Common gene variants in the Tumor Necrosis Factor (TNF) and TNF receptor superfamilies and NF-kB transcription factors and non-hodgkin lymphoma risk

Sophia S. Wang, Mark P. Purdue, James R Cerhan, Tongzhang Zheng, Idan Menashe, Bruce K. Armstrong, Qing Lan, Patricia Hartge, Anne Kricker, Yawei Zhang, Lindsay M. Morton, Claire M. Vajdic, Theodore R. Holford, Richard K. Severson, Andrew Grulich, Brian P. Leaderer, Scott Davis, Wendy Cozen, Meredith Yeager, Stephen J. ChanockNilanjan Chatterjee, Nathaniel Rothman

Research output: Contribution to journalArticle

80 Citations (Scopus)

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-α, activates the nuclear factor kappa beta (NF-κB) transcription factor, and is critical for inflammatory and apoptotic responses in cancer progression. We hypothesized that the TNF and NF-κB 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-κB and related transcription factors, in 1946 NHL cases and 1808 controls pooled from three independent population-based case-control studies. We obtaineded 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-κB 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.

Original languageEnglish (US)
Article numbere5360
JournalPLoS One
Volume4
Issue number4
DOIs
StatePublished - Apr 24 2009

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non-Hodgkin lymphoma
transcription factor NF-kappa B
NF-kappa B
tumor necrosis factors
Tumor Necrosis Factor Receptors
Non-Hodgkin's Lymphoma
transcription factors
Tumor Necrosis Factor-alpha
Genes
Polymorphism
receptors
genes
Nucleotides
Chromosomes
single nucleotide polymorphism
Single Nucleotide Polymorphism
Transcription Factors
chromosomes
Logistics
Cells

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Common gene variants in the Tumor Necrosis Factor (TNF) and TNF receptor superfamilies and NF-kB transcription factors and non-hodgkin lymphoma risk. / Wang, Sophia S.; Purdue, Mark P.; Cerhan, James R; Zheng, Tongzhang; Menashe, Idan; Armstrong, Bruce K.; Lan, Qing; Hartge, Patricia; Kricker, Anne; Zhang, Yawei; Morton, Lindsay M.; Vajdic, Claire M.; Holford, Theodore R.; Severson, Richard K.; Grulich, Andrew; Leaderer, Brian P.; Davis, Scott; Cozen, Wendy; Yeager, Meredith; Chanock, Stephen J.; Chatterjee, Nilanjan; Rothman, Nathaniel.

In: PLoS One, Vol. 4, No. 4, e5360, 24.04.2009.

Research output: Contribution to journalArticle

Wang, SS, Purdue, MP, Cerhan, JR, Zheng, T, Menashe, I, Armstrong, BK, Lan, Q, Hartge, P, Kricker, A, Zhang, Y, Morton, LM, Vajdic, CM, Holford, TR, Severson, RK, Grulich, A, Leaderer, BP, Davis, S, Cozen, W, Yeager, M, Chanock, SJ, Chatterjee, N & Rothman, N 2009, 'Common gene variants in the Tumor Necrosis Factor (TNF) and TNF receptor superfamilies and NF-kB transcription factors and non-hodgkin lymphoma risk', PLoS One, vol. 4, no. 4, e5360. https://doi.org/10.1371/journal.pone.0005360
Wang, Sophia S. ; Purdue, Mark P. ; Cerhan, James R ; Zheng, Tongzhang ; Menashe, Idan ; Armstrong, Bruce K. ; Lan, Qing ; Hartge, Patricia ; Kricker, Anne ; Zhang, Yawei ; Morton, Lindsay M. ; Vajdic, Claire M. ; Holford, Theodore R. ; Severson, Richard K. ; Grulich, Andrew ; Leaderer, Brian P. ; Davis, Scott ; Cozen, Wendy ; Yeager, Meredith ; Chanock, Stephen J. ; Chatterjee, Nilanjan ; Rothman, Nathaniel. / Common gene variants in the Tumor Necrosis Factor (TNF) and TNF receptor superfamilies and NF-kB transcription factors and non-hodgkin lymphoma risk. In: PLoS One. 2009 ; Vol. 4, No. 4.
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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-α, activates the nuclear factor kappa beta (NF-κB) transcription factor, and is critical for inflammatory and apoptotic responses in cancer progression. We hypothesized that the TNF and NF-κB 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-κB and related transcription factors, in 1946 NHL cases and 1808 controls pooled from three independent population-based case-control studies. We obtaineded 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-κB 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.",
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TY - JOUR

T1 - Common gene variants in the Tumor Necrosis Factor (TNF) and TNF receptor superfamilies and NF-kB transcription factors and non-hodgkin lymphoma risk

AU - Wang, Sophia S.

AU - Purdue, Mark P.

AU - Cerhan, James R

AU - Zheng, Tongzhang

AU - Menashe, Idan

AU - Armstrong, Bruce K.

AU - Lan, Qing

AU - Hartge, Patricia

AU - Kricker, Anne

AU - Zhang, Yawei

AU - Morton, Lindsay M.

AU - Vajdic, Claire M.

AU - Holford, Theodore R.

AU - Severson, Richard K.

AU - Grulich, Andrew

AU - Leaderer, Brian P.

AU - Davis, Scott

AU - Cozen, Wendy

AU - Yeager, Meredith

AU - Chanock, Stephen J.

AU - Chatterjee, Nilanjan

AU - Rothman, Nathaniel

PY - 2009/4/24

Y1 - 2009/4/24

N2 - 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-α, activates the nuclear factor kappa beta (NF-κB) transcription factor, and is critical for inflammatory and apoptotic responses in cancer progression. We hypothesized that the TNF and NF-κB 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-κB and related transcription factors, in 1946 NHL cases and 1808 controls pooled from three independent population-based case-control studies. We obtaineded 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-κB 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.

AB - 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-α, activates the nuclear factor kappa beta (NF-κB) transcription factor, and is critical for inflammatory and apoptotic responses in cancer progression. We hypothesized that the TNF and NF-κB 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-κB and related transcription factors, in 1946 NHL cases and 1808 controls pooled from three independent population-based case-control studies. We obtaineded 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-κB 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.

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