Background. There is strong evidence that dysregulation of the immune system increases risk of non-Hodgkin lymphoma (NHL), which might include imbalances in B- and T-cell homeostasis and unregulated T-cell activation. CD40 ligand (CD154), a member of the tumor necrosis factor superfamily, is a transmembrane protein expressed primarily on activated CD4+ T cells. Mutations in the CD154 gene, located on the long arm of the X chromosome, are associated with rare autoimmune disorders such as X linked hyper-IgM syndrome and Kawasaki disease. The CD154 receptor, CD40, is a major costimulatory molecule primarily expressed on B cells and antigen presenting cells. This receptor-ligand pair drives activation and proliferation of T-cells and induces B-cell differentiation, proliferation, isotype switching, antibody secretion and anti-apoptotic behavior in germinal center B-cells. In light of their important roles in immune regulation, we hypothesized that genetic polymorphisms in CD154 and CD40 may affect NHL risk. Methods. To test this hypothesis, 4 single nucleotide polymorphisms (SNPs) in CD40 and 5 SNPs in CD154 were examined using DNA from white non-Hispanic participants (n=308 cases, n=684 controls) in a population-based case-control study conducted in the San Francisco Bay Area between 1988-1995. SNP- and haplotype-specific data analyses were performed using age- and sex-adjusted unconditional logistic regression. Results. A reduced risk of NHL was observed among carriers of the homozygous variant genotypes CD40 -4983G>T (rs1009373; OR=0.54, 95% CI: 0.28-1.0) and CD40 1115C>T (rs1535045; OR=0.54, 95% CI: 0.29-1.0). Furthermore, the heterozygous genotype for CD40 14913C>T (rs1883838) conferred an increased risk for NHL (OR=1.5, 95% CI:1.1-2.1) and follicular lymphoma (FL) (OR=2.1, 95% CI:1.3-3.4). No differences were observed in genotype frequencies between cases and controls for CD40 -1C>T, a functional SNP associated with reduced CD40 protein expression. However, this SNP was in strong linkage disequilibrium with the CD40 -4983G>T and CD40 1115C>T SNPs. The homozygous genotype for CD154 3005 G>A (rs715762) was associated with a modest increased risk of NHL (OR=1.6, 95% CI: 0.97-2.7) and FL (OR=1.7, 95% CI: 0.80-3.8) in men, but not women. No other associations were found between CD154 or CD40 SNPs or haplotypes. Conclusions. These findings suggest that genetic variation in the CD154 and CD40 genes may play a critical role in the pathogenesis of lymphoma, although the underlying mechanisms involved require further analyses.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]