Genetic Variation In Toll-like Receptors Research Articles

Genetic Variation in Toll-Like Receptors (TLRs) 2, 4, and 9 Influences HIV Disease Progression Toward Active TB and AIDS.

Toll-like receptors (TLRs) are identified as one of the key components of the innate immune system. The objective of this study was to explore the influence of genetic variability in these TLRs on human immunodeficiency virus (HIV) disease progression with and without tuberculosis (TB) co-infection. This prospective, cross-sectional, and longitudinal study included 373 HIV-positive patients without TB infection. This study aimed to examine the genetic variation in TLRs (TLR2, TLR4, and TLR9) between patients with HIV-1 infection and those who progressed to active TB during the two years of follow-up. During the two year follow-up of 373 positive patients, 98 patients progressed to active TB/AIDS (acquired immunodeficiency syndrome). When comparing 98 HIV patients who developed active TB/AIDS to 275 HIV patients who did not, it was discovered that the frequency of the A allele in TLR9 was considerably higher (p <0.001) in HIV patients progressed to active TB/AIDS. Ninety eight HIV individuals who advanced to active TB/AIDS showed a significantly higher frequency of the AA genotype in TLR9 than did in HIV patients who had no TB/AIDS (p <0.001). The increased association of the AA genotype of TLR9 in HIV patients who progressed to active TB during follow-up suggests that HIV-positive patients with the AA genotype of TLR9 have increased susceptibility towards TB during the disease progression.

Genetic variation in toll-like receptor 4 gene with primary antiphospholipid syndrome susceptibility: a cohort of Egyptian patients

BackgroundAs toll-like receptor 4 (TLR4) plays important roles in cellular immunity and TLR4 polymorphisms have been shown to be associated with susceptibility to a range of diseases, the present study aimed to investigate the association between TLR4 gene polymorphisms and the incidence of primary antiphospholipid syndrome (PAPS).MethodsTwo TLR4 single nucleotide polymorphisms (rs4986790 and rs4986791) were assessed in 110 subjects of Egyptian ethnicity, including 65 female patients with PAPS and 45 matched healthy controls, using polymerase chain reaction-restriction fragment length polymorphism. Results were verified using automated sequencing.ResultsThe homozygous wild-type (AA, aspartic acid) rs4986790 variant and (CC, threonine) rs4986791 variant were the predominant genotypes in the control and PAPS groups.ConclusionThe results of this preliminary study of TLR4 gene variants among patients with PAPS in an Egyptian population found no association between the rs4986790 and rs4986791 variants and susceptibility to PAPS.

Genetic variations of toll-like receptors: Impact on susceptibility, severity and prognosis of bacterial meningitis.

Bacterial meningitis (BM) is a serious infectious disease of the central nervous system，which is mainly caused by Streptococcus pneumoniae, Neisseria meningitidis, Haemophilus influenzae, Group B Streptococcus and Listeria monocytogenes. Throughout the world, BM has become one of the most lethal diseases that commonly occurs in children. Toll like receptors (TLRs) are one of the most important immune defense lines in infectious diseases, and play an essential role in host defense. Accumulating evidence shows that genetic variations in TLRs are associated with host responses in BM. This review aims to summarize the role of different TLRs and their genetic variations in the susceptibility, severity and prognosis of BM and discuss the identified risk factors for better treatment and improvement of the course and outcome of BM.

Toll-Like Receptors Gene Polymorphisms in Autoimmune Disease.

Toll-like receptors (TLRs) are important initiators of the immune response, both innate and acquired. Evidence suggests that gene polymorphisms within TLRs cause malfunctions of certain key TLR-related signaling pathways, which subsequently increases the risk of autoimmune diseases. We illustrate and discuss the current findings on the role of Toll-like receptor gene polymorphisms in numerous autoimmune diseases in this review, such as type 1 diabetes mellitus, Graves’ disease, rheumatoid arthritis, systemic lupus erythematosus and multiple sclerosis. The study of genetic variation in TLRs in different populations has shown a complex interaction between immunity and environmental factors. This interaction suggests that TLR polymorphisms affect the susceptibility to autoimmune diseases differently in various populations. The identification of Toll-like receptor gene polymorphisms can expand our understanding of the pathogenesis of autoimmune diseases, which will subsequently guide effective medical management and provide insight into prognosis and advanced treatments.

