Meta- and Pooled Analyses Tumor Necrosis Factor ( TNF ) and Lymphotoxin- a ( LTA ) Polymorphisms and Risk of Non-Hodgkin Lymphoma in the InterLymph Consortium

In an International Lymphoma Epidemiology Consortium pooled analysis, polymorphisms in 2 immune-system-related genes, tumor necrosis factor ( TNF ) and interleukin-10 ( IL10 ), were associated with non-Hodgkin lymphoma (NHL) risk. Here, 8,847 participants were added to previous data (patients diagnosed from 1989 to 2005 in 14 case-control studies; 7,999 cases, 8,452 controls) for testing of polymorphisms in the TNF –308G > A (rs1800629), lymphotoxin- a ( LTA ) 252A > G (rs909253), IL10 –3575T > A (rs1800890, rs1800896), and nucleotide-binding oligomerization domain containing 2 ( NOD2 ) 3020insC (rs2066847) genes. Odds ratios were estimated for non-Hispanic whites and several ethnic subgroups using 2-sided tests. Consistent with previous findings, odds ratios were increased for ‘‘new’’ participant TNF –308A carriers (NHL: per-allele odds ratio (OR allelic ) ¼ 1.10, P trend ¼ 0.001; diffuse large B-cell lymphoma (DLBCL): OR allelic ¼ 1.23, P trend ¼ 0.004). In the combined population, odds ratios were increased for TNF –308A carriers (NHL: OR allelic ¼ 1.13, P trend ¼ 0.0001; DLBCL: OR allelic ¼ 1.25, P trend ¼ 3.7 3 10 (cid:1) 6 ; marginal zone lymphoma: OR allelic ¼ 1.35, P trend ¼ 0.004) and LTA 252G carriers (DLBCL: OR allelic ¼ 1.12, P trend ¼ 0.006; mycosis fungoides: OR allelic ¼ 1.44, P trend ¼ 0.015). The LTA 252A > G /TNF –308G > A haplotype containing the LTA/TNF variant alleles was strongly associated with DLBCL ( P ¼ 2.9 3 10 (cid:1) 8 ). Results suggested associations between IL10 –3575T > A and DLBCL ( P trend ¼ 0.02) and IL10 –1082A > G and mantle cell lymphoma ( P trend ¼ 0.04). These findings strengthen previous results for DLBCL and the LTA 252A > G /TNF –308A locus and provide robust evidence that these TNF/LTA gene variants, or others in linkage disequilibrium, in NHL etiology.