Pandemic influenza A/H1N1 virus infection and TNF, LTA, IL1B, IL6, IL8, and CCLpolymorphisms in Mexican population: a case–control study

Abstract

BackgroundSome patients have a greater response to viral infection than do others having a similar level of viral replication. Hypercytokinemia is the principal immunopathological mechanism that contributes to a severer clinical course in cases of influenza A/H1N1. The benefit produced, or damage caused, by these cytokines in severe disease is not known. The genes that code for these molecules are polymorphic and certain alleles have been associated with susceptibility to various diseases. The objective of the present study was to determine whether there was an association between polymorphisms of TNF, LTA, IL1B, IL6, IL8, and CCL1 and the infection and severity of the illness caused by the pandemic A/H1N1 in Mexico in 2009.MethodsCase–control study. The cases were patients confirmed with real time PCR with infection by the A/H1N1 pandemic virus. The controls were patients with infection like to influenza and non-familial healthy contacts of the patients with influenza. Medical history and outcome of the disease was registered. The DNA samples were genotyped for polymorphisms TNF rs361525, rs1800629, and rs1800750; LTA rs909253; IL1B rs16944; IL6 rs1818879; IL8 rs4073; and CCL1 rs2282691. Odds ratio (OR) and the 95% confidence interval (95% CI) were calculated. The logistic regression model was adjusted by age and severity of the illness in cases.ResultsInfection with the pandemic A/H1N1 virus was associated with the following genotypes: TNF rs361525 AA, OR = 27.00; 95% CI = 3.07–1248.77); LTA rs909253 AG (OR = 4.33, 95% CI = 1.82–10.32); TNF rs1800750 AA (OR = 4.33, 95% CI = 1.48–12.64); additionally, LTA rs909253 AG showed a limited statistically significant association with mortality (p = 0.06, OR = 3.13). Carriers of the TNF rs1800629 GA genotype were associated with high levels of blood urea nitrogen (p = 0.05); those of the TNF rs1800750 AA genotype, with high levels of creatine phosphokinase (p=0.05). The IL1B rs16944 AA genotype was associated with an elevated number of leukocytes (p <0.001) and the IL8 rs4073 AA genotype, with a higher value for PaO2 mm Hg.ConclusionThe polymorphisms of genes involved in the inflammatory process contributed to the severity of the clinical behavior of infection by the pandemic influenza A/H1N1 virus.

Risk of Severe Influenza Infection: Hypercytokinemia Gene Polymorphisms and Related Plasma Proteome in Canadian Young Adults

“…In addition, the AT genotype at rs4073 in IL8 [16] and the AG at rs909253 in LTα, also known as TNF-β [16,26], were associated with the inflammatory response [13]. In the present study, the genotypes identified to play a role in IAV, were also rep- compared to those with "no-risk" genotype.…”

“…One-way analysis of variance test showed a significant difference between these risk genotypes groups in the average levels of some nutritional factors such as licated to have similar effects in another study among a Greek population [27]. Such polymorphisms in hypercytokinemia genes are associated with an increased potential to synthesize cytokines and chemokines and influence the nature and effectivness of the inflammatory immune response [13,27]. Overall, risk alleles of IL8 and TNF-β were associated with a 1.5 to 3-fold increased risk of IAV infection and with a 1.2 to 2.4 increased risk of death [16,28].…”

“…Risk alleles and the specific genotypes identified in polymorphic genes of Mexican Mestizos during the 2009 flu pandemic include the AG genotype at rs1800750 in TNF, AG genotype at rs16944 in IL1B and the AA genotype at rs2282691 in CCL1 [13]. In addition, the AT genotype at rs4073 in IL8 [16] and the AG at rs909253 in LTα, also known as TNF-β [16,26], were associated with the inflammatory response [13].…”

“…Previous studies have examined the proteomic profile associated with the response to IAV infection and the heritability of risk of severe disease in Mexican, Chinese, African and American Indigenous populations [13,[22][23][24][25]. However, studies comparing the association between variants in cytokine-coding genes and various proteome biomarkers of risk for severe infection are lacking in the general healthy population and in Canation and code for cytokine synthesis and proteomic biomarkers in a population of young Canadian adults.…”

“…Several variants in the genes encoding these cytokines, e.g., TNF (rs1800750 G/A), IL1B (rs16944 G/A), CCL (rs2282691 A/T) and IFITM3 (rs12252 T/C) have been associated with risk of severe clinical manifestations in IAV [13]. Furthermore, elevated levels of the resultant pro-inflammatory cytokines and chemokines were found in the plasma of patients with acute respiratory distress syndrome caused by IAV [14,15].…”