TLRs in Mycobacterial Pathogenesis: Black and White or Shades of Gray.

Toll-like receptors (TLRs) play critical role in the innate recognition of pathogens besides orchestrating innate and adaptive immune responses. These receptors exhibit exquisite specificity for different pathogens or their products and, through a complex network of signalling, generate appropriate immune responses. TLRs induce both pro- and anti-inflammatory signals depending on interactions with the adapter molecules thereby impacting the outcome of infection. Hence, TLR signalling ought to be stringently regulated to avoid harmful effects on the host. Mycobacteria express antigens which are sensed by TLRs leading to activation of various signalling molecules important for initiating the death of infected cells and containment of pathogens. Conversely, it also utilizes TLRs for immune evasion and persistence. Due to the enormous diversity in the repertoire of virulence traits expressed by mycobacteria, genetic variations in TLRs often impair the host's ability to respond to mycobacterial-stress, affecting health and disease manifestations. Thus, understanding TLR signalling is of great importance for insights into host-mycobacterial interactions and designing effective measures for controlling the spread and persistence of the bacterium.

Impact of Genetic Variation in TLR4 3'UTR on NSCLC Genetic Susceptibility.

Toll-like receptors (TLRs) are expressed not only in immune cells but also in a variety of tumor cells. Single-nucleotide polymorphisms (SNPs) located in the TLRs' promoter or the 3′ untranslated region may affect gene expression by affecting the activity of the promoter or regulating the binding of mRNA to miRNA. This study aimed to investigate the association of the SNPs in TLR genes with the susceptibility to NSCLC. This case-control study involved 700 lung cancer patients and 700 healthy controls. All individuals were genotyped for all selected SNPs in TLR genes using polymerase chain reaction (PCR) test-based restriction fragment length polymorphism (PCR-RFLP) and TaqMan SNP genotyping assay. The association of genetic variations in TLRs with the susceptibility to NSCLC was evaluated by unconditional logistic regression with OR (95% CI). After evaluating transcriptional factor or miRNA binding capability by bioinformatics methods, six TLRs were identified for further analysis. We did not find that TLR3 rs5743303, TLR4 rs1927914, TLR4 rs11536891, TLR5 rs1640816, and TLR7 rs3853839 were associated with NSCLC risk (P > 0.05). Our data showed that TLR4 rs7869402 C > T polymorphism reduced the risk of NSCLC with OR (95% CI) of 0.63 (0.45–0.89). When stratified by gender and age, the individuals carrying at least one rs7869402T allele significantly decreased the NSCLC risk among males (OR = 0.58, 95% CI = 0.38–0.87) and among youngsters (OR = 0.43, 95% CI = 0.27–0.69). Smoking stratification analysis showed that the rs7869402T allele-containing genotype reduced the risk of NSCLC with OR (95% CI) of 0.50 (0.29–0.87) among smokers but not among nonsmokers (P > 0.05). When the individuals were classed by the pathological type, we found that the rs7869402T-containing genotype was associated with the risk of adenocarcinoma (OR = 0.62, 95% CI = 0.41–0.92) but not with that of squamous cell carcinoma (OR = 0.71, 95% CI = 0.44–1.13) and other types (OR = 0.23, 95% CI = 0.03–1.70). Compared with the TLR4 Ars1927914-Crs7869402-Trs11536891 haplotype, the Grs1927914-Trs7869402-Trs11536891 haplotype was associated with a decreased risk for developing NSCLC with OR (95% CI) of 0.57 (0.41–0.80). These results indicated that the TLR4 rs7869402 variation affects the genetic susceptibility to NSCLC.

Polymorphisms of TLR9 gene are associated with a decreased risk of H. pylori infection in a Chinese population.

