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 = .61; 95% CI, 0.36-0.98). In genotype-phenotype studies, significantly reduced circulating soluble CD40 was observed in TNFRSF5 -1TT compared with -1CC carriers. Further, dendritic cells from those with -1TT versus -1CC genotypes exhibited lower CD40 cell surface expression. These results suggest that the TNFRSF5 -1C>T polymorphism may increase FL susceptibility through mechanisms that hinder cellular immune responses. Further studies are needed to explore these findings.

Figure 1

sCD40 blood concentrations by TNFRSF5 −1C>T genotypes. (A) sCD40 concentrations in plasma of healthy controls by TNFRSF5–1C>T genotypes. (B) sCD40 concentrations in sera of healthy controls and follicular and diffuse large B-cell lymphoma cases by TNFRSF5 −1CC and −1TT genotypes. Means (bars) with standard errors (box) and one SD (whiskers) are shown (*P < .05).

Figure 2

CD40 surface expression levels on lipopolysaccharide (LPS)–activated dendritic cells. (A) Monocytes fractionated from peripheral blood mononuclear cells were stained with CD14, CD11c, and CD80 (green) and after 6 days of IL-4 and GM-CSF stimulation, a dendritic cell phenotype was observed (blue). (B) Monocyte-derived dendritic cells treated with (blue) and without (green) LPS were stained with CD40 antibody. A replicate experiment for the TNFRSF5 −1CT individual is shown (red) overlapping the previous experiment. (C) Representative plots of differences between lipopolysaccharide (LPS) untreated and treated CD40 peak levels (TNFRSF5 −1CC/−1CT n = 7, −1TT n = 4). Means (bars) with standard errors (boxes) and one SD (whiskers) are plotted. Data from −1CC and −1CT carriers were pooled due to similarities in their CD40 shifts.