Top

BMC Medical Genetics

Published in:

Open Access 01-12-2017 | Research article

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

Authors: V. Henmyr, D. Carlberg, E. Manderstedt, C. Lind-Halldén, T. Säll, L. O. Cardell, C. Halldén

Published in: BMC Medical Genetics | Issue 1/2017

Abstract

Background

Variation 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.

Methods

Sanger 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.

Results

The 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.

Conclusions

Most 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.

Available only for authorised users

Brozek JL, Bousquet J, Baena-Cagnani CE, Bonini S, Casale TB, van Wijk RG, et al. Allergic rhinitis and its impact on asthma (ARIA) guidelines: 2010 revision. J Allergy Clin Immunol. 2010;126:466–76.CrossRefPubMed

Fagnani C, Annesi-Maesano I, Brescianini S, D’Ippolito C, Medda E, Nisticò L, et al. Heritability and shared genetic effects of asthma and hay fever: an Italian study of young twins. Twin Res Hum Genet. 2008;11:121–31.CrossRefPubMed

Willemsen G, van Beijsterveldt TC, van Baal CG, Postma D, Boomsma DI. Heritability of self reported asthma and allergy: a study in adult Dutch twins, siblings and parents. Twin Res Hum Genet. 2008;11:132–42.CrossRefPubMed

Pandey S, Agrawal DK. Immunobiology of Toll-like receptors: emerging trends. Immunol Cell Biol. 2006;84:333–41.CrossRefPubMed

Oosting M, Cheng SC, Bolscher JM, Vestering-Stenger R, Plantinga TS, Verschueren IC, et al. Human TLR10 is an anti-inflammatory pattern-recognition receptor. Proc Natl Acad Sci U S A. 2014;111(42):E4478–84.CrossRefPubMedPubMedCentral

Tesse R, Pandey RC, Kabesch M. Genetic variations in toll-like receptor pathway genes influence asthma and atopy. Allergy. 2011;66:307–16.CrossRefPubMed

Georgel P, Macquin C, Bahram S. The heterogeneous allelic repertoire of human Toll-like receptor (TLR) genes. PLoS ONE. 2009;4:e7803.CrossRefPubMedPubMedCentral

Ma X, Liu Y, Gowen BB, Graviss EA, Clark AG, Musser JM. Full-exon resequencing reveals Toll-like receptor variants contribute to human susceptibility to tuberculosis disease. PLoS ONE. 2007;2:e1318.CrossRefPubMedPubMedCentral

Abecasis GR, Auton A, Brooks LD, DePristo MA, Durbin RM, Handsaker RE, et al. An integrated map of genetic variation from 1,092 human genomes. Nature. 2012;491:56–65.CrossRefPubMed

10.

Medvedev AE. Toll-like receptor polymorphisms, inflammatory and infectious diseases, allergies, and cancer. J Interferon Cytokine Res. 2013;33:467–84.CrossRefPubMedPubMedCentral

11.

Salpietro C, Rigoli L, Miraglia Del Giudice M, Cuppari C, Di Bella C, Salpietro A, et al. TLR2 and TLR4 gene polymorphisms and atopic dermatitis in Italian children: a multicenter study. Int J Immunopathol Pharmacol. 2011;24:33–40.CrossRefPubMed

12.

Kerkhof M, Postma DS, Brunekreef B, Reijmerink NE, Wijga AH, de Jongste JC, et al. Toll-like receptor 2 and 4 genes influence susceptibility to adverse effects of traffic-related air pollution on childhood asthma. Thorax. 2010;65:690–7.CrossRefPubMed

13.

Miedema KG, Tissing WJ, Te Poele EM, Kamps WA, Alizadeh BZ, Kerkhof M, et al. Polymorphisms in the TLR6 gene associated with the inverse association between childhood acute lymphoblastic leukemia and atopic disease. Leukemia. 2012;26:1203–10.CrossRefPubMed

14.

Lachheb J, Dhifallah IB, Chelbi H, Hamzaoui K, Hamzaoui A. Toll-like receptors and CD14 genes polymorphisms and susceptibility to asthma in Tunisian children. Tissue Antigens. 2008;71:417–25.CrossRefPubMed

15.

Møller-Larsen S, Nyegaard M, Haagerup A, Vestbo J, Kruse TM, Borglum AD. Association analysis identifies TLR7 and TLR8 as novel risk genes in asthma and related disorders. Thorax. 2008;63:1064–9.CrossRefPubMed

16.

