TY - JOUR
T1 - Cross-phenotype association mapping of the MHC identifies genetic variants that differentiate psoriatic arthritis from psoriasis
AU - Bowes, John
AU - Ashcroft, James
AU - Dand, Nick
AU - Jalali-Najafabadi, Farideh
AU - Bellou, Eftychia
AU - Ho, Pauline
AU - Marzo-Ortega, Helena
AU - Helliwell, Philip S.
AU - Feletar, Marie
AU - Ryan, Anthony W.
AU - Kane, David J.
AU - Korendowych, Eleanor
AU - Simpson, Michael A.
AU - Packham, Jonathan
AU - McManus, Ross
AU - Brown, Matthew A.
AU - Smith, Catherine H.
AU - Barker, Jonathan N.
AU - McHugh, Neil
AU - FitzGerald, Oliver
AU - Warren, Richard B.
AU - Barton, Anne
PY - 2017/10/1
Y1 - 2017/10/1
N2 - 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.
AB - 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.
KW - genetic susceptibility
KW - MHC
KW - psoriasis
KW - psoriatic arthritis
KW - selection bias
UR - http://www.scopus.com/inward/record.url?scp=85030615900&partnerID=8YFLogxK
U2 - 10.1136/annrheumdis-2017-211414
DO - 10.1136/annrheumdis-2017-211414
M3 - Article
C2 - 28821532
AN - SCOPUS:85030615900
SN - 0003-4967
VL - 76
SP - 1774
EP - 1779
JO - Annals of the rheumatic diseases
JF - Annals of the rheumatic diseases
IS - 10
ER -