IL17A genetic variation is associated with altered susceptibility to Gram-positive infection and mortality of severe sepsis

We tested for the association of IL17A SNPs with susceptibility to infection and clinical outcome of severe sepsis using two cohorts of European ancestry (derivation cohort, St Paul's Hospital (SPH), n = 679; validation cohort, Vasopressin and Septic Shock Trial (VASST), n = 517). The primary outcome variable was susceptibility to Gram-positive bacterial infection. The secondary outcome variable was 28-day mortality.Of four tested IL17A tag SNPs (rs4711998, rs8193036, rs2275913, rs1974226), rs1974226 SNP was associated with altered susceptibility to Gram-positive infection in the derivation SPH cohort (corrected P = 0.014). Patients having the rs1974226 GG genotype were more susceptible to Gram-positive infection, compared to AG/AA genotype in the two cohorts of severe sepsis (SPH, P = 0.0036, odds ratio (OR) 2.19, 95% confidence interval (CI) 1.28-3.72; VASST, P = 0.011, OR 1.95, 95%CI 1.16-3.27) and in the subgroup having lung infection (P = 0.017, OR 1.90, 95%CI 1.12-3.21). Furthermore, the IL17A rs1974226 G allele was associated with increased 28-day mortality in two cohorts (SPH, adjusted OR 1.44, 95%CI 1.04-2.02, P = 0.029; VASST, adjusted OR 1.67, 95%CI 1.17-2.40, P = 0.0052).IL17A genetic variation is associated with altered susceptibility to Gram-positive infection and 28-day mortality of severe sepsis.Interleukin 17A (IL17A) plays a key role in host defense against infection and development of inflammatory diseases [1-5]. IL17A production is increased as an innate response to bacterial infection in human immune cells [6,7], and elevated serum IL17A levels are observed in human [8] and animal models of sepsis [9,10]. In contrast, deficiency of the IL17 response impairs bacterial clearance, delays recovery from infection [1,11] and increases susceptibility to infection [12-15].Recently two autosomal mutations of IL17 pathway genes were identified in patients with chronic mucocutaneous candidiasis disease, which is characterized by recurrent or persistent muc