TLR1 polymorphisms in Europeans and spontaneous pregnancy loss (original) (raw)
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Single nucleotide polymorphisms of Toll-like receptors and susceptibility to infectious disease
The Lancet infectious diseases, 2005
Toll-like receptors (TLRs) play an important part in the innate immune recognition of invading microorganisms, initiating sufficient immune responses. Growing amounts of data suggest that the ability of certain individuals to respond properly to TLR ligands may be impaired by single nucleotide polymorphisms (SNPs) within TLR genes, resulting in an altered susceptibility to, or course of, infectious or inflammatory disease. Most studies have focused on two cosegregating SNPs-Asp299Gly and Thr399Ile-within the gene encoding TLR4, the receptor for bacterial lipopolysaccharide. These SNPs are present in approximately 10% of white individuals, and have been found to be positively correlated with several infectious diseases. However, these SNPs seem to protect from atherosclerosis and related diseases, which is reviewed in this article also. Meanwhile, SNPs of genes encoding other TLRs-eg, TLR2, which recognises a wide variety of microbial ligands-have been reported, and preliminary studies indicate an impact on susceptibility to infectious and inflammatory diseases as well. This review summarises and discusses the results obtained, and draws conclusions from these data.
Toll-like receptor polymorphisms and susceptibility to human disease
Clinical Science, 2008
Although several lines of evidence suggest that variation in human inflammation is genetically controlled, the genes which regulate these responses are largely unknown. TLRs (Toll-like receptors) mediate recognition of microbes, regulate activation of the innate immune response and influence the formation of adaptive immunity. Cellular and molecular studies over the past several years have identified a number of common TLR polymorphisms that modify the cellular immune response and production of cytokines in vitro. In addition, human genetic studies suggest that some of these polymorphisms are associated with susceptibility to a spectrum of diseases. In this review, we summarize studies of common TLR polymorphisms and how this work is beginning to illuminate the influence of human variation on inflammation and disease susceptibility.
Genes and Immunity, 2014
Innate and adaptive immune responses in humans have evolved as protective mechanisms against infectious microorganisms. Toll-like receptors (TLRs) have an important role in the recognition of invading microorganisms. TLRs are the first receptors to detect potential pathogens and to initiate the immune response, and they form the crucial link between the innate and adaptive immune responses. TLRs also have an important role in the pathophysiology of infectious and inflammatory diseases. Increasing data suggest that the ability of certain individuals to respond properly to TLR ligands may be impaired by single-nucleotide polymorphisms (SNPs) within TLR genes, resulting in an altered susceptibility to infectious or inflammatory disease that might contribute to the pathogenesis of complex diseases such as cancer. The associations between diseases and SNPs are in the early stage of discovery. Important clinical insights are emerging, and these polymorphisms provide new understanding of common diseases. This review summarizes and discusses the studies that shed light on the relevance of these polymorphisms in human infectious and inflammatory diseases and cancer.
Pregnancy Hypertension, 2019
Introduction: Altered maternal inflammatory responses may play a role in the development of hypertensive disorders of pregnancy like preeclampsia, its more severe early-onset form and intrauterine growth restriction. We evaluated the relation of common allelic variants of Toll-like receptor 4 (TLR4), known to impair the inflammatory response, with the susceptibility to early-onset preeclampsia in Central Greece. Methods: We compared the occurrence of TLR4 (Asp299Gly and Thr399Ile) alleles in heterozygous (A/G, C/T) and homozygous (G/G, T/T) states in 84 women with a history of early-onset preeclampsia and 94 age matched controls with a history of only uneventful pregnancies, by direct sequencing. Results: Heterozygous TLR4 allelic variants were more common in women with a history of early-onset preeclampsia than in controls (GA for Asp299Gly: 14.3% vs 6.4% (AA), p = 0.053 & CT for Thr399Ile: 16.7% vs. 6.4% (CC), p = 0.019) and a stronger association was obtained when homozygous allelic carriers were also included (GA/GG for Asp299Gly: 16.7% vs. 6.4% (AA), p = 0.03 & TC/TT for Thr399Ile: 19.0% vs. 6.4% (CC), p = 0.01). Discussion: We recorded association between common TLR4 gene variants and early-onset preeclampsia. Our findings support the involvement of maternal innate immune system in severe hypertensive disorders of pregnancy and point to the potential value of maternal TLR4 polymorphisms as predictors-risk factors of susceptibility to early-onset preeclampsia in Central Greece.