BackgroundA series of evidence suggests that genetic variation in toll-like receptor (TLR) 9 might influence the outcome of Helicobacter pylori (H. pylori) infection and play an important role in gastric carcinogenesis.MethodsWe conducted a case-control study to evaluate TLR9 polymorphisms on the risk of H. pylori infection and non-cardia gastric cancer (GC) in a Chinese population. We genotyped a tagging single-nucleotide polymorphism (SNP), rs164640, and a potentially functional SNP, rs187084, by TaqMan technique among 288 patients with non-cardia GC and 281 controls. Unconditional logistic regression (LR) was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for SNPs in association with H. pylori infection and non-cardia GC risk.ResultsOur results indicated that among normal controls, the minor allele homozygotes of both SNPs were significantly associated with a decreased risk of H. pylori infection when compared with their major allele homozygotes (for rs164640: OR =0.41, 95% CI, 0.18–0.93; for 187084: OR =0.38, 95% CI, 0.17–0.85). However, neither of the two SNPs demonstrated a significant association with non-cardia GC risk.ConclusionsOur results revealed that TLR9 polymorphisms might have effects on the risk of H. pylori infection, but they do not seem to contribute to the risk of non-cardia GC in our studied population.

Lesion size is associated with genetic polymorphisms in TLR1, TLR6, and TIRAP genes in patients with major abscesses and diabetic foot infections

Genetic variation in Toll-like receptors (TLRs) has previously been associated with susceptibility to complicated skin and skin structure infections (cSSSIs). The aim of this study was to investigate associations between the severity of cSSSIs, i.e., major abscesses and diabetic foot infections (DFIs), and a set of genetic polymorphisms in the Toll-like receptor pathway. A total of 121 patients with major abscesses and 132 with DFIs participating in a randomized clinical trial were genotyped for 13 nonsynonymous single-nucleotide polymorphisms (SNPs) in genes coding for TLRs and the signaling adaptor molecule TIRAP. Infection severity was defined by lesion size at clinical presentation for both types of infections. The PEDIS infection score was also used to define severity of DFIs. Linear regression models were used to study factors independently associated with severity. In patients with large abscesses, hetero- or homozygosity for the allelic variant TLR6 (P249S) was associated with significantly smaller lesions while homozygosity for the allelic variant TLR1 (R80T) was associated with significantly larger lesions. PRRs genes were not significantly associated with PEDIS. However, patients with DFI hetero- or homozygous for the allelic variant TLR1 (S248N) had significantly larger lesions. Polymorphisms in TLR1 and TLR6 influence the severity of cSSSIs as assessed by the lesion size of major abscesses and DFIs. ClinicalTrial.gov Identifier: NCT 00402727

Rapid detection of functional gene polymorphisms of TLRs and IL-17 using high resolution melting analysis

Genetic variations in toll-like receptors (TLRs) and IL-17A have been widely connected to different diseases. Associations between susceptibility and resistance to different infections and single nucleotide polymorphisms (SNPs) in TLR1 to TLR4 and IL17A have been found. In this study, we aimed to develop a rapid and high throughput method to detect functional SNPs of above mentioned proteins. The following most studied and clinically important SNPs: TLR1 (rs5743618), TLR2 (rs5743708), TLR3 (rs3775291), TLR4 (rs4986790) and IL17 (rs2275913) were tested. High resolution melting analysis (HRMA) based on real-time PCR combined with melting analysis of a saturating double stranded-DNA binding dye was developed and used. The obtained results were compared to the “standard” sequencing method. A total of 113 DNA samples with known genotypes were included. The HRMA method correctly identified all genotypes of these five SNPs. Co-efficient values of variation of intra- and inter-run precision repeatability ranged from 0.04 to 0.23%. The determined limit of qualification for testing samples was from 0.5 to 8.0 ng/μl. The identical genotyping result was obtained from the same sample with these concentrations. Compared to “standard” sequencing methods HRMA is cost-effective, rapid and simple. All the five SNPs can be analyzed separately or in combination.

Gene Polymorphism of Toll-Like Receptors and Lung Function at Five to Seven Years of Age after Infant Bronchiolitis.

