title: Association of Toll-like receptor 4 (TLR4) with chronic plaque type psoriasis and psoriatic arthritis.
abstract: Family studies have provided overwhelming evidence for an underlying genetic component to psoriasis. Toll-like receptors (TLRs) are key transmembrane proteins in both the innate and adaptive immune responses which are known to be integral processes in psoriasis. Recent functional studies support this notion having suggested a role for TLR4 in the pathogenesis of psoriasis. Furthermore a missense polymorphism in the TLR4 gene has been associated with a number of autoimmune conditions, including Crohn diseases, making TLR4 a viable candidate gene for investigation. The aim of this study was to investigate polymorphisms across the TLR4 region with a high-density single nucleotide polymorphism (SNP) panel in a large cohort of patients with chronic plaque type psoriasis. Twenty SNPs were successfully genotyped using Sequenom iPLEX Gold platform in 2826 UK chronic plaque type psoriasis patients including subgroup data on presence of confirmed psoriatic arthritis (n = 1839) and early-onset psoriasis (n = 1466) was available. Allele frequencies for psoriasis patients were compared against imputed Wellcome Trust Case Control Consortium controls (n = 4861). Significant association was observed between a missense variant rs4986790 of TLR4 (Asp229Gly) and plaque type psoriasis (p = 2 × 10(-4)) which was also notable in those with psoriatic arthritis (p = 2 × 10(-4)) and early-onset psoriasis (p = 8 × 10(-4)). We present data suggestive of an association between a functional variant and an intronic variant of TLR4 and chronic plaque type psoriasis and psoriatic arthritis. However, validation of this association in independent cohorts will be necessary.
authors.affiliation: The Dermatology Centre, Salford Royal NHS Foundation Trust, University of Manchester, Manchester Academic Health Science Centre, Manchester, M6 8HD, UK.|Arthritis Research UK Centre for Genetics and Genomics, Centre for Musculoskeletal Research, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.
authors.forename: Rh Ll
authors.initials: RL
authors.lastname: Smith
authors.affiliation: The Dermatology Centre, Salford Royal NHS Foundation Trust, University of Manchester, Manchester Academic Health Science Centre, Manchester, M6 8HD, UK.|Arthritis Research UK Centre for Genetics and Genomics, Centre for Musculoskeletal Research, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.
authors.forename: H L
authors.initials: HL
authors.lastname: Hébert
authors.affiliation: Arthritis Research UK Centre for Genetics and Genomics, Centre for Musculoskeletal Research, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.
authors.forename: J
authors.initials: J
authors.lastname: Massey
authors.affiliation: Arthritis Research UK Centre for Genetics and Genomics, Centre for Musculoskeletal Research, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.
authors.forename: J
authors.initials: J
authors.lastname: Bowes
authors.affiliation: NIHR-Leeds Musculoskeletal Biomedical Research Unit, Leeds Institute of Molecular Medicine, University of Leeds, Leeds, UK.
authors.forename: H
authors.initials: H
authors.lastname: Marzo-Ortega
authors.affiliation: The Kellgren Centre for Rheumatology, Central Manchester Foundation Trust, Manchester, UK.
authors.forename: P
authors.initials: P
authors.lastname: Ho
authors.affiliation: Royal National Hospital for Rheumatic Diseases and Department of Pharmacy and Pharmacology, University of Bath, Bath, UK.
authors.forename: N J
authors.initials: NJ
authors.lastname: McHugh
authors.affiliation: Arthritis Research UK Centre for Genetics and Genomics, Centre for Musculoskeletal Research, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.
authors.forename: J
authors.initials: J
authors.lastname: Worthington
authors.affiliation: Arthritis Research UK Centre for Genetics and Genomics, Centre for Musculoskeletal Research, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.|NIHR Manchester Musculoskeletal Biomedical Research Unit, Central Manchester Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.
authors.forename: A
authors.initials: A
authors.lastname: Barton
authors.affiliation: The Dermatology Centre, Salford Royal NHS Foundation Trust, University of Manchester, Manchester Academic Health Science Centre, Manchester, M6 8HD, UK.
authors.forename: C E M
authors.initials: CE
authors.lastname: Griffiths
authors.affiliation: The Dermatology Centre, Salford Royal NHS Foundation Trust, University of Manchester, Manchester Academic Health Science Centre, Manchester, M6 8HD, UK. richard.warren@manchester.ac.uk.
authors.forename: R B
authors.initials: RB
authors.lastname: Warren
mesh_terms: D017668:Age of Onset; D015535:Arthritis, Psoriatic / Q000453:epidemiology / Q000235:genetics; D016022:Case-Control Studies; D002908:Chronic Disease; D015331:Cohort Studies; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007438:Introns / Q000235:genetics; D008297:Male; D020125:Mutation, Missense; D020641:Polymorphism, Single Nucleotide; D011565:Psoriasis / Q000453:epidemiology / Q000235:genetics*; D051197:Toll-Like Receptor 4 / Q000235:genetics*; D006113:United Kingdom / Q000453:epidemiology
chemical_list: C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4
keywords: Genetic susceptibility; Psoriasis; Psoriatic arthritis; TLR4
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