Characterization of genetic variation in <i><scp>TLR</scp>8</i> in relation to allergic rhinitis

Henmyr, Viktor; Lind‐Halldén, Christina; Carlberg, Daniel; Halldén, Christer; Wickman, Magnus; Bergström, Anna; Säll, Torbjörn; Cardell, Lars Olaf

doi:10.1111/all.12805

Cited by 10 publications

(9 citation statements)

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“…These SNPs are all located in the same haploblock and reflects the association observed earlier for the TLR7 - TLR8 region [ 16 ]. However, no signs of any accumulation of rare variants was detected in TLR8 which was also demonstrated in a previous study [ 25 ].…”

Section: Discussionsupporting

confidence: 85%

Genetic variation of the Toll-like receptors in a Swedish allergic rhinitis case population

et al. 2017

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BackgroundVariation in the 10 toll-like receptor (TLR) genes has been significantly associated with allergic rhinitis (AR) in several candidate gene studies and three large genome-wide association studies. These have all investigated common variants, but no investigations for rare variants (MAF ≤ 1%) have been made in AR. The present study aims to describe the genetic variation of the promoter and coding sequences of the 10 TLR genes in 288 AR patients.MethodsSanger sequencing and Ion Torrent next-generation sequencing was used to identify polymorphisms in a Swedish AR population and these were subsequently compared and evaluated using 1000Genomes and Exome Aggregation Consortium (ExAC) data.ResultsThe overall level of genetic variation was clearly different among the 10 TLR genes. The TLR10-TLR1-TLR6 locus was the most variable, while the TLR7-TLR8 locus was consistently showing a much lower level of variation. The AR patients had a total of 37 promoter polymorphisms with 14 rare (MAF ≤ 1%) and 14 AR-specific polymorphisms. These numbers were highly similar when comparing the AR and the European part of the 1000Genomes populations, with the exception of TLR10 where a significant (P = 0.00009) accumulation of polymorphisms were identified. The coding sequences had a total of 119 polymorphisms, 68 were rare and 43 were not present in the European part of the 1000Genomes population. Comparing the numbers of rare and AR-specific SNPs in the patients with the European part of the 1000Genomes population it was seen that the numbers were quite similar both for individual genes and for the sum of all 10 genes. However, TLR1, TLR5, TLR7 and TLR9 showed a significant excess of rare variants in the AR population when compared to the non-Finnish European part of ExAC. In particular the TLR1 S324* nonsense mutation was clearly overrepresented in the AR population.ConclusionsMost TLR genes showed a similar level of variation between AR patients and public databases, but a significant excess of rare variants in AR patients were detected in TLR1, TLR5, TLR7, TLR9 and TLR10. This further emphasizes the frequently reproduced TLR10-TLR1-TLR6 locus as being involved in the pathogenesis of allergic rhinitis.Electronic supplementary materialThe online version of this article (doi:10.1186/s12881-017-0379-6) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 85%

Genetic variation of the Toll-like receptors in a Swedish allergic rhinitis case population

et al. 2017

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“…A number of studies have established the association of AR with other cytokines and genes such as IL-6 (Zhao et al, 2016); IL-10 and TGF-β polymorphisms (Nasiri et al, 2016); IL-12B (Wei et al, 2016); IL33/IL1RL1, IL-13-RAD50 and C11orf30/LRRC32 (Li et al, 2015); JAK1 gene polymorphisms (Shen et al, 2016). In contrast, Henmyr et al (2016) found no associations between the genetic variation in TLR8 and AR. Moreover, a study on a North Indian population showed that the IL-18 -137G/C polymorphism conferred a significant protection from asthma.…”

Section: Discussionmentioning

confidence: 75%

Research Article Alteration of -656(G/T) and -607(C/A) polymorphisms in interleukin-18 (IL-18) gene in house dust mite-sensitive allergic rhinitis patients in Thailand.

