Candidate long-range regulatory sites acting on the IL17-pathway genes TRAF3IP2 and IL17RA are associated with psoriasis

Joanne Nititham, Calum Fergusson, Colin Palmer, Wilson Liao (Lead / Corresponding author), John Foerster (Lead / Corresponding author)

Research output: Contribution to journalArticle

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Abstract

Background: Drug-mediated disruption of IL17A, IL17F, and IL17RA proteins is effective in psoriasis. However, disruption of the IL17 pathway by functional mutations has so far only been shown to affect risk in IL23R and TRAF3IP2. It is unclear if this is due to rarity of disruptive mutations.

Objective: (i) to delineate the prevalence of mutations in key IL17-pathway genes; (ii) to identify candidate regulatory sites acting on IL23R, IL17A, IL17RA, TRAF3IP2 from a distance.

Methods: Extraction of mutation frequencies from ExAc data, evolutionary sequence alignment; mapping of long-range-interacting (LRI) enhancers; genetic association testing in a novel psoriasis cohort.

Results: the prevalence of disruptive mutations in genes such as IL17RA is sufficient to have been detectable by existing datasets. Therefore, lack of their association with psoriasis indicates that genetic risk primarily resides in variants acting from a distance. We identify two LRI enhancer sites, regulating IL17RA and TRAF3IP2, respectively. The TRAF3IP2 regulator localises to the TRAF3IP2-antisense promoter, suggesting feedback-regulation. Both LRI sites are associated with psoriasis in a novel Scottish psoriasis cohort and the TRAF3IP2-LRI at rs71562294 replicates in the WTCCC cohort.

Conclusion: Genetic risk for psoriasis may be encoded at LRI sites regulating IL17 pathway genes from a distance.

Original languageEnglish
Pages (from-to)1294-1297
Number of pages4
JournalExperimental Dermatology
Volume27
Issue number11
Early online date4 Aug 2018
DOIs
Publication statusE-pub ahead of print - 4 Aug 2018

Fingerprint

Psoriasis
Genes
Mutation
Feedback
Sequence Alignment
Genetic Testing
Testing
Mutation Rate
Pharmaceutical Preparations
Proteins

Keywords

  • IL17A
  • biologics
  • cohort
  • genetics
  • psoriasis

Cite this

@article{b1233ae0b55144ed80a430872e59e517,
title = "Candidate long-range regulatory sites acting on the IL17-pathway genes TRAF3IP2 and IL17RA are associated with psoriasis",
abstract = "Background: Drug-mediated disruption of IL17A, IL17F, and IL17RA proteins is effective in psoriasis. However, disruption of the IL17 pathway by functional mutations has so far only been shown to affect risk in IL23R and TRAF3IP2. It is unclear if this is due to rarity of disruptive mutations.Objective: (i) to delineate the prevalence of mutations in key IL17-pathway genes; (ii) to identify candidate regulatory sites acting on IL23R, IL17A, IL17RA, TRAF3IP2 from a distance.Methods: Extraction of mutation frequencies from ExAc data, evolutionary sequence alignment; mapping of long-range-interacting (LRI) enhancers; genetic association testing in a novel psoriasis cohort.Results: the prevalence of disruptive mutations in genes such as IL17RA is sufficient to have been detectable by existing datasets. Therefore, lack of their association with psoriasis indicates that genetic risk primarily resides in variants acting from a distance. We identify two LRI enhancer sites, regulating IL17RA and TRAF3IP2, respectively. The TRAF3IP2 regulator localises to the TRAF3IP2-antisense promoter, suggesting feedback-regulation. Both LRI sites are associated with psoriasis in a novel Scottish psoriasis cohort and the TRAF3IP2-LRI at rs71562294 replicates in the WTCCC cohort.Conclusion: Genetic risk for psoriasis may be encoded at LRI sites regulating IL17 pathway genes from a distance.",
keywords = "IL17A, biologics, cohort, genetics, psoriasis",
author = "Joanne Nititham and Calum Fergusson and Colin Palmer and Wilson Liao and John Foerster",
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Candidate long-range regulatory sites acting on the IL17-pathway genes TRAF3IP2 and IL17RA are associated with psoriasis. / Nititham, Joanne; Fergusson, Calum; Palmer, Colin; Liao, Wilson (Lead / Corresponding author); Foerster, John (Lead / Corresponding author).

