Toll-Like Receptor 4 Gene ( TLR4 ), but Not TLR2 , Polymorphisms Modify the Risk of Tonsillar Disease Due to Streptococcus pyogenes and Haemophilus influenzae

Abstract

Tonsillar disease (recurrent tonsillitis and/or tonsillar hypertrophy) is one of the most common human disorders, with Streptococcus pyogenes (group A beta-hemolytic streptococcus [GAS]) and Haemophilus influenzae representing the most common pathogens. Until now, no study has investigated why some individuals are more susceptible to tonsillar infections caused by specific bacteria than others. The aim of this study was to uncover possible associations between common Toll-like receptor gene (TLR) polymorphisms and tonsillar disease. The TLR2-R753Q, TLR4-D299G, and TLR4-T399I polymorphisms were determined in a cohort of 327 patients subjected to tonsillectomy due to recurrent tonsillitis (n ‫؍‬ 245) and tonsillar hypertrophy (n ‫؍‬ 82) and 245 healthy bone marrow donors. Associations of the aforementioned polymorphisms with the isolated bacterial strains after tonsillectomy were also investigated. Interestingly, carriers of the TLR4 polymorphisms displayed an approximately 3-fold increased risk for GAS infections (for TLR4-D299G, odds ratio [OR] ‫؍‬ 2.81, 95% confidence interval [CI] ‫؍‬ 1.16 to 6.79, P ‫؍‬ 0.038; for TLR4-T399I, OR ‫؍‬ 3.01, 95% CI ‫؍‬ 1.29 to 7.02, P ‫؍‬ 0.023), and this association was more profound in patients with recurrent tonsillitis. On the contrary, the presence of the TLR4-T399I polymorphism was associated with a 2-fold decreased risk of Haemophilus influenzae carriage (OR ‫؍‬ 0.38, 95% CI ‫؍‬ 0.15 to 0.96, P ‫؍‬ 0.038). In the end, no significant differences were observed, considering the genotype and allele frequencies of the above-mentioned polymorphisms, between patients and controls. Our findings indicate that, regarding tonsillar infections, TLR4 polymorphisms predispose individuals to GAS infection, while they are protective against Haemophilus influenzae infection. This result further elucidates the role that host immune genetic variations might play in the susceptibility to common infections and tonsillar disease.

Frequency of TLR4 (1063A/G and 1363C/T) polymorphisms in healthy and HIV-infected Omani individuals and their relationship to viral load and T cell count

“…The frequencies of the TLR4 SNPs in Omani HIV-infected and control individuals enrolled in this study were similar to those found in Spanish HIV-infected and control individuals (Soriano-Sarabia et al, 2008). Moreover, the frequencies in the healthy population were similar to those in patients with tonsillar disease and infected with Streptococcus pyogenes (Liadaki et al, 2011). The significant difference in the frequency of TLR4 1063GG genotype between the HIV-infected patients and the control group might be due to differences in the ethnic background of the enrolled individuals in both groups although they are all Omanis.…”

Genetic polymorphisms of innate and adaptive immunity as predictors of outcome in critically ill patients

“…Moreover, a protective effect TLR4 SNPs against infections was also reported by other non-ICU studies (Hawn et al 2009;Liadaki et al 2011;Yuan et al 2008). The reason why the impact of TLR4 polymorphisms in susceptibility to sepsis differs in medical and surgical patients is not obvious.…”

“…As mentioned above, both TLR4 SNPs are usually detected in a co-segregated state (Arbour et al 2000;Ferwerda et al 2008;Liadaki et al 2011;Speletas et al 2009); the impact of this linkage has not been fully explored. Carriers of both TLR4 SNPs may appear in four haplotypes, namely wt/wt, D299G/wt, T399I/wt and D299G/T399I.…”

“…Genomic DNA was initially extracted using the QIAamp DNA Blood Mini Kit (Qiagen, Crawley, UK), according to manufacturer's instructions. The detection of the genetic polymorphisms rs4986790 (TLR4-D299G), rs4986791 (TLR4-T399I), rs9332736 (C2-c.841 849+19del28), and rs34557412 (TACI-C104R), was performed as previously described in detail (Johnson et al 1992;Liadaki et al 2011;Speletas et al 2011).…”

The common genetic variants of toll-like receptor and susceptibilityto adenoid hypertrophy: a hospital-based cohort study

“…TLR4 missense mutations might act in concert with other genetic changes to influence the complex immunologic response; they may also be modifying factors for AH and other phenotypes, and particularly for allergies and asthma (4). Recently it was shown that TLR4 mutations are linked to an increased risk of recurrent tonsillitis and/or tonsillar hypertrophy (31). The adenoids are similar to tonsils, and they are important components of the lymphoid tissue situated in the upper airways, known as Waldeyer's ring (1).…”