AimToll-like receptors (TLR) play a crucial role in innate immunity, protecting the host from pathogens such as viruses. Genetic variations in TLRs have been associated with the severity of viral bronchiolitis in infancy and with the later occurrence of post-bronchiolitis asthma. The aim of the present study was to evaluate if there are any exploratory associations between TLR gene polymorphisms and lung function at 5 to 7 years of age in former bronchiolitis patients.MethodsWe performed impulse oscillometry (IOS) at the median age of 6.3 years for 103 children who had been hospitalized for bronchiolitis at less than six months of age. The main parameters evaluated were airway resistance and reactance at 5Hz in baseline and post-exercise measurements. Data on single nucleotide polymorphisms (SNP) of TLR1 rs5743618, TLR2 rs5743708, TLR6 rs5743810 and TLR10 rs4129009 (TLR2 subfamily) and TLR3 rs3775291, TLR4 rs4986790, TLR7 rs179008, TLR8 rs2407992 and TLR 9 rs187084 were available for analyses.ResultsThe TLR4 rs4986790 wild genotype A/A was associated with a greater Rrs5 response (0.72 vs. -0.42, p = 0.03) to exercise. In TLR6 rs5743810, the minor allele T was associated with greater Rrs5 response (0.80 vs. -0.03, p = 0.04) to exercise. In TLR7 rs179008, the major allele A was associated with baseline decline in dRrs/df (-1.03 vs 0.61, p = 0.01) and increased Fres (2.28 vs. 0.89, p = 0.01) in girls.ConclusionAmong the nine studied TLRs, only TLR7 rs179008 showed some exploratory associations with post-bronchiolitis lung function deficiency, and polymorphisms of TLR4 rs4986790, and TLR6 rs5743810 in particular, with airway reactivity. These findings call for further confirmatory studies.

Toll-Like Receptor Polymorphisms in Allogeneic Hematopoietic Cell Transplantation

To assess the impact of the genetic variation in toll-like receptors (TLRs) on outcome after allogeneic myeloablative conditioning hematopoietic cell transplantation (HCT), we investigated 29 single nucleotide polymorphisms across 10 TLRs in 816 patients and donors. Only donor genotype of TLR8 rs3764879, which is located on the X chromosome, was significantly associated with outcome at the Bonferroni-corrected level P ≤ .001. Male hemizygosity and female homozygosity for the minor allele were significantly associated with disease-free survival (hazard ratio [HR], 1.47 [95% confidence interval {CI}, 1.16 to 1.85]; P = .001). Further analysis stratified by donor sex due to confounding by sex was suggestive for associations with overall survival (male donor: HR, 1.41 [95% CI, 1.09 to 1.83], P = .010; female donor: HR, 2.78 [95% CI, 1.43 to 5.41], P = .003), disease-free survival (male donor: HR, 1.45 [95% CI, 1.12 to 1.87], P = .005; female donor: HR, 2.34 [95% CI, 1.18 to 4.65], P = .015), and treatment-related mortality (male donor: HR, 1.49 [95% CI, 1.09 to 2.04], P = .012; female donor: HR, 3.12 [95% CI, 1.44 to 6.74], P = .004). In conclusion, our findings suggest that the minor allele of TLR8 rs3764879 of the donor is associated with outcome after myeloablative conditioned allogeneic HCT.

Toll-like receptor 2 and 9 genetic polymorphisms and the susceptibility to B cell Non-Hodgkin Lymphoma in Egypt.

Non-Hodgkin lymphomas (NHL) entail considerable heterogeneity regarding their morphology, clinical course, etiological factors, or response to therapy. Increased incidence of NHL in immunocompromised individuals and after autoimmune diseases suggests that infections and immune dysregulation could play a role in the susceptibility to NHL. Accordingly, genetic variation in Toll-like receptor (TLR) genes might be considered as molecular risk factors for NHL. The aim of the current study was to investigate the possible association between genetic polymorphism of the TLRs genes and B cell NHL (B-NHL) risk in Egypt. The present study included 100 B-NHL patients and 100 healthy controls. Genotyping of TLR2-1350 T/C and TLR9-1237 T/C were done by polymerase chain reaction restricted fragment length polymorphism (PCR-RFLP) technique. The frequency of TLR2-1350 T/C polymorphic genotypes in B-NHL patients was 18 % for the heteromutant genotype (TC) and 1 % for the homomutant (CC). There was no statistical difference in the distribution of TLR2-1350 T/C genotypes between B-NHL patients and controls. As for TLR9-1237 T/C, the frequency of the heteromutant genotype (TC) was 58 % and the homomutant genotype (CC) was 1 % in B-NHL patients. Calculated risk estimation revealed that TLR9-1237 (TC) heterotype conferred almost fourfold increased risk of B-NHL (odds ratio (OR) = 3.93, 95 % confidence interval (CI) = 2.16-7.14), and the risk was higher in patients with indolent subtypes (OR = 6.64, 95 %CI = 2.31-9.08). In conclusion, the study revealed that TLR9-1237 T/C polymorphism can be considered as molecular risk factor for B-NHL among Egyptians.

