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Cross-phenotype association mapping of the MHC identifies genetic variants that differentiate psoriatic arthritis from psoriasis

Research output: Contribution to journalArticlepeer-review

John Bowes, James Ashcroft, Nick Dand, Farideh Jalali-Najafabadi, Eftychia Bellou, Pauline Ho, Helena Marzo-Ortega, Philip S. Helliwell, Marie Feletar, Anthony W. Ryan, David J. Kane, Eleanor Korendowych, Michael A. Simpson, Jonathan Packham, Ross McManus, Matthew A. Brown, Catherine H. Smith, Jonathan N. Barker, Neil McHugh, Oliver FitzGerald & 2 more Richard B. Warren, Anne Barton

Original languageEnglish
Pages (from-to)1774-1779
Number of pages6
JournalAnnals of the rheumatic diseases
Volume76
Issue number10
Early online date17 Aug 2017
DOIs
Accepted/In press1 Jul 2017
E-pub ahead of print17 Aug 2017
Published1 Oct 2017

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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=9.57×10−66, OR 0.37). The HLA-C*06:02 risk allele was associated with a younger age of psoriasis onset in all patients (p=1.01×10−59). 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=1.54×10−9) 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.

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