Common Gene Variants in the Tumor Necrosis Factor (TNF) and TNF Receptor Superfamilies and NF-kB Transcription Factors and Non-Hodgkin Lymphoma Risk

BackgroundA 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 FindingsWe 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/SignificanceOur 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.

研究背景：促炎细胞因子肿瘤坏死因子（tumor necrosis factor, TNF）启动子区多态性位点TNF G-308A与非霍奇金淋巴瘤（non-Hodgkin lymphoma, NHL）风险升高相关。其编码蛋白产物TNF-α可激活核因子κB（nuclear factor kappa beta, NF-κB）转录因子，在肿瘤进展过程中的炎症应答与凋亡应答中发挥关键作用。我们提出假设：TNF与NF-κB通路对NHL的发生具有重要意义，该通路内的基因变异可能改变NHL的发病风险。
研究方法与主要结果：我们整合了三项独立的人群为基础的病例对照研究数据，对1946例NHL病例与1808例对照样本进行基因分型，检测了TNF、TNF受体超家族、NF-κB及相关转录因子的48个候选基因区域（定义为基因上游20 kb、下游10 kb区间）内的500个标签单核苷酸多态性（single nucleotide polymorphisms, SNPs）。通过计算最小P值（minP检验），我们得到了基因区域水平的关联分析汇总结果。采用逻辑回归分析计算NHL及其四种主要亚型与SNP基因型及单倍型关联的比值比与95%置信区间。针对NHL的分析显示，尾部强度统计量证实TNF/NF-κB通路与NHL存在总体关联（p=0.02）。我们验证了6号染色体6p21.3区域内的TNF/LTA位点与NHL的关联，并发现LTA rs2844484位点与主要亚型弥漫大B细胞淋巴瘤（diffuse large B-cell lymphoma, DLBCL）的关联性最为显著且具有亚型特异性（趋势P值=0.001）。我们还首次证实了6p21.3区域内的NFKBIL1变异与NHL相关。其他经统计学检验证实与NHL显著相关的基因区域包括FAS、IRF4、TNFSF13B、TANK、TNFSF7及TNFRSF13C。其中，与NHL关联最显著的单个SNP分别为FAS rs4934436（趋势P值=0.0024）、IRF4 rs12211228（趋势P值=0.0026）、TNFSF13B rs2582869（趋势P值=0.0055）、TANK rs1921310（趋势P值=0.0025）、TNFSF7 rs16994592（趋势P值=0.0024）以及TNFRSF13C rs6002551（趋势P值=0.0074）。所有关联在各独立研究中均保持一致，且未观察到对NHL亚型的明显特异性。
研究结论与意义：本研究结果提供了一致的证据，表明TNF基因超家族的变异，尤其是6p21.3区域内的基因变异，可影响淋巴瘤发生过程。对这些易感位点的进一步表征以及功能变异体的鉴定均值得开展。