Nilsson D, Andiappan AK, Halldén C, De Yun W, Säll T, Tim CF, et al. Toll-like receptor gene polymorphisms are associated with allergic rhinitis: a case control study. BMC Med Genet. 2012;13:66.CrossRefPubMedPubMedCentral

17.

Ramasamy A, Curjuric I, Coin LJ, Kumar A, McArdle WL, Imboden M, et al. A genome-wide meta-analysis of genetic variants associated with allergic rhinitis and grass sensitization and their interaction with birth order. J Allergy Clin Immunol. 2011;128:996–1005.CrossRefPubMed

18.

Bønnelykke K, Matheson MC, Pers TH, Granell R, Strachan DP, Alves AC, et al. Meta-analysis of genome-wide association studies identifies ten loci influencing allergic sensitization. Nat Genet. 2013;45:902–6.CrossRefPubMedPubMedCentral

19.

Hinds DA, McMahon G, Kiefer AK, Do CB, Eriksson N, Evans DM, et al. A genome-wide association meta-analysis of self-reported allergy identifies shared and allergy-specific susceptibility loci. Nat Genet. 2013;45:907–11.CrossRefPubMedPubMedCentral

20.

Nilsson D, Henmyr V, Halldén C, Säll T, Kull I, Wickman M, et al. Replication of genome-wide associations with allergic sensitization and allergic rhinitis. Allergy. 2014;69:1506–14.CrossRefPubMed

21.

Ferreira MAR, Matheson MC, Tang CS, Granell R, Ang W, Hui J, et al. Genome-wide association analysis identifies 11 risk variants associated with the asthma with hay fever phenotype. J Allergy Clin Immunol. 2014;133(6):1564–71.CrossRefPubMed

22.

Bousquet J, Heinzerling L, Bachert C, Papadopoulos NG, Bousquet PJ, Burney PG, et al. Practical guide to skin prick tests in allergy to aeroallergens. Allergy. 2011;67:18–24.CrossRefPubMed

23.

Sim NL, Kumar P, Hu J, Henikoff S, Schneider G, Ng PC. SIFT web server: predicting effects of amino acid substitutions on proteins. Nucleic Acids Res. 2012. doi: 10.1093/nar/gks539.

24.

Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, et al. A method and server for predicting damaging missense mutations. Nat Methods. 2010;7:248–9.CrossRefPubMedPubMedCentral

25.

Henmyr V, Lind-Halldén C, Carlberg D, Halldén C, Melén E, Wickman M, Bergström A, Säll T, Cardell LO. Characterization of genetic variation in TLR8 in relation to allergic rhinitis. Allergy. 2016;71(3):333–41.CrossRefPubMed

26.

Lonsdale J, Thomas J, Salvatore M, Phillips R, Lo E, Shad S. The Genotype-Tissue Expression (GTEx) project. Nat Genet. 2013;45:580–5.CrossRef

27.

Tizaoui K, Kaabachi W, Hamzaoui K, Hamzaoui A. Association of single nucleotide polymorphisms in toll-like receptor genes with asthma risk: a systematic review and meta-analysis. Allergy, Asthma Immunol Res. 2015;7(2):130–40.CrossRef

Title: Genetic variation of the Toll-like receptors in a Swedish allergic rhinitis case population
Authors: V. Henmyr
D. Carlberg
E. Manderstedt
C. Lind-Halldén
T. Säll
L. O. Cardell
C. Halldén
Publication date: 01-12-2017
Publisher: BioMed Central
Published in: BMC Medical Genetics / Issue 1/2017
Electronic ISSN: 1471-2350
DOI: https://doi.org/10.1186/s12881-017-0379-6

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

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

Abstract

Background

Methods

Results

Conclusions

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2017

Hypotonia and intellectual disability without dysmorphic features in a patient with PIGN-related disease

Severe child form of primary hyperoxaluria type 2 - a case report revealing consequence of GRHPR deficiency on metabolism

African ancestry is associated with facial melasma in women: a cross-sectional study

PEAR1 is not a major susceptibility gene for cardiovascular disease in a Flemish population

Identification of established arrhythmogenic right ventricular cardiomyopathy mutation in a patient with the contrasting phenotype of hypertrophic cardiomyopathy

Novel mutations in PANK2 and PLA2G6 genes in patients with neurodegenerative disorders: two case reports