Toll-like Receptor 1 Polymorphisms Affect Innate Immune Responses and Outcomes in Sepsis

Abstract

Rationale: Polymorphisms affecting Toll-like receptor (TLR)-mediated responses could predispose to excessive inflammation during an infection and contribute to an increased risk for poor outcomes in patients with sepsis. Objectives: To identify hypermorphic polymorphisms causing elevated TLR-mediated innate immune cytokine and chemokine responses and to test whether these polymorphisms are associated with increased susceptibility to death, organ dysfunction, and infections in patients with sepsis. Methods: We screened single-nucleotide polymorphisms (SNPs) in 43 TLR-related genes to identify variants affecting TLR-mediated inflammatory responses in blood from healthy volunteers ex vivo. The SNP associated most strongly with hypermorphic responses was tested for associations with death, organ dysfunction, and type of infection in two studies: a nested case-control study in a cohort of intensive care unit patients with sepsis, and a case-control study using patients with sepsis, patients with sepsis-related acute lung injury, and healthy control subjects. Measurements and Main Results: The SNP demonstrating the most hypermorphic effect was the G allele of TLR1 27202A/G (rs5743551), which associated with elevated TLR1-mediated cytokine production (P , 2 3 10 220 ). TLR1 27202G marked a coding SNP that causes higher TLR1-induced NF-kB activation and higher cell surface TLR1 expression. In the cohort of patients with sepsis TLR1 27202G predicted worse organ dysfunction and death (odds ratio, 1.82; 95% confidence interval, 1.07-3.09). In the case-control study TLR1 27202G was associated with sepsis-related acute lung injury (odds ratio, 3.40; 95% confidence interval, 1.59-7.27). TLR1 27202G also associated with a higher prevalence of gram-positive cultures in both clinical studies. Conclusions: Hypermorphic genetic variation in TLR1 is associated with increased susceptibility to organ dysfunction, death, and grampositive infection in sepsis.

Role of type 2 deiodinase in response to acute lung injury (ALI) in mice

“…7). NF-κB, an important mediator of immune and inflammatory responses, has been strongly implicated in ALI (46)(47)(48)(49)(50)(51). Evidence supports the notion that NF-κB induces transcription of human and rat D2 gene expression, and, indeed, a potent NF-κB-binding site has been demonstrated in the human D2 gene (52,53).…”

Haplotype structure and positive selection at TLR1

“…52 The simplifying explanation is that all of these polymorphisms are in strong LD with an uncharacterized regulatory variant. However, reduced TLR1 function decreases the risk of sepsis, 19,20 leprosy, 21,22,25,26,28 tuberculosis, 13,27 and other diseases. 18,31,50 Thus, variants that disrupt the function of TLR1 may be beneficial to the survival of the organism.…”

“…14,21,25,26 Reduced TLR1 activity has also been shown to result in a reduced risk of sepsis. 19,20 TLR1-derived alleles have also been linked to a variety of other diseases including placental malaria, IgA nephropathy, and invasive aspergillosis. 18,31,50 Positive selection and distribution at rs5743618 This study represents the first global typing in a large panel of welldefined populations of rs5743618, c.2079T4G (p. (Ile602Ser)), a missense polymorphism in TLR1 that inhibits the surface trafficking of the TLR1-TLR2 dimer.…”

“…10,[12][13][14][15][16][17][18] Activation of the TLR1-TLR2 heterodimer is not always beneficial to the organism, as multiple studies have found that derived alleles at some SNPs inhibit TLR1 activity and reduce the risk of sepsis, leprosy, prostate cancer, pelvic inflammatory disease, and tuberculosis. [19][20][21][22][23][24][25][26][27] The foremost of these is rs5743618, whose derived allele c.2079T4G (p.(Ile602Ser)) reduces surface trafficking of the TLR1-TLR2 heterodimer, 28 resulting in a reduced response to heterodimer antagonists and, in turn, reduced activation of the NFkB pathway. 29 This phenotype is especially evident in the homozygous derived state.…”

Entendendo o conceito PIRO: da teoria à prática clínica - Parte 1

“…Recently, polymorphisms in the Toll-like receptor 1 gene were reported to be associated with increased susceptibility to organ dysfunction, death, and Gram-positive infection in sepsis. (21) Racial differences in susceptibility to and outcomes from sepsis are well described, (22) and older patients are known to be at increased risk of developing sepsis with poorer outcomes. (23) Gender differences are reported in several studies and women are less likely to develop sepsis than men.…”