Interleukin -1 receptor-associated kinases (IRAKs) are a family of molecules, which play an important role in the regulation of natural immune system, as mediators of TLR/IL1R superfamily signaling. There are four IRAK genes found in the human genome (IRAK1, IRAK2, IRAK3 or IRAKM, and IRAK4). All of them have the similar domain structures, including a praline/serine/threonine-rich (PEST) kinase domain (KD) and an conserved N-terminal death domain (DD), which is important for dimerization and interaction with MyD88. Except for IRAK4, the other three mebers in IRAK famil all contain a C-terminal domain, which is required for TRAF6 binding and activation [26].

The relationship between IRAK1, IRAK3 and outcomes of major trauma patients were investigated (Table 2). One MODS -related polymorphism in IRAK1 gene was found out. IRAK1 encodes the interleukin-1 receptor-associated kinase 1, a serine/threonine kinases belongs to the Toll/IL-1 receptor (TIR) signaling family and a key regulator of NF-kappa B pathway. Sperry et al. [27] studied a cohort of 321 patients with a median ISS of 16 for the 1595T/C substitution (rs1059703) in exon 12 of IRAK1 which results in a non-synonymous mutation (p.L532S). They found patients carrying this polymorphism have an eightfold and 11-fold risk of MOF and death, respectively. Specially,this phenomenon is most prominent in males, whereas females carrying heterozygous are more likely to have a worse outcome. Meyer et al. [28] genotyped 25 candidate genes for 474 critically ill trauma patients with acute lung injury (ALI) in a prospective cohort study using the IBC chip. IRAK3 was found to be associated with ALI in patients from African descent but not in European ancestry trauma subjects.

Nuclear factor-κB (NF-κB) family contains five members, p50, p52, p65 (RelA), RelB and c-Rel. The complexity of NF-κB can be activated by either canonical or non-canonical pathways and plays an essential role in inflammation [29]. More and more evidence indicates that polymorphisms in the NF-κB family genes may affect the magnitude of proinflammatory response. Our research investigated the relationship between Tag SNPs selected from NF-κB family genes, including NFKB1, NFKB2, RELA, RELB and REL, and outcomes in a Chinese trauma cohort [30]. One SNP, rs842647 in REL gene, was found to be associated with lower sepsis morbidity and MOD scores. Patients carrying rs842647 A allele had lower plasma TNF-α levels.

In the course of sepsis, there is a comprehensive and systemic activation of immune responses. The markedly imbalanced cytokine response accompanying with sepsis forms a kind of ‘cytokine storm’, which converts normally beneficial responses of anti-inflammation into excessive, and finally causes damage to normal tissues. Various cytokines released from immune cells work as effectors and play an important role in the inflammatory response to infection. Thus, a number of polymorphisms in cytokine genes have been investigated using association studies (Table 3).