Genetic variations in Toll-like receptors (TLRs 3/7/8) are associated with systemic lupus erythematosus in a Taiwanese population

Toll-like receptors (TLRs), as innate immunity sensors, play critical roles in immune responses. Six SNPs of TLR3, TLR7, and TLR8 were genotyped to determine their associations with systemic lupus erythematosus (SLE) and clinical manifestations of SLE. TLR7 SNP rs3853839 was independently associated with SLE susceptibility in females (G vs. C: p = 0.0051). TLR7 rs3853839-G (G vs. C: p = 0.0100) and TLR8 rs3764880-G (recessive model: p = 0.0173; additive model: p = 0.0161) were associated with pericardial effusion in females relative to healthy females. Anti-SSA positive cases were more likely to have the dominant TLR7 rs179010-T allele than normal controls (p = 0.0435). TLR3 rs3775296-T was associated with photosensitivity (p = 0.0020) and anemia (p = 0.0082). The “G-G” haplotype of TLR7 rs3853839 and TLR8 rs3764880 increased risk of SLE in females (age adjusted p = 0.0032). These findings suggest that TLR variations that modify gene expression affect risk for SLE susceptibility, clinical phenotype development, and production of autoantibodies.

Toll-like receptor 1 polymorphisms and associated outcomes in sepsis after traumatic injury: a candidate gene association study.

To determine whether single nucleotide polymorphisms (SNPs) in TLR1 are associated with mortality, specifically sepsis-associated mortality, in a traumatically injured population. Innate immune responses mediated by toll-like receptors (TLRs) induce early inflammatory responses to pathogen and damage-associated molecular patterns. Genetic variation in TLRs has been associated with susceptibility and outcomes in a number of infectious and noninfectious disease states. Patients admitted to the trauma intensive care unit at a level 1 trauma center serving 4 states were enrolled and followed for development of infection, sepsis, and death. Genomic DNA was genotyped and logistic regression analysis was performed to determine associations between TLR1 SNPs and mortality. We further examined for associations between TLR1 SNPs and mortality in subgroups on the basis of the presence of sepsis and the type of sepsis-associated organism. We enrolled 1961 patients. TLR1-7202G (rs5743551) was associated with increased mortality after traumatic injury and this association was primarily observed in the subset of patients who developed sepsis [adjusted odds ratio (OR): 3.16; 95% confidence interval (CI): 1.43-6.97, P=0.004]. This association persisted after further restriction to gram-positive sepsis. TLR1(742A/G(Asn248Ser)) (rs4833095), a coding SNP in LD with TLR1-7202G, was also associated with mortality in gram-positive sepsis (adjusted OR: 4.16; 95% CI: 1.22-14.19, P=0.023). Genetic variation in TLR1 is associated with increased mortality in patients with sepsis after traumatic injury and may represent a novel marker of risk for death in critically injured patients.

Genetic variation in toll‐like receptors and retinoic acid‐inducible gene I and outcome of hepatitis C virus infection: a candidate gene association study

We evaluated the effects of genetic variation in toll-like receptors (TLR), retinoic acid-inducible gene I (RIG-I) and their signalling pathways on spontaneous hepatitis C virus (HCV) resolution. We screened 95 single-nucleotide polymorphisms (SNPs) in 22 genes. SNPs significantly associated with resolution in the discovery cohort were genotyped in a validation cohort. Multivariate logistic regression adjusted for sex, hepatitis B surface antigen, HIV infection and the interleukin-28B rs12979860 SNP was performed in the combined cohort. Haplotype reconstruction and linkage disequilibrium analysis were performed. srs2233437, rs730775 and rs28362857 in Inhibitor of NF-kB ε (IkBε) and rs352140 in TLR9 were associated with spontaneous HCV resolution (P ≤ 0.05) in the discovery cohort (n = 308). In the validation cohort (n = 216), we replicated a significant association with HCV resolution for two SNPs in the IkBε, rs2233437 and rs730775. Presence of one or two of the variant allele in rs2233437 had more than twofold higher odds of resolution in adjusted logistic regression (adjusted odds ratio (aOR), 2.6; (95% CI, 1.4, 4.8) P = 0.002). We identified polymorphisms in the IkBε gene associated with spontaneous HCV resolution in two independent cohorts.

