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Ann Rheum Dis. 2017 Oct;76(10):1774-1779. doi: 10.1136/annrheumdis-2017-211414. Epub 2017 Aug 18.

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

Author information

1
Arthritis Research UK Centre for Genetics and Genomics, Centre for Musculoskeletal Research, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK.
2
Division of Genetics and Molecular Medicine, King's College London, Guy's Hospital, London, UK.
3
NIHR Manchester Musculoskeletal Biomedical Research Unit, Manchester Academic Health Science Centre, Manchester, UK.
4
NIHR Leeds Musculoskeletal 12 Biomedical Research Unit, Leeds Teaching Hospitals Trust and Leeds Institute of Rheumatic and Musculoskeletal Disease, University of Leeds, Leeds, UK.
5
Department of Rheumatology, Emeritus Research, Melbourne, Victoria, Australia.
6
Department of Clinical Medicine, Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland.
7
Adelaide and Meath Hospital and Trinity College Dublin, Dublin, Ireland.
8
Royal National Hospital for Rheumatic Diseases and Department Pharmacy and Pharmacology, University of Bath, Bath, UK.
9
Department of Rheumatology, St Vincent's University Hospital, UCD School of Medicine and Medical Sciences and Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland.
10
Haywood Academic Rheumatology Centre, Institute of Applied Clinical Science, Keele University, Stoke on Trent, UK.
11
Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Australia.
12
St John's Institute of Dermatology, Guys and St Thomas' Foundation Trust, London, UK.
13
St John's Institute of Dermatology, Division of Genetics and Molecular Medicine, Faculty of Life Sciences and Medicine, King's College London, London, UK.
14
Dermatology Centre, Salford Royal NHS Foundation Trust, University of Manchester, Manchester, UK.

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.

KEYWORDS:

MHC; genetic susceptibility; psoriasis; psoriatic arthritis; selection bias

PMID:
28821532
PMCID:
PMC5629941
DOI:
10.1136/annrheumdis-2017-211414
[Indexed for MEDLINE]
Free PMC Article

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