et al. 2017

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Allergic rhinitis (AR) is an IgE-mediated inflammation of the nasal membranes, which is naturally triggered by aeroallergens. House dust mites (HDM) are the most common inhalant allergens. Interleukin-18 (IL-18) has been established as an essential cytokine that can activate the generation of IgE. This randomized controlled study aimed to identify the possible relationship of the genetic variations in the IL-18 gene with AR in mite-sensitive Thai patients. Study subjects consisted of 150 AR patients and 50 normal participants. Genomic DNA of 30 randomized AR patients and 30 randomized controls were screened by sequencing for the selection of candidate single nucleotide polymorphisms (SNPs), and further analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay for all subjects. The following five SNPs were detected in the IL-18 gene: -656 G/T, -607 C/A, and -137 G/C in promoter 1 and -920 C/T and -373 C/G in promoter 2. The results showed that -656 G/T and -607 C/A SNPs were significantly correlated with IgE levels specific to Dermatophagoides pteronyssinus (Der p) allergen (P = 0.045 and P = 0.045, respectively), and significant differences were observed in the genotype distribution of AR patients when compared with controls [P = 0.044 and P = 0.044, respectively; odds ratios (ORs): 1.941 (95%CI, 1.014-3.715) and 1.941 (95%CI, 1.014-3.715), respectively]. Our findings indicate that the IL-18 alleles, -656T (rs1946519) and -607A (rs1946518), might be associated with the higher production of Der p allergen-specific IgE in mite-sensitive AR patients.

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“…In contrast, the duodenal mucosa shows no inflammatory activity despite comparable profile expression of the same TLR genes. This study adds to the cumulative literature investigating the role of TLRs in different gastrointestinal inflammatory conditions, including inflammatory bowel disease 29 , 45 , 46 , celiac disease 30 , 47 , food allergy 48 , and several atopic disorders 49 , 50 .…”

Section: Discussionmentioning

confidence: 97%

Toll-like receptors-mediated pathways activate inflammatory responses in the esophageal mucosa of adult eosinophilic esophagitis

Arias

Vicario

Bernardo

et al. 2018

Clinical and Translational Gastroenterology

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ObjectivesEsophageal microbiota and regulation of adaptive immunity are increasingly being investigated in eosinophilic esophagitis (EoE). Toll-like receptors (TLRs) play a central role in the initiation and maintenance of innate immune activity. Our objective was to characterize the esophageal and duodenal innate immune response in EoE and its modulation by dietary therapy.MethodsEsophageal and duodenal biopsy samples were collected from 10 adults with untreated EoE, before and after effective treatment with a six-food elimination diet (SFED), and 10 controls with normal esophagus. In all cases, bacterial load (by mRNA expression of 16S), TLRs, mucins, transcription factors, interleukins, components of the NKG2D system, and innate immunity effectors were assessed by qPCR. Protein expression of TLRs were also determined by immunofluorescence.ResultsBacterial load and TLR1, TLR2, TLR4, and TLR9 were overexpressed on biopsies with active EoE compared with controls. Muc1 and Muc5B genes were downregulated while Muc4 was overexpressed. Upregulation of MyD88 and NFκB was found together with IL-1β, IL-6, IL-8, and IL-10 mediators and PER-1, iNOS, and GRZA effectors. NG-K2D components (KLRK1, IL-15, MICB) were also upregulated. In all cases, changes in active EoE were normalized following SFED and mucosal healing. Duodenal samples also showed increased expressions of TLR-1, TLR-2, and TLR-4, but not 16S or any other mediators nor effectors of inflammation.ConclusionsEsophageal TLR-dependent signaling pathways in EoE support the potential implication of microbiota and the innate immune system in the pathogenesis of this disease.

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Characterization of genetic variation in TLR8 in relation to allergic rhinitis

Abstract: Rare variants in TLR8 are not associated with AR. Comparison of present and previous association studies reveals contradictory results for common variants. Thus, no associations exist between genetic variation in TLR8 and AR.

Cited by 10 publications

References 36 publications

Genetic variation of the Toll-like receptors in a Swedish allergic rhinitis case population

Genetic variation of the Toll-like receptors in a Swedish allergic rhinitis case population

Research Article Alteration of -656(G/T) and -607(C/A) polymorphisms in interleukin-18 (IL-18) gene in house dust mite-sensitive allergic rhinitis patients in Thailand.

Toll-like receptors-mediated pathways activate inflammatory responses in the esophageal mucosa of adult eosinophilic esophagitis

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