Genetic variation in TLR or NFkappaB pathways and the risk of breast cancer: a case-control study

BackgroundToll-like receptors (TLRs) and the transcription factor nuclear factor-κB (NFκB) are important in inflammation and cancer.MethodsWe examined the association between breast cancer risk and 233 tagging single nucleotide polymorphisms within 31 candidate genes involved in TLR or NFκB pathways. This population-based study in the Seattle area included 845 invasive breast cancer cases, diagnosed between 1997 and 1999, and 807 controls aged 65–79.ResultsVariant alleles in four genes were associated with breast cancer risk based on gene-level tests: MAP3K1, MMP9, TANK, and TLR9. These results were similar when the risk of breast cancer was examined within ductal and luminal subtypes. Subsequent exploratory pathway analyses using the GRASS algorithm found no associations for genes in TLR or NFκB pathways. Using publicly available CGEMS GWAS data to validate significant findings (N = 1,145 cases, N = 1,142 controls), rs889312 near MAP3K1 was confirmed to be associated with breast cancer risk (P = 0.04, OR 1.15, 95% CI 1.01–1.30). Further, two SNPs in TANK that were significant in our data, rs17705608 (P = 0.05) and rs7309 (P = 0.04), had similar risk estimates in the CGEMS data (rs17705608 OR 0.83, 95% CI 0.72–0.96; CGEMS OR 0.90, 95% CI 0.80–1.01 and rs7309 OR 0.83, 95% CI 0.73–0.95; CGEMS OR 0.91, 95% CI 0.81–1.02).ConclusionsOur findings suggest plausible associations between breast cancer risk and genes in TLR or NFκB pathways. Given the few suggestive associations in our data and the compelling biologic rationale for an association between genetic variation in these pathways and breast cancer risk, further studies are warranted that examine these effects.

Gene-Gene Interaction and Functional Impact of Polymorphisms on Innate Immune Genes in Controlling Plasmodium falciparum Blood Infection Level

Genetic variations in toll-like receptors and cytokine genes of the innate immune pathways have been implicated in controlling parasite growth and the pathogenesis of Plasmodium falciparum mediated malaria. We previously published genetic association of TLR4 non-synonymous and TNF-α promoter polymorphisms with P.falciparum blood infection level and here we extend the study considerably by (i) investigating genetic dependence of parasite-load on interleukin-12B polymorphisms, (ii) reconstructing gene-gene interactions among candidate TLRs and cytokine loci, (iii) exploring genetic and functional impact of epistatic models and (iv) providing mechanistic insights into functionality of disease-associated regulatory polymorphisms. Our data revealed that carriage of AA (P = 0.0001) and AC (P = 0.01) genotypes of IL12B 3′UTR polymorphism was associated with a significant increase of mean log-parasitemia relative to rare homozygous genotype CC. Presence of IL12B+1188 polymorphism in five of six multifactor models reinforced its strong genetic impact on malaria phenotype. Elevation of genetic risk in two-component models compared to the corresponding single locus and reduction of IL12B (2.2 fold) and lymphotoxin-α (1.7 fold) expressions in patients'peripheral-blood-mononuclear-cells under TLR4Thr399Ile risk genotype background substantiated the role of Multifactor Dimensionality Reduction derived models. Marked reduction of promoter activity of TNF-α risk haplotype (C-C-G-G) compared to wild-type haplotype (T-C-G-G) with (84%) and without (78%) LPS stimulation and the loss of binding of transcription factors detected in-silico supported a causal role of TNF-1031. Significantly lower expression of IL12B+1188 AA (5 fold) and AC (9 fold) genotypes compared to CC and under-representation (P = 0.0048) of allele A in transcripts of patients' PBMCs suggested an Allele-Expression-Imbalance. Allele (A+1188C) dependent differential stability (2 fold) of IL12B-transcripts upon actinomycin-D treatment and observed structural modulation (P = 0.013) of RNA-ensemble were the plausible explanations for AEI. In conclusion, our data provides functional support to the hypothesis that de-regulated receptor-cytokine axis of innate immune pathway influences blood infection level in P. falciparum malaria.

