Association of Polymorphisms in IRAK1, IRAK4 and MyD88, and Severe Invasive Pneumococcal Disease

Background: Severe invasive pneumococcal disease (SIPD) has high morbidity and mortality, conditioned by pneumococcus and host factors, such as Toll-like receptors and their Toll-IL1R common signaling pathway. The objectives of this study are (1) to correlate single nucleotide polymorphisms (SNPs) involved in some Toll-IL1R signaling pathway proteins (IRAK1, IRAK4, IRAKM and MyD88) with SIPD by comparing patients versus healthy controls. (2) To determine whether these SNPs influence SIPD outcome. Methods: Case-control prospective observational study: 60 pediatric patients with IPD and systemic inflammatory response syndrome, and 120 healthy volunteers. Well-known immunodeficiencies were excluded. Independent variables: SNPs genotypes and alleles. Other variables: demographic, previous infections, and clinical, analytical and microbiological evolution data. Results: We have detected significant disequilibrium of SNPs frequencies between SIPD patients and controls in rs1059701-CC (IRAK1; P = 0.0067), rs4251513-CC (IRAK4; P < 0.0001), rs1461567-T (IRAK4; P = 0.0158) and rs6853-AA (MyD88; P < 0.0001). SIPD patients showed significant association between: leukocytosis > 15,000/mmc and rs1059702-nonTT (IRAK1; P = 0.0460), pleuropneumonia and rs1624395-G (IRAKM; P = 0.0147), and rs1370128-C (IRAKM; P = 0.0055), sequelae, and rs4251513-nonGG (IRAK4; P = 0.0055), death and rs6853-nonAA (P = 0.0054) and rs6853-G (P = 0.0065; MyD88). Conclusions: This is the first study to show an association between SNPs in IRAK1, IRAK4 and MyD88, and the presence of SIPD. Our data showed that some SNPs may lead to a higher risk of developing SIPD while other are related with the outcome in SIPD patients. Following PIRO score (predisposition, insult, response, organ dysfunction), identifying SNPs predisposing to infectious diseases, such as SIPD might help stratify patients with severe infectious diseases and design specific treatments.