In: Experimental Dermatology, Vol. 27, No. 11, 04.08.2018, p. 1294-1297.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Candidate long-range regulatory sites acting on the IL17-pathway genes TRAF3IP2 and IL17RA are associated with psoriasis

AU - Nititham, Joanne

AU - Fergusson, Calum

AU - Palmer, Colin

AU - Liao, Wilson

AU - Foerster, John

N1 - This article is protected by copyright. All rights reserved.

PY - 2018/8/4

Y1 - 2018/8/4

N2 - Background: Drug-mediated disruption of IL17A, IL17F, and IL17RA proteins is effective in psoriasis. However, disruption of the IL17 pathway by functional mutations has so far only been shown to affect risk in IL23R and TRAF3IP2. It is unclear if this is due to rarity of disruptive mutations.Objective: (i) to delineate the prevalence of mutations in key IL17-pathway genes; (ii) to identify candidate regulatory sites acting on IL23R, IL17A, IL17RA, TRAF3IP2 from a distance.Methods: Extraction of mutation frequencies from ExAc data, evolutionary sequence alignment; mapping of long-range-interacting (LRI) enhancers; genetic association testing in a novel psoriasis cohort.Results: the prevalence of disruptive mutations in genes such as IL17RA is sufficient to have been detectable by existing datasets. Therefore, lack of their association with psoriasis indicates that genetic risk primarily resides in variants acting from a distance. We identify two LRI enhancer sites, regulating IL17RA and TRAF3IP2, respectively. The TRAF3IP2 regulator localises to the TRAF3IP2-antisense promoter, suggesting feedback-regulation. Both LRI sites are associated with psoriasis in a novel Scottish psoriasis cohort and the TRAF3IP2-LRI at rs71562294 replicates in the WTCCC cohort.Conclusion: Genetic risk for psoriasis may be encoded at LRI sites regulating IL17 pathway genes from a distance.

AB - Background: Drug-mediated disruption of IL17A, IL17F, and IL17RA proteins is effective in psoriasis. However, disruption of the IL17 pathway by functional mutations has so far only been shown to affect risk in IL23R and TRAF3IP2. It is unclear if this is due to rarity of disruptive mutations.Objective: (i) to delineate the prevalence of mutations in key IL17-pathway genes; (ii) to identify candidate regulatory sites acting on IL23R, IL17A, IL17RA, TRAF3IP2 from a distance.Methods: Extraction of mutation frequencies from ExAc data, evolutionary sequence alignment; mapping of long-range-interacting (LRI) enhancers; genetic association testing in a novel psoriasis cohort.Results: the prevalence of disruptive mutations in genes such as IL17RA is sufficient to have been detectable by existing datasets. Therefore, lack of their association with psoriasis indicates that genetic risk primarily resides in variants acting from a distance. We identify two LRI enhancer sites, regulating IL17RA and TRAF3IP2, respectively. The TRAF3IP2 regulator localises to the TRAF3IP2-antisense promoter, suggesting feedback-regulation. Both LRI sites are associated with psoriasis in a novel Scottish psoriasis cohort and the TRAF3IP2-LRI at rs71562294 replicates in the WTCCC cohort.Conclusion: Genetic risk for psoriasis may be encoded at LRI sites regulating IL17 pathway genes from a distance.

KW - IL17A

KW - biologics

KW - cohort

KW - genetics

KW - psoriasis

U2 - 10.1111/exd.13761

DO - 10.1111/exd.13761

M3 - Article

C2 - 30076642

VL - 27

SP - 1294

EP - 1297

JO - Experimental Dermatology

JF - Experimental Dermatology

SN - 0906-6705

IS - 11

ER -