Genetic variation in Toll-like receptors and disease susceptibility

Toll-like receptors (TLRs) are key initiators of the innate immune response and promote adaptive immunity. Much has been learned about the role of TLRs in human immunity from studies linking TLR genetic variation with disease. First, monogenic disorders associated with complete deficiency in certain TLR pathways, such as MyD88-IRAK4 or TLR3-Unc93b-TRIF-TRAF3, have demonstrated the specific roles of these pathways in host defense against pyogenic bacteria and herpesviruses, respectively. Second, common polymorphisms in genes encoding several TLRs and associated genes have been associated with both infectious and autoimmune diseases. The study of genetic variation in TLRs in various populations combined with information on infection has demonstrated complex interaction between genetic variation in TLRs and environmental factors. This interaction explains the differences in the effect of TLR polymorphisms on susceptibility to infection and autoimmune disease in various populations.

Different Patterns of Toll-Like Receptor 2 Polymorphisms in Populations of Various Ethnic and Geographic Origins

Upon the invasion of the host by microorganisms, innate immunity is triggered through pathogen recognition by pattern recognition receptors (PRRs). Toll-like receptors (TLRs) are the best-studied class of PRRs, and they recognize specific pathogen-associated molecular patterns (PAMPs) from various microorganisms. A large number of studies have shown that genetic variation in TLRs may influence susceptibility to infections. We assessed the genetic variation of TLR2, which encodes one of the most important TLRs, in various populations around the globe and correlated it with changes in the function of the molecule. The three best-known nonsynonymous TLR2 polymorphisms (1892C>A, 2029C>T, and 2258G>A) were assessed in different populations from the main continental masses: Romanians, Vlax-Roma, Dutch (European populations), Han Chinese (East Asia), Dogon, Fulani (Africa), and Trio Indians (America). The 2029C>T polymorphism was absent in both European and non-European populations, with the exception of the Vlax-Roma, suggesting that this polymorphism most likely arose in Indo-Aryan people after migration into South Asia. The 1892C>A polymorphism that was found exclusively in European populations, but not in Asian, African, or American volunteers, probably occurred in proto-Indo-Europeans. Interestingly, 2258G>A was present only in Europeans, including Vlax-Roma, but at a very low frequency. The differential pattern of the TLR2 polymorphisms in various populations may explain some of the differences in susceptibility to infections between these populations.

Toll-like receptor 4 region genetic variants are associated with susceptibility to melioidosis

Melioidosis is a tropical infection caused by the Gram-negative soil saprophyte Burkholderia pseudomallei. Despite broad exposure of northeast Thais, disease develops in only a small proportion of individuals. Although diabetes is a risk factor, the mechanisms of host susceptibility to melioidosis are still poorly understood. We postulated that Toll-like receptors (TLRs) regulate host susceptibility to disease, and that genetic variation in TLRs is associated with melioidosis. We analyzed the frequency of eight previously described TLR pathway polymorphisms in 490 cases compared to 950 non-hospitalized controls or 458 hospitalized controls. Based on these results, we then analyzed the frequency of additional TLR4 or TLR6-1-10 region polymorphisms in cases and controls. We found that the TLR41196C>T variant was associated with protection from melioidosis when compared to non-hospitalized controls. The TLR1742A>G and TLR1−7202A>G variants were associated with melioidosis when compared to hospitalized controls. In further analyses, we found that two additional TLR4 region polymorphisms were associated with disease. In diabetics, three other TLR6-1-10 region polymorphisms were associated with disease when compared to hospitalized controls. We conclude that TLR genetic variants may modulate host susceptibility to melioidosis. Confirmation of these findings and further investigation of the mechanisms is required.