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A pooled investigation of Toll-like receptor gene variants and risk of non-Hodgkin lymphoma.

ABSTRACT: Toll-like receptors (TLRs) may influence the development of non-Hodgkin lymphoma (NHL) given their important roles in recognizing microbial pathogens and stimulating multiple immune pathways. We conducted an investigation of TLR gene variants in a pooled analysis including three population-based case-control studies of NHL (1946 cases and 1808 controls). Thirty-six tag single-nucleotide polymorphisms (SNPs) in TLR2, TLR4 and the TLR10-TLR1-TLR6 gene cluster were genotyped. Two TLR10-TLR1-TLR6 variants in moderate linkage disequilibrium were significantly associated with NHL: rs10008492 [odds ratio for CT genotype (OR(CT)) 1.12, 95% confidence interval (CI) 0.97-1.30; OR(TT) 1.40, 95% CI 1.15-1.71; P(trend) = 0.001] and rs4833103 (OR(AC) 0.75, 95% CI 0.64-0.88; OR(AA) 0.74, 95% CI 0.62-0.90; P(trend) = 0.002; P(dominant) = 0.0002). Associations with these SNPs were consistent across all the three studies and did not appreciably differ by histologic subtype. We found little evidence of association between TLR2 variation and all NHL, although the rare variant rs3804100 was significantly associated with marginal zone lymphoma (MZL), both overall (OR(CT/CC) 1.89, 95% CI 1.27-2.81; P(dominant) = 0.002) and in two of the three studies. No associations with TLR4 variants were observed. This pooled analysis provides strong evidence that variation in the TLR10-TLR1-TLR6 region is associated with NHL risk and suggests that TLR2 variants may influence susceptibility to MZL.

SUBMITTER: Purdue MP

PROVIDER: S-EPMC2639046 | biostudies-literature | 2009 Feb

REPOSITORIES: biostudies-literature

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A pooled investigation of Toll-like receptor gene variants and risk of non-Hodgkin lymphoma.

Purdue Mark P MP Lan Qing Q Wang Sophia S SS Kricker Anne A Menashe Idan I Zheng Tong-Zhang TZ Hartge Patricia P Grulich Andrew E AE Zhang Yawei Y Morton Lindsay M LM Vajdic Claire M CM Holford Theodore R TR Severson Richard K RK Leaderer Brian P BP Cerhan James R JR Yeager Meredith M Cozen Wendy W Jacobs Kevin K Davis Scott S Rothman Nathaniel N Chanock Stephen J SJ Chatterjee Nilanjan N Armstrong Bruce K BK

Carcinogenesis 20081124 2

Toll-like receptors (TLRs) may influence the development of non-Hodgkin lymphoma (NHL) given their important roles in recognizing microbial pathogens and stimulating multiple immune pathways. We conducted an investigation of TLR gene variants in a pooled analysis including three population-based case-control studies of NHL (1946 cases and 1808 controls). Thirty-six tag single-nucleotide polymorphisms (SNPs) in TLR2, TLR4 and the TLR10-TLR1-TLR6 gene cluster were genotyped. Two TLR10-TLR1-TLR6 va ...[more]

PMID: 19029192

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Project description: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. METHODOLOGY/PRINCIPAL FINDINGS: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/SIGNIFICANCE: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.

Dataset Information

A pooled investigation of Toll-like receptor gene variants and risk of non-Hodgkin lymphoma.

Publications

A pooled investigation of Toll-like receptor gene variants and risk of non-Hodgkin lymphoma.

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