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

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 others Richard B Warren, Anne Barton

Research output: Contribution to journalArticle

13 Citations (Scopus)

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.

LanguageEnglish
Pages1774-1779
JournalAnnals of the Rheumatic Diseases
Volume76
Early online date18 Aug 2017
DOIs
StatusPublished - 1 Oct 2017

Fingerprint

HLA-C Antigens
Psoriatic Arthritis
HLA-B Antigens
Major Histocompatibility Complex
Psoriasis
Phenotype
Amino Acids
Asparagine
Age of Onset
Population Control
Alleles
Serine
Refining
Genetic Crosses
Spondylarthropathies
Ankylosing Spondylitis
Arthritis
Single Nucleotide Polymorphism

Keywords

  • Journal Article

Cite this

Cross-phenotype association mapping of the MHC identifies genetic variants that differentiate psoriatic arthritis from psoriasis. / Bowes, John; Ashcroft, James; Dand, Nick; Jalali-Najafabadi, Farideh; Bellou, Eftychia; Ho, Pauline; Marzo-Ortega, Helena; Helliwell, Philip S; Feletar, Marie; Ryan, Anthony W; Kane, David J; Korendowych, Eleanor; Simpson, Michael A; Packham, Jonathan; McManus, Ross; Brown, Matthew A; Smith, Catherine H; Barker, Jonathan N; McHugh, Neil; Fitzgerald, Oliver; Warren, Richard B; Barton, Anne.

In: Annals of the Rheumatic Diseases, Vol. 76, 01.10.2017, p. 1774-1779.

Research output: Contribution to journalArticle

Bowes, J, Ashcroft, J, Dand, N, Jalali-Najafabadi, F, Bellou, E, Ho, P, Marzo-Ortega, H, Helliwell, PS, Feletar, M, Ryan, AW, Kane, DJ, Korendowych, E, Simpson, MA, Packham, J, McManus, R, Brown, MA, Smith, CH, Barker, JN, McHugh, N, Fitzgerald, O, Warren, RB & Barton, A 2017, 'Cross-phenotype association mapping of the MHC identifies genetic variants that differentiate psoriatic arthritis from psoriasis', Annals of the Rheumatic Diseases, vol. 76, pp. 1774-1779. https://doi.org/10.1136/annrheumdis-2017-211414
Bowes, John ; Ashcroft, James ; Dand, Nick ; Jalali-Najafabadi, Farideh ; Bellou, Eftychia ; Ho, Pauline ; Marzo-Ortega, Helena ; Helliwell, Philip S ; Feletar, Marie ; Ryan, Anthony W ; Kane, David J ; Korendowych, Eleanor ; Simpson, Michael A ; Packham, Jonathan ; McManus, Ross ; Brown, Matthew A ; Smith, Catherine H ; Barker, Jonathan N ; McHugh, Neil ; Fitzgerald, Oliver ; Warren, Richard B ; Barton, Anne. / Cross-phenotype association mapping of the MHC identifies genetic variants that differentiate psoriatic arthritis from psoriasis. In: Annals of the Rheumatic Diseases. 2017 ; Vol. 76. pp. 1774-1779.
@article{535eeca931eb4154a01fcd1756e36492,
title = "Cross-phenotype association mapping of the MHC identifies genetic variants that differentiate psoriatic arthritis from psoriasis",
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.",
keywords = "Journal Article",
author = "John Bowes and James Ashcroft and Nick Dand and Farideh Jalali-Najafabadi and Eftychia Bellou and Pauline Ho and Helena Marzo-Ortega and Helliwell, {Philip S} and Marie Feletar and Ryan, {Anthony W} and Kane, {David J} and Eleanor Korendowych and Simpson, {Michael A} and Jonathan Packham and Ross McManus and Brown, {Matthew A} and Smith, {Catherine H} and Barker, {Jonathan N} and Neil McHugh and Oliver Fitzgerald and Warren, {Richard B} and Anne Barton",
note = "{\circledC} Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.",
year = "2017",
month = "10",
day = "1",
doi = "10.1136/annrheumdis-2017-211414",
language = "English",
volume = "76",
pages = "1774--1779",
journal = "Annals of the Rheumatic Diseases",
issn = "0003-4967",
publisher = "BMJ Publishing Group Ltd",

}

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

N1 - © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

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=9.57x10-66, 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.

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=9.57x10-66, 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.

KW - Journal Article

UR - https://doi.org/10.1136/annrheumdis-2017-211414

U2 - 10.1136/annrheumdis-2017-211414

DO - 10.1136/annrheumdis-2017-211414

M3 - Article

VL - 76

SP - 1774

EP - 1779

JO - Annals of the Rheumatic Diseases

T2 - Annals of the Rheumatic Diseases

JF - Annals of the Rheumatic Diseases

SN - 0003-4967

ER -