Four Genetic Polymorphisms of Lymphotoxin-Alpha Gene and Cancer Risk: A Systematic Review and Meta-Analysis

Lymphotoxin-alpha (LTA) is a pro-inflammatory cytokine that plays an important role in the inflammatory and immunologic response. Numerous studies have shown LTA polymorphisms as risk factors for cancers, but the results remain inconclusive. The goal of the present meta-analyses is to establish the associations between cancers and four LTA variants (rs1041981, rs2239704, rs2229094 and rs746868). A total of 30 case-control studies involving 58,649 participants were included in the current meta-analyses. Our results showed significant associations with increased cancer risk for rs1041981 (odd ratio (OR) = 1.15, 99% confidential interval (CI) = 1.07-1.25, P 2 = 12.2%), rs2239704 (OR = 1.08, 99% CI = 1.01-1.16, P = 0.021, I2 = 0.0%) and rs2229094 (OR = 1.28, 99% CI = 1.09-1.50, P = 0.003, I2 = 0.0%). No evidence was found for the association between rs746868 and cancer risk (OR = 1.01, 99% CI = 0.93-1.10, P = 0.771, I2 = 0.0%). Subgroup meta-analysis suggested that rs2239704 was likely to increase the risk of hematological malignancy (OR = 1.10, 99% CI = 1.01–1.20, P = 0.023, I2 = 0.0%), and rs2229094 was specific for the increased risk of adenocarcinoma (OR = 1.33, 99% CI = 1.11-1.59, P = 0.002, I2 = 0.0%). In conclusion, our meta-analyses suggested that the LTA rs1041981, rs2239704 and rs2229094 polymorphisms contributed to the increased risk of cancers. Future functional studies were needed to clarify the mechanistic roles of the three variants in the cancer risk.淋巴毒素α（Lymphotoxin-alpha, LTA）是一种促炎细胞因子（pro-inflammatory cytokine），在炎症应答与免疫反应中发挥关键作用。诸多研究指出LTA基因多态性可作为癌症的风险因素，但相关研究结论尚未达成统一共识。本项荟萃分析（meta-analysis）旨在明确癌症与四种LTA基因变异位点（rs1041981、rs2239704、rs2229094及rs746868）之间的关联。本次荟萃分析共纳入30项病例对照研究（case-control study），涉及58649名研究对象。本研究结果显示，rs1041981位点变异与癌症风险升高存在显著关联（比值比（odds ratio, OR）=1.15，99%置信区间（confidence interval, CI）=1.07~1.25，I²=12.2%）；rs2239704位点变异同样与癌症风险升高显著相关（OR=1.08，99%CI=1.01~1.16，P=0.021，I²=0.0%）；rs2229094位点变异亦与癌症风险升高显著关联（OR=1.28，99%CI=1.09~1.50，P=0.003，I²=0.0%）。未发现rs746868位点变异与癌症风险存在关联（OR=1.01，99%CI=0.93~1.10，P=0.771，I²=0.0%）。亚组荟萃分析结果显示，rs2239704位点变异可能升高血液系统恶性肿瘤（hematological malignancy）的发病风险（OR=1.10，99%CI=1.01~1.20，P=0.023，I²=0.0%）；而rs2229094位点变异则与腺癌（adenocarcinoma）的风险升高特异性相关（OR=1.33，99%CI=1.11~1.59，P=0.002，I²=0.0%）。综上，本项荟萃分析表明，LTA基因的rs1041981、rs2239704及rs2229094位点多态性会升高癌症发病风险。未来需开展功能研究，以阐明这三个变异位点在癌症风险中的作用机制。