Bowes, J and Ashcroft, J and Dand, N and Jalali-najafabadi, F and Bellou, E and Ho, P and Marzo-Ortega, H and Helliwell, PS and Feletar, M and Ryan, AW and Kane, DJ and Korendowych, E and Simpson, MA and Packham, J and McManus, R and Brown, MA and Smith, CH and Barker, JN and McHugh, N and FitzGerald, O and Warren, RB and Barton, A (2017) Cross-phenotype association mapping of the MHC identifies genetic variants that differentiate psoriatic arthritis from psoriasis. Annals of the Rheumatic Diseases. ISSN 0003-4967

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Abstract

Objectives Psoriatic arthritis (PsA) is a chronic inflammatory arthritis, with a strong heritable component, affecting patients with psoriasis. Here we attempt to identify genetic variants within the major histocompatibility complex (MHC) that differentiate patients with PsA from patients with cutaneous psoriasis alone (PsC).Methods 2808 patients with PsC, 1945 patients with PsA and 8920 population controls were genotyped. We imputed SNPs, amino acids and classical HLA alleles across the MHC and tested for association with PsA compared to population controls and the PsC patient group. In addition we investigated the impact of the age of disease onset on associations.Results HLA-C*06:02 was protective of PsA compared to PsC (p=9.57x10-66, OR 0.37). The HLA-C*06:02 risk allele was associated with a younger age of psoriasis onset in all patients (p=1.01x10-59). After controlling for the age of psoriasis onset no association of PsA to HLA-C*06:02 (p=0.07) was observed; instead, the most significant association was to amino acid at position 97 of HLA-B (p=1.54x10-9) where the presence of asparagine or serine residue increased PsA risk. Asparagine at position 97 of HLA-B defines the HLA-B*27 alleles.Conclusions By controlling for the age of psoriasis onset, we show, for the first time, that HLA-C*06:02 is not associated with PsA and that amino acid position 97 of HLA-B differentiates PsA from PsC. This amino acid also represents the largest genetic effect for ankylosing spondylitis, thereby refining the genetic overlap of these two spondyloarthropathies. Correcting for bias has important implications for cross-phenotype genetic studies.

Item Type: Article
Additional Information: This is the final published version of the article (version of record). It first appeared online via BMJ at http://ard.bmj.com/content/early/2017/08/18/annrheumdis-2017-211414 Please refer to any applicable terms of use of the publisher.
Depositing User: Symplectic
Date Deposited: 22 Aug 2017 13:28
Last Modified: 22 Aug 2017 13:32
URI: http://eprints.keele.ac.uk/id/eprint/3925

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