American Journal of Clinical and Experimental Medicine, 2016
In the absence of confirmed causes for around 50% of recurrent pregnancy loss (RPL) cases this study was conducted in order to investigate the association between single nucleotide polymorphism (SNP) in regulatory T-cell related STAT3 (rs4796793 C/G), FOXP3 (rs3761548 A/C), LIF (rs3753082 T/C), NKG7 (rs71358833 A/G) and CCR5 (rs34418657 G/T) genes and unexplained RPL in a group of Palestinian women residing in Gaza strip. A retrospective case-control study was carried out during the period (August 2015 to March 2016). A total of 200 females, 100 RPL patients and 100 control women without previous history of RPL, aged 20-35 years were included in the study. STAT3 (rs4796793 C/G), FOXP3 (rs3761548 A/C), LIF (rs375082 T/C), NKG7 (rs71358833 A/G) and CCR5 (rs34418657 G/T) polymorphisms were tested by PCR-RFLP. Statistically significant difference existed between RPL cases and controls in terms of the genotypic distribution of the tested polymorphisms. STAT3 CC, FOXP3 AA, LIF CC, NKG7 AA and CCR5 GG genotypes were significantly higher in the RPL group. The tested polymorphisms shape the first elements of immune tolerance-related risk SNPs panel for RPL in the investigated population and may lead to improved therapeutic approaches.
Racial Variation in Toll-like Receptor Variants Among Women With Pelvic Inflammatory Disease
Journal of Infectious Diseases, 2013
Background. Racial disparities exist in gynecological diseases. Variations in Toll-like receptor (TLR) genes may alter signaling following microbial recognition. Methods. We explored genotypic differences in 6 functional variants in 4 TLR genes (TLR1, TLR2, TLR4, TLR6) and the adaptor molecule TIRAP between 205 African American women and 51 white women with clinically suspected pelvic inflammatory disease (PID). A permutated P < .007 was used to assess significance. Associations between race and endometritis and/or upper genital tract infection (UGTI) were explored. Logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs). Results. The TT genotype for TLR1 rs5743618, the GG genotype for TLR1 rs4833095, the CC genotype for TLR2 rs3804099, the TLR6 rs5743810 T allele, and the CC genotype for TIRAP rs8177374 significantly differed between races (P < .007). African American race was associated with endometritis and/or UGTI (OR, 4.2 [95% CI, 2.0-8.7]; P = .01). Among African Americans, the TLR6 rs5743810 T allele significantly decreased endometritis and/or UGTI (OR, 0.4 [95% CI, .2-.9]; P = .04). Additionally, rs5743618, rs4833095, and rs8177374 increased endometritis and/or UGTI, albeit not significantly. Conclusions. Among women with PID, TLR variants that increase inflammation are associated with African American race and may mediate the relationship between race and endometritis and/or UGTI.
Ethnic Differences of Polymorphisms in Cytokine and Innate Immune System Genes in Pregnant Women
Obstetrics & Gynecology, 2004
Investigations of the possible role of polymorphic genes in pregnancy outcome may be influenced by ethnic variations in genotype or allele frequencies. Differences in allelic carriage of immune system-related genes among white, black, and Hispanic pregnant women living in New York City and Boston were evaluated. METHODS: DNA was extracted from buccal or vaginal epithelial cells collected from 198 white, 75 black, and 114 Hispanic pregnant women who delivered at term and who had no history of a preterm birth. Genetic polymorphisms in the immunoregulatory genes encoding interleukin (IL)-1, tumor necrosis factor-␣, IL-4, IL-10, IL-1 receptor antagonist (IL-1ra), mannose-binding lectin, toll-like receptor-4, and the 70-kDa heat shock protein were determined. RESULTS: Allele 2 of the IL-1ra gene (IL1RN*2) and IL-4-590C homozygosity were 4-fold less common in blacks than in whites or Hispanics (P < .001). The IL-4 ؊590T allele was almost 2-fold more common in Hispanics than in whites (P < .001). The frequency of the 70-kDa heat shock protein 1267G allele was at least 1.4 times greater in blacks compared with whites (P < .001) or Hispanics (P ؍ .002), whereas the homozygous mannose-binding lectin codon 54G allele was observed at least 4.5 times more often in Hispanics compared with whites (P ؍ .007) or blacks (P ؍ .02). CONCLUSION: Investigations of the role of genetic factors affecting pregnancy outcome must be cognizant of ethnic variations when enrolling case and control subjects for studies on allele and genotype frequencies.
