TNF, IL6, and IL1B Polymorphisms Are Associated with Severe Influenza A (H1N1) Virus Infection in the Mexican Population

Abstract

BackgroundHypercytokinemia 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.Methods145 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.ResultsThe 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.ConclusionsThe TNF gene was associated with disease severity, whereas IL1B and IL6 SNPs were associated with influenza A (H1N1) virus infection.

Hero turned villain: NLRP3 inflammasome-induced inflammation during influenza A virus infection

“…High concentrations of IL-1b and IL-18 in the lung and sera are associated with severe and fatal IAV infections in humans [90][91][92]. A number of single-nucleotide polymorphisms in the human Il1b gene have been shown to be associated with increased susceptibility to 2009 H1N1 pandemic IAV infection [93][94][95], suggesting that IL-1b may play a protective role during IAV infections in humans. Collectively, NLRP3-dependent production of IL-1b and IL-18 could have downstream consequences with regard to IAV-induced inflammation and disease.…”

IL‐1B rs16944 polymorphism is related to septic shock and death

“…Conversely, AA genotype has showed a reduced Aspergillus‐induced IL‐1β production and TNF α secretion by PBMCs . However, there are some discrepancies as some studies did not find any genetic association of rs16944 with IL‐1β levels , infection or sepsis . In non‐European population, the rs16944 AA genotype has been related to lower risk of infection , and the GG genotype was associated with production of IL‐1β and higher risk of infection .…”

Retrospective review of factors associated with severe hospitalised community‐acquired influenza in a tertiary paediatric hospital in South Australia

“…Another issue, not explored in this study, is the impact of host genetic factors on influenza disease susceptibility and/or severity. Genetic polymorphisms in certain immune effector proteins such as the interferon‐induced transmembrane protein‐3 (IFITM3) and the tumour necrosis factor‐alpha (TNF‐α) and interleukin genes have been reported in the literature as being linked to poorer outcomes with influenza. An IFITM3 genetic variant, rs12252‐C, which is more prevalent among East Asian populations, has been shown to increase influenza susceptibility and disease severity .…”