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

Abstract

Introduction: Interleukin 17A (IL17A) plays a key role in host defense against microbial infection including Gram-positive bacteria. Genetic factors contribute to the host defense, but the role of IL17A single nucleotide polymorphisms (SNPs) has not yet been investigated in severe sepsis. Therefore, we hypothesized that SNPs in the IL17A gene alter susceptibility to infection and clinical outcome of severe sepsis.

Methods: 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.

Results: 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).

Conclusions: IL17A genetic variation is associated with altered susceptibility to Gram-positive infection and 28-day mortality of severe sepsis.

Figure 1

Frequency of patients who had Gram-positive or Gram-negative bacterial culture-positive by IL17A rs1974226 genotype in two cohorts of severe sepsis. IL17A rs1974226 GG genotype patients had an increased culture-positive rate of Gram-positive bacteria compared to the AA/AG genotype patients and a decreased rate of Gram-negative bacteria in two cohorts (AA/AG versus GG, SPH, Gram-positive P = 0.0036, Gram-negative P = 0.0086; VASST, Gram-positive P = 0.011, Gram-negative P = 0.13). SPH, St Paul's Hospital; VASST, Vasopressin and Septic Shock Trial. P values were calculated using chi-square test. *P < 0.05

Figure 2

Frequency of Gram-positive bacteria infection by site. Patients who had the GG genotype of IL17A rs1974226 SNP had significantly increased Gram-positive infection compared to AA/AG genotype in the lung, and non-significant trends in the same direction were observed in other sites (AA/AG versus GG, SPH+VASST, lung, P = 0.017; blood, P = 0.53; abdomen, P = 0.91; skin and soft tissue [SST], P = 0.22; genitourinary system [GU], P = 0.25). SPH, St Paul's Hospital; VASST, Vasopressin and Septic Shock Trial. P values were calculated using a logistic regression controlling for the cohort. *P < 0.05

Figure 3

Survival curves over 28 days by IL17A rs1974226 genotype in two cohorts of septic shock. Patients with IL17A rs1974226 GG genotype had increased mortality in the SPH and VASST cohort of septic shock compared to the AG or AA genotype patients (SPH P = 0.029, VASST, P = 0.010). SPH, St Paul's Hospital; VASST, Vasopressin and Septic Shock Trial. P values were calculated using a log-rank test for trend.