TLR polymorphism in host immune response to infectious diseases: A review
Scandinavian Journal of Immunology, 2019
Immunopolymorphism is considered as an important aspect behind the resistance or susceptibility of the host to an infectious disease. Over the years, researchers have explored many genetic factors for their role in immune surveillance against infectious diseases. Polymorphic characters in the gene encoding Toll-like receptors (TLRs) play profound roles in inducing differential immune responses by the host against parasitic infections. Protein(s) encoded by TLR gene(s) are immensely important due to their ability of recognizing different types of pathogen associated molecular patterns (PAMPs). This study reviews the polymorphic residues present in the nucleotide or in the amino acid sequence of TLRs and their influence on alteration of inflammatory signalling pathways promoting either susceptibility or resistance to major infectious diseases, including tuberculosis, leishmaniasis, malaria and filariasis. Population-based studies exploring TLR polymorphisms in humans are primarily emphasized to discuss the association of the polymorphic residues with the occurrence and epidemiology of the mentioned infectious diseases. Principal polymorphic residues in TLRs influencing immunity to infection are mostly single nucleotide polymorphisms (SNPs). I602S (TLR1), R677W (TLR2), P554S (TLR3), D299G (TLR4), F616L (TLR5), S249P (TLR6), Q11L (TLR7), M1V (TLR8), G1174A (TLR9) and G1031T (TLR10) are presented as the major influential SNPs in shaping immunity to pathogenic infections. The contribution of these SNPs in the structure-function relationship of TLRs is yet not clear. Therefore, molecular studies on such polymorphisms can improve our understanding on the genetic basis of the immune response and pave the way for therapeutic intervention in a more feasible way.
Genes & Immunity, 2013
Significant variability in cytokine and chemokine expression after Toll-like receptor (TLR) stimulation has been observed between individuals. In this study, we determined the immunophenotypic variation in a cohort of 152 neonates associated with specific single-nucleotide polymorphisms (SNPs). We identified 23 SNPs in 12 genes of the innate immune system to be significantly associated with differential cytokine and chemokine production. SNPs in three gene families, namely STAT, IRF and SYK, accounted for most associations. These gene families are important signaling components of the innate anti-viral response. A potentially damaging non-synonymous SNP in the TLR3 gene (rs3775291) associated with significant differences in expression of interferon-g after stimulation with the synthetic TLR3 ligand, poly (I:C). Additionally, a general increase in cytokine production was observed in subjects of Asian descent. This observation could be associated with differences in SNP genotype distribution between racial groups in our cohort. Taken together, our data suggest that particular aspects of the newborn innate response to TLR stimulation are closely associated with genetic variation. These findings provide the basis for detailed molecular dissection of cause-effect relationships between genotype and immune responses, and may account for inter-individual differences in response to vaccination and risk for infection and autoimmune disease.
Molecular and Cellular Probes, 2007
Toll-like receptors (TLRs) are cellular receptors that mediate recognition of microbial challenges and the subsequent inflammatory response. Genetic variations within these inflammation-associated genes may alter host-pathogen defence mechanisms affecting susceptibility towards infectious diseases. Taking into account the significance of these genes, we developed a simple and rapid method based in the bi-directional PCR amplification of specific alleles (Bi-PASA) for genotyping known sequence variants in TLR4 (Asp299Gly and Thr399Ile) and TLR9 (T-1237C) genes. This method allows genotype determination in a single reaction and is amenable to largescale analysis. We used Bi-PASA to characterize the distribution of these polymorphisms in the Portuguese population. A total of 388 randomly selected blood donors of Portuguese origin (203 females and 185 males) were genotyped and allele frequencies were determined. Among the tested individuals, 11.1% and 10.8% were heterozygous for Asp299Gly and Thr399Ile, respectively. In what concerns the T-1237C variation in TLR9, the variant allele was present in 19.4% of the individuals tested. Besides confirming the usefulness of the Bi-PASA in polymorphism analysis, the data presented provide valuable information on TLR polymorphisms in the Portuguese population that can be used to stratify risk patients with increased susceptibility to infection. r