title: Common gene variants in the tumor necrosis factor (TNF) and TNF receptor superfamilies and NF-kB transcription factors and non-Hodgkin lymphoma risk.
abstract: BACKGROUND
  A promoter polymorphism in the pro-inflammatory cytokine tumor necrosis factor (TNF) (TNF G-308A) is associated with increased non-Hodgkin lymphoma (NHL) risk. The protein product, TNF-alpha, activates the nuclear factor kappa beta (NF-kappaB) transcription factor, and is critical for inflammatory and apoptotic responses in cancer progression. We hypothesized that the TNF and NF-kappaB pathways are important for NHL and that gene variations across the pathways may alter NHL risk.
  
  
  RESULTS
  We genotyped 500 tag single nucleotide polymorphisms (SNPs) from 48 candidate gene regions (defined as 20 kb 5', 10 kb 3') in the TNF and TNF receptor superfamilies and the NF-kappaB and related transcription factors, in 1946 NHL cases and 1808 controls pooled from three independent population-based case-control studies. We obtained a gene region-level summary of association by computing the minimum p-value ("minP test"). We used logistic regression to compute odds ratios and 95% confidence intervals for NHL and four major NHL subtypes in relation to SNP genotypes and haplotypes. For NHL, the tail strength statistic supported an overall relationship between the TNF/NF-kappaB pathway and NHL (p = 0.02). We confirmed the association between TNF/LTA on chromosome 6p21.3 with NHL and found the LTA rs2844484 SNP most significantly and specifically associated with the major subtype, diffuse large B-cell lymphoma (DLBCL) (p-trend = 0.001). We also implicated for the first time, variants in NFKBIL1 on chromosome 6p21.3, associated with NHL. Other gene regions identified as statistically significantly associated with NHL included FAS, IRF4, TNFSF13B, TANK, TNFSF7 and TNFRSF13C. Accordingly, the single most significant SNPs associated with NHL were FAS rs4934436 (p-trend = 0.0024), IRF4 rs12211228 (p-trend = 0.0026), TNFSF13B rs2582869 (p-trend = 0.0055), TANK rs1921310 (p-trend = 0.0025), TNFSF7 rs16994592 (p-trend = 0.0024), and TNFRSF13C rs6002551 (p-trend = 0.0074). All associations were consistent in each study with no apparent specificity for NHL subtype.
  
  
  CONCLUSIONS
  Our results provide consistent evidence that variation in the TNF superfamily of genes and specifically within chromosome 6p21.3 impacts lymphomagenesis. Further characterization of these susceptibility loci and identification of functional variants are warranted.
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Rockville, Maryland, United States of America. wangso@mail.nih.gov
authors.forename: Sophia S
authors.initials: SS
authors.lastname: Wang
authors.forename: Mark P
authors.initials: MP
authors.lastname: Purdue
authors.forename: James R
authors.initials: JR
authors.lastname: Cerhan
authors.forename: Tongzhang
authors.initials: T
authors.lastname: Zheng
authors.forename: Idan
authors.initials: I
authors.lastname: Menashe
authors.forename: Bruce K
authors.initials: BK
authors.lastname: Armstrong
authors.forename: Qing
authors.initials: Q
authors.lastname: Lan
authors.forename: Patricia
authors.initials: P
authors.lastname: Hartge
authors.forename: Anne
authors.initials: A
authors.lastname: Kricker
authors.forename: Yawei
authors.initials: Y
authors.lastname: Zhang
authors.forename: Lindsay M
authors.initials: LM
authors.lastname: Morton
authors.forename: Claire M
authors.initials: CM
authors.lastname: Vajdic
authors.forename: Theodore R
authors.initials: TR
authors.lastname: Holford
authors.forename: Richard K
authors.initials: RK
authors.lastname: Severson
authors.forename: Andrew
authors.initials: A
authors.lastname: Grulich
authors.forename: Brian P
authors.initials: BP
authors.lastname: Leaderer
authors.forename: Scott
authors.initials: S
authors.lastname: Davis
authors.forename: Wendy
authors.initials: W
authors.lastname: Cozen
authors.forename: Meredith
authors.initials: M
authors.lastname: Yeager
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Chanock
authors.forename: Nilanjan
authors.initials: N
authors.lastname: Chatterjee
authors.forename: Nathaniel
authors.initials: N
authors.lastname: Rothman
mesh_terms: D016022:Case-Control Studies; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008228:Lymphoma, Non-Hodgkin / Q000235:genetics*; D016328:NF-kappa B / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics*; D012307:Risk Factors; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
chemical_list: D016328:NF-kappa B; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha