TNF, IL6, and IL1B Polymorphisms Are Associated with Severe Influenza A (H1N1) Virus Infection in the Mexican Population.
TNF, IL6, and IL1B Polymorphisms Are Associated with Severe Influenza A (H1N1) Virus Infection in the Mexican Population.
复制标题
DOI：
10.1371/journal.pone.0144832
复制
发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Mejía-Aranguré JM
中科院分区：
文献类型：
--
作者：
García-Ramírez RA;Ramírez-Venegas A;Quintana-Carrillo R;Camarena ÁE;Falfán-Valencia R;Mejía-Aranguré JM
高细胞因子血症是导致甲型H1N1流感病毒感染临床病程更严重的主要免疫病理机制。大多数感染甲型H1N1流感pdm 09病毒的患者全身促炎细胞因子水平升高，包括白细胞介素IL-6、IL-8和肿瘤坏死因子-α（TNF-α）。我们认为促炎基因启动子区的单核苷酸多态性（SNP）与甲型H1N1流感病毒感染的严重程度相关。纳入145例甲型H1N1流感（pA/H1N1）患者、133例流感样疾病（ILI）患者和360例无症状健康接触者（AHC）。使用实时PCR对六个基因（TNF、LT、IL 1B、IL 6、CCL 1和IL 8）中的11个SNP进行基因分型;使用祖先基因型进行比较。基因型与27个临床严重程度变量相关。在Luminex 100上测量10种细胞因子（GM-CSF、TNF-α、IL-2、IL-1β、IL-6、IL-8、IFN-γ、IL-10、IL-5和IL-4）。IL 6 rs 1818879（GA）杂合基因型与严重甲型H1N1流感病毒感染相关（比值比[OR] = 5.94，95%置信区间[CI] 3.05-11.56），两个IL 1B SNP rs 16944 AG和rs3136558 TC与感染风险降低相关（OR = 0.52和OR = 0.51）。确定遗传易感性（PA/H1N1 vs. AHC）：LTA rs 909253 TC杂合基因型赋予更大的风险（OR = 1.9），并观察到与IL 1B rs3136558 CC基因型（OR = 1.89）的类似关联。此外，还将重症患者与中度患者进行了比较。TNF-238 GA基因型与疾病严重程度风险增加相关（OR = 16.06，p = 0.007）。与ILI相比，重度甲型H1N1流感病毒感染患者血清IL-5（p <0.001）和IL-6（p = 0.007）水平升高。 TNF基因与疾病严重程度相关，而IL 1B和IL 6 SNP与甲型H1N1流感病毒感染相关。
Hypercytokinemia is the main immunopathological mechanism contributing to a more severe clinical course in influenza A (H1N1) virus infections. Most patients infected with the influenza A (H1N1) pdm09 virus had increased systemic levels of pro-inflammatory cytokines; including interleukin IL-6, IL-8, and tumor necrosis factor-alpha (TNF-α). We propose that single-nucleotide polymorphisms (SNPs) in the promoter regions of pro-inflammatory genes are associated with the severity of influenza A (H1N1) pdm09 virus infection. 145 patients with influenza A (H1N1) (pA/H1N1), 133 patients with influenza-like illness (ILI), and 360 asymptomatic healthy contacts (AHCs) were included. Eleven SNPs were genotyped in six genes (TNF, LT, IL1B, IL6, CCL1, and IL8) using real-time PCR; the ancestral genotype was used for comparison. Genotypes were correlated with 27 clinical severity variables. Ten cytokines (GM-CSF, TNF-α, IL-2, IL-1β, IL-6, IL-8, IFN-γ, IL-10, IL-5, and IL-4) were measured on a Luminex 100. The IL6 rs1818879 (GA) heterozygous genotype was associated with severe influenza A (H1N1) virus infection (odds ratio [OR] = 5.94, 95% confidence interval [CI] 3.05–11.56), and two IL1B SNPs, rs16944 AG and rs3136558 TC, were associated with a decreased risk of infection (OR = 0.52 and OR = 0.51, respectively). Genetic susceptibility was determined (pA/H1N1 vs. AHC): the LTA rs909253 TC heterozygous genotype conferred greater risk (OR = 1.9), and a similar association was observed with the IL1B rs3136558 CC genotype (OR = 1.89). Additionally, severely ill patients were compared with moderately ill patients. The TNF-238 GA genotype was associated with an increased risk of disease severity (OR = 16.06, p = 0.007). Compared with ILIs, patients with severe pA/H1N1 infections exhibited increased serum IL-5 (p <0.001) and IL-6 (p = 0.007) levels. The TNF gene was associated with disease severity, whereas IL1B and IL6 SNPs were associated with influenza A (H1N1) virus infection.