The Role of TLR4 896 A>G and 1196 C>T in Susceptibility to Infections: A Review and Meta-Analysis of Genetic Association Studies

Background: Toll-like receptor 4 plays a role in pathogen recognition, and common polymorphisms may alter host susceptibility to infectious diseases. Purpose: To review the association of two common polymorphisms (TLR4 896A>G and TLR4 1196C>T) with infectious diseases. Data Sources: We searched PubMed and EMBASE up to March 2013 for pertinent literature in English, and complemented search with references lists of eligible studies. Study Selection: We included all studies that: reported an infectious outcome; had a case-control design and reported the TLR4 896A>G and/or TLR4 1196C>T genotype frequencies; 59 studies fulfilled these criteria and were analyzed. Data Extraction: Two authors independently extracted study data. Data Synthesis: The generalized odds ratio metric (ORG) was used to quantify the impact of TLR4 variants on disease susceptibility. A meta-analysis was undertaken for outcomes reported in >1 study. Eleven of 37 distinct outcomes were significant. TLR4 896 A>G increased risk for all parasitic infections (ORG 1.59; 95% CI 1.05-2.42), malaria (1.31; 95% CI 1.04-1.66), brucellosis (2.66; 95% CI 1.66-4.27), cutaneous leishmaniasis (7.22; 95% CI 1.91-27.29), neurocysticercosis (4.39; 95% CI 2.53-7.61), Streptococcus pyogenes tonsillar disease (2.93; 95% CI 1.24-6.93), typhoid fever (2.51; 95% CI 1.18-5.34) and adult urinary tract infections (1.98; 95% CI 1.04-3.98), but was protective for leprosy (0.36; 95% CI 0.22-0.60). TLR4 1196 C>T effects were similar to TLR4 896 A>G for brucellosis, cutaneous leishmaniasis, leprosy, typhoid fever and S. pyogenes tonsillar disease, and was protective for bacterial vaginosis in pregnancy (0.55; 95% CI 0.31-0.98) and Haemophilus influenzae tonsillar disease (0.42; 95% CI 0.17-1.00). The majority of significant associations were among predominantly Asian populations and significant associations were rare among European populations. Conclusions: Depending on the type of infection and population, TLR4 polymorphisms are associated with increased, decreased or no difference in infectious disease. This may be due to differential functional expression of TLR4, the co-segregation of TLR4 variants or a favorable inflammatory response.