A clinical trial such as the one presented here can only yield associations of genetic selleck chemicals variations and the observed findings. For proving a causal link an animal model is needed with transgenic mice carrying either the human gene(s) of interest or its mutated variant(s). Our interpretation that the decreased ability to induce cytokines is a cause of an altered course of infectious diseases at this point is pure speculation.An interesting observation was the lack of differences of cytokine stimulations between patients carrying WT alleles and those carrying SNP alleles on day 7. The only probable explanation may come from the known changes of responsiveness of monocytes to ex vivo stimulation during the course of sepsis, which could depend on other factors such as secondary infections or the anti-inflammatory response.

We were not able to associate these mechanisms to clinical or cytokine data in our patients.In addition, recently generated data in TLR2 and TLR4 knock-out mice give strong evidence that the TLR-pathway plays a pivotal role in the stress-hormone axis after LPS-challenge as well [38]. So the course of infections in patients with the described SNPs is potentially linked to an altered stress response and may therefore influence severity of sepsis. However, data on the influence of TIRAP/Mal variants on the stress-hormone axis are lacking to date.The TLR4 SNP Asp299Gly/Thr399Ile studied here was found to cosegregate in 98% of the individuals in these European populations, confirming previous data in the literature [11].

In the present study the 299/399 TLR4 haplotype, when present without TIRAP/Mal mutations, was only weakly associated with susceptibility and course of disease in both groups. Our results also failed to show an association of the TLR4 299/399 haplotype with the incidence or type of microorganisms in surgical infections. Small previous studies on the TLR4 Asp299Gly/Thr399Ile haplotype showed higher disease susceptibility and higher incidence of infections caused by Gram-negative microorganisms [39], but this was not supported by subsequent studies [40,41]. The normal responses of individuals bearing this allele following LPS challenge in vitro [42-44] and in vivo [45] support this lack of association.

Whether the presence of TLR4 haplotypes containing only the Asp299Gly or Thr399Ile SNPs is associated with Gram-negative infection susceptibility cannot be concluded from our study, due Anacetrapib to the small number of patients carrying these haplotypes. However, in individuals bearing the Asp299Gly TLR4 haplotype alone an altered cytokine response to LPS and increased susceptibility for sepsis has been reported [15,46].As mentioned above, both TLR4 and TIRAP/Mal genetic variants differ significantly in their frequency according to geographic locations [14,15].