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

Abstract

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.

Polymorphisms in the myeloid differentiation primary response 88 pathway do not explain low expression levels in sudden infant death syndrome

“…None of the genetic variations included in this study appear to be associated with SIDS and are not likely to be (14,15) 3 0 -UTR NA rs41285117 Intron Met-Ile rs56253885 Intron Lys-Asn rs989298…”

“…A total of 17 single nucleotide variants (SNVs) were selected for analysis in the genes encoding MyD88 (8 SNVs), IRAK4 (4 SNVs) and TLR4 (5 SNVs) ( Table 2). Among the SNVs included in this study, 12 have been reported to have functional effect, either on the regulation of the expression level of the gene or on the functionality of the protein the gene is coding for ( Table 2) (8,9,(14)(15)(16)(17)(18)(19)(20)(21). The remaining five SNVs are expected to have a functional effect due to the resulting amino acid change.…”

Variation of 46 Innate Immune Genes Evaluated for their Contribution in Pneumococcal Meningitis Susceptibility and Outcome

“…With this study we were able to look at the signals of variations previously associated IPD and pneumococcal meningitis. Variations for CARD8 , IL-10 , IRAK4 , MAL , MYD88 , TLR2 and TLR4 genes have been reported in association studies and were included in our data (Carrasco-Colom et al, 2015, Ellis et al, 2015, Geldhoff et al, 2013, Khor et al, 2007, Schaaf et al, 2003, van Well et al, 2013, van Well et al, 2012, Yuan et al, 2008). None of the published variants reach significance within our analysis, even prior to correction for multiple testing (Table 4).…”

“…bVariations have been reported in Carrasco-Colom et al (2015), Ellis et al (2015), van Well et al (2012) and Yuan et al (2008).…”

Streptococcus pneumoniae and chronic endobronchial infections in childhood

“…It has been associated with disease progression in cystic fibrosis, while in adults with bronchiectasis, MBL serum deficiency (<200 ng/mL) was associated with increased exacerbations, hospital admissions, and radiographic severity . However, in adults with severe IPD or pneumococcal sepsis, conflicting results have been reported for associations between genetic variants of the MBL2 gene and TLR signaling pathway proteins . Conflicting results have also been reported for the association between MBL2 SNPs and susceptibility to IPD in children …”