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

Henmyr, V. LU ; Carlberg, D; Manderstedt, E. LU ; Lind-Halldén, C; Säll, T. LU ; Cardell, L. O. LU and Halldén, C. LU (2017) In BMC Medical Genetics 18(1).
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... (More)

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.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Allergic rhinitis, Mutation spectrum, Next-generation sequencing, Rare variants, Toll-like receptor
in
BMC Medical Genetics
volume
18
issue
1
publisher
BioMed Central
external identifiers
  • scopus:85013825917
  • wos:000397484800001
ISSN
1471-2350
DOI
10.1186/s12881-017-0379-6
language
English
LU publication?
yes
id
ffe896c0-af8e-44d9-8d3d-f2a0f7face35
date added to LUP
2017-03-09 12:49:05
date last changed
2018-08-12 04:34:34
@article{ffe896c0-af8e-44d9-8d3d-f2a0f7face35,
  abstract     = {<p>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.</p>},
  articleno    = {18},
  author       = {Henmyr, V. and Carlberg, D and Manderstedt, E. and Lind-Halldén, C and Säll, T. and Cardell, L. O. and Halldén, C.},
  issn         = {1471-2350},
  keyword      = {Allergic rhinitis,Mutation spectrum,Next-generation sequencing,Rare variants,Toll-like receptor},
  language     = {eng},
  month        = {02},
  number       = {1},
  publisher    = {BioMed Central},
  series       = {BMC Medical Genetics},
  title        = {Genetic variation of the Toll-like receptors in a Swedish allergic rhinitis case population},
  url          = {http://dx.doi.org/10.1186/s12881-017-0379-6},
  volume       = {18},
  year         = {2017},
}