title: TNF, IL6, and IL1B Polymorphisms Are Associated with Severe Influenza A (H1N1) Virus Infection in the Mexican Population.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  The TNF gene was associated with disease severity, whereas IL1B and IL6 SNPs were associated with influenza A (H1N1) virus infection.
authors.affiliation: Coordination of Health Research, Mexican Institute of Social Security (IMSS), Av. Cuauhtémoc 330, 06720, Mexico, D. F., México.|Graduate Program in Biological Sciences, National Autonomous University of Mexico (UNAM), México, D. F., 04360, México.|HLA Laboratory, National Institute of Respiratory Diseases, Ismael Cosio Villegas, México, D. F., 14080, México.
authors.forename: Román Alejandro
authors.initials: RA
authors.lastname: García-Ramírez
authors.affiliation: Research Department on Smoking and COPD, National Institute of Respiratory Diseases, Ismael Cosío Villegas. Mexico, D. F., 14080, México.
authors.forename: Alejandra
authors.initials: A
authors.lastname: Ramírez-Venegas
authors.affiliation: Research Department on Smoking and COPD, National Institute of Respiratory Diseases, Ismael Cosío Villegas. Mexico, D. F., 14080, México.
authors.forename: Roger
authors.initials: R
authors.lastname: Quintana-Carrillo
authors.affiliation: HLA Laboratory, National Institute of Respiratory Diseases, Ismael Cosio Villegas, México, D. F., 14080, México.
authors.forename: Ángel Eduardo
authors.initials: ÁE
authors.lastname: Camarena
authors.affiliation: HLA Laboratory, National Institute of Respiratory Diseases, Ismael Cosio Villegas, México, D. F., 14080, México.
authors.forename: Ramcés
authors.initials: R
authors.lastname: Falfán-Valencia
authors.affiliation: Coordination of Health Research, Mexican Institute of Social Security (IMSS), Av. Cuauhtémoc 330, 06720, Mexico, D. F., México.
authors.forename: Juan Manuel
authors.initials: JM
authors.lastname: Mejía-Aranguré
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000302:isolation & purification*; D007251:Influenza, Human / Q000235:genetics* / Q000821:virology*; D053583:Interleukin-1beta / Q000235:genetics*; D015850:Interleukin-6 / Q000235:genetics*; D008297:Male; D008800:Mexico / Q000453:epidemiology; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
chemical_list: C508585:IL1B protein, human; D053583:Interleukin-1beta; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha