Major histocompatibility complex associations of ankylosing spondylitis are complex and involve further epistasis with ERAP1

Adrian Cortes; Sara L. Pulit; Paul J. Leo; Jenny J. Pointon; Philip C. Robinson; Michael H. Weisman; Michael Ward; Lianne S. Gensler; Xiaodong Zhou; Henri-Jean Garchon; Gilles Chiocchia; Johannes Nossent; Benedicte A. Lie; Øystein Førre; Jaakko Tuomilehto; Kari Laiho; Linda A. Bradbury; Dirk Elewaut; Ruben Burgos-Vargas; Simon Stebbings; Louise Appleton; Claire Farrah; Jonathan Lau; Nigil Haroon; Juan Mulero; Francisco J. Blanco; Miguel A. Gonzalez-Gay; C Lopez-Larrea; Paul Bowness; Karl Gaffney; Hill Gaston; Dafna D. Gladman; Proton Rahman; Walter P Maksymowych; J Bart A Crusius; Irene E van der Horst-Bruinsma; Raphael Valle-Oñate; Consuelo Romero-Sánchez; Inger Myrnes Hansen; Fernando M Pimentel-Santos; Robert D Inman; Javier Martin; Maxime Breban; Bryan Paul Wordsworth; John D Reveille; David M Evans; Paul I W de Bakker; Matthew A Brown

doi:10.1038/ncomms8146

Major histocompatibility complex associations of ankylosing spondylitis are complex and involve further epistasis with ERAP1

Adrian Cortes, Sara L. Pulit, Paul J. Leo, Jenny J. Pointon, Philip C. Robinson, Michael H. Weisman, Michael Ward, Lianne S. Gensler, Xiaodong Zhou, Henri-Jean Garchon, Gilles Chiocchia, Johannes Nossent, Benedicte A. Lie, Øystein Førre, Jaakko Tuomilehto, Kari Laiho, Linda A. Bradbury, Dirk Elewaut, Ruben Burgos-Vargas, Simon StebbingsLouise Appleton, Claire Farrah, Jonathan Lau, Nigil Haroon, Juan Mulero, Francisco J. Blanco, Miguel A. Gonzalez-Gay, C Lopez-Larrea, Paul Bowness, Karl Gaffney, Hill Gaston, Dafna D. Gladman, Proton Rahman, Walter P Maksymowych, J Bart A Crusius, Irene E van der Horst-Bruinsma, Raphael Valle-Oñate, Consuelo Romero-Sánchez, Inger Myrnes Hansen, Fernando M Pimentel-Santos, Robert D Inman, Javier Martin, Maxime Breban, Bryan Paul Wordsworth, John D Reveille, David M Evans, Paul I W de Bakker, Matthew A Brown

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Abstract

Ankylosing spondylitis (AS) is a common, highly heritable, inflammatory arthritis for which HLA-B*27 is the major genetic risk factor, although its role in the aetiology of AS remains elusive. To better understand the genetic basis of the MHC susceptibility loci, we genotyped 7,264 MHC SNPs in 22,647 AS cases and controls of European descent. We impute SNPs, classical HLA alleles and amino-acid residues within HLA proteins, and tested these for association to AS status. Here we show that in addition to effects due to HLA-B*27 alleles, several other HLA-B alleles also affect susceptibility. After controlling for the associated haplotypes in HLA-B, we observe independent associations with variants in the HLA-A, HLA-DPB1 and HLA-DRB1 loci. We also demonstrate that the ERAP1 SNP rs30187 association is not restricted only to carriers of HLA-B*27 but also found in HLA-B*40:01 carriers independently of HLA-B*27 genotype.

Original language	English
Article number	7146
Journal	Nature Communications
Volume	6
DOIs	https://doi.org/10.1038/ncomms8146
Publication status	Published - 21 May 2015

Keywords

Aminopeptidases/genetