title: 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.
authors.affiliation: Division of Environmental Health Sciences, School of Public Health, University of California, Berkeley, CA 94720-7360, USA. chrisfs@berkeley.edu
authors.forename: Christine F
authors.initials: CF
authors.lastname: Skibola
authors.forename: Alexandra
authors.initials: A
authors.lastname: Nieters
authors.forename: Paige M
authors.initials: PM
authors.lastname: Bracci
authors.forename: John D
authors.initials: JD
authors.lastname: Curry
authors.forename: Luz
authors.initials: L
authors.lastname: Agana
authors.forename: Danica R
authors.initials: DR
authors.lastname: Skibola
authors.forename: Alan
authors.initials: A
authors.lastname: Hubbard
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Becker
authors.forename: Martyn T
authors.initials: MT
authors.lastname: Smith
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Holly
mesh_terms: D000328:Adult; D000368:Aged; D019013:CD40 Antigens / Q000097:blood / Q000235:genetics*; D023201:CD40 Ligand / Q000235:genetics; D016001:Confidence Intervals; D003596:Cytosine; D003713:Dendritic Cells / Q000187:drug effects; D020022:Genetic Predisposition to Disease; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D008224:Lymphoma, Follicular / Q000235:genetics*; D008875:Middle Aged; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012995:Solubility; D013941:Thymine
chemical_list: D019013:CD40 Antigens; D008070:Lipopolysaccharides; D023201:CD40 Ligand; D003596:Cytosine; D013941:Thymine