

CD40 and its ligand, CD154, are major costimulatory molecules whose interactions are important in humoral and cellular immunity. We hypothesized that single nucleotide polymorphisms (SNPs) in TNFRSF5 and TNFSF5 encoding the CD40 and CD154 proteins, respectively, influence lymphoma risk, particularly a functional TNFRSF5 SNP (؊1C>T, rs1883832) associated with reduced B-cell CD40 expression. TNFRSF5 and TNFSF5 SNPs were examined in a population-based case-control study of non-Hodgkin lymphoma (376 cases/801 controls with DNA), and compelling findings were followed up in 2 independent populations. Pooled analyses of all 3 case-control studies (total N ‫؍‬ 1776 non-Hodgkin lymphoma cases, N ‫؍‬ 2482 controls) revealed an increased risk of follicular lymphoma (FL) associated with the TNFRSF5 ؊1TT genotype (odds ratio ‫؍‬ 1.6; 95% confidence interval, 1.1-2.4). In addition, among women, an inverse association was found between the variant A allele for a TNFSF5 6809G>A SNP and FL risk (OR ‫؍‬ . IntroductionLymphomas are a heterogeneous group of malignancies derived from different stages of B-cell maturation. 1 The germinal center reaction plays a pivotal role in the generation of the majority of B-cell lymphomas, such as follicular (FL), and some diffuse large B-cell (DLBCL) 2,3 and Hodgkin lymphomas (HL). 4 Thus, genetic and environmental factors that disrupt normal germinal center reactions may increase the risk of these lymphomas. Accumulating evidence underscores the essential roles of the costimulatory molecules CD40 receptor and its ligand CD154 (CD40L) in the generation and maintenance of humoral and cellular immune responses. 5,6 CD40 is a member of the tumor necrosis factor (TNF) receptor family that is expressed constitutively on antigenpresenting cells (APCs). 6 CD154 is primarily expressed on activated CD4 ϩ T cells but also on a variety of cells, including CD8 ϩ T cells, mast cells, monocytes, macrophages, natural killer cells, and dendritic cells. 7 Soluble forms of CD40 (sCD40) and sCD154 also are present in the serum and plasma 8,9 through transmembrane cleavage of bound CD40 and CD154 by ADAM family member proteases. 10,11 sCD40 and sCD154 may regulate distinct signaling pathways or complement the biologic activity of their membranebound counterparts. CD40-CD154 ligation is crucial for the maturation and activation of B cells, dendritic cells, and other APCs. 6 Activated B cells that receive low CD40-CD154 signals in the germinal center have limited lifespans and display impaired immunoglobulin (Ig) production, isotype switching, and B-cell memory. 12 Moreover, dendritic cells and other APCs that express low CD40 have reduced tumor-specific immune responses involving cytotoxic T-lymphocyte activation. 7 Mutations in the TNFSF5 and TNFRSF5 genes that encode CD154 and CD40, respectively, are associated with a severe form of immunodeficiency called hyper-immunoglobulin M (HIGM) syndrome. 13 The HIGM disorders are characterized by reduced CD154 or CD40 protein expression, elevated IgM levels, defective cla...

A single nucleotide polymorphism determines protein isoform production of the human c-FLIP protein

“…1,2,33,[38][39][40] In line with our data, the CD40 gene polymorphism associated with follicular lymphoma causes an impaired rather than an increased CD40 expression. 37 Altogether, these observations underline the potential impact of SNPs on genes involved in lymphocyte regulation for the development of follicular lymphoma.…”

“…Interestingly, a recent study identified an increased risk of follicular lymphoma associated with an SNP in the CD40 gene. 37 Stimulation of B cell-expressed CD40 by T cellexpressed CD40 ligand is highly important for the delivery of B-cell survival signals, including up-regulation of c-FLIP. 1,2,33,[38][39][40] In line with our data, the CD40 gene polymorphism associated with follicular lymphoma causes an impaired rather than an increased CD40 expression.…”

Association analysis of CD40 gene polymorphism with acute coronary syndrome

“…Patients with ACS show increased coexpression of the CD40-CD40L system, which may create a proinflammatory and prothrombotic milieu for aggravating the development of atherosclerosis and the instability of atherosclerotic plaques and may be a valuable marker for predicting the severity of ACS [3]. Many researchers have demonstrated that a C/T polymorphism at position -1 of the CD40 gene is associated with diseases related with inflammatory responses such as Graves' disease, low bone mass and follicular lymphoma [10,[14][15][16][17], Until now, little research had explored the association between the SNP (-1C/T) and genetic susceptibility to ACS in the Chinese population. In our study, we investigated the relationship between the SNP (-1C/T) of CD40 gene and ACS.…”

Role of Host Genetics in Lymphoma

“…For example, individuals carrying TNFRSF5 gene (CD40) polymorphisms associated with an increased risk of development of NHL, have been shown to have lower expression of CD40 on dendritic cells and lower soluble CD40 in the serum, [23] suggesting that reduced immune surveillance due to impaired CD40 signaling may be leading to increased lymphoma outgrowth. One of the promising tumor biomarkers that can predict DLBCL outcome is LMO2.…”

“…In particular, given the associations between inflammation, the immune response and the development, biology, and clinical outcome of NHL, many studies have focused on genes such as cytokines and their receptors (IL10, TNF, BLYS) or innate immunity genes (TLR4) [15][16][17][18][19][20][21][22][23]. One of the largest studies, performed by the InterLymph Consortium, analyzed 3586 patients with NHL and 4018 control patients from seven centers using a PCR-based methodology to detect 12 SNPs in nine genes that have important pro-inflammatory or antiinflammatory effects (IL1A, IL1RN, IL1B, IL2, IL6, IL10, TNF, LTA, and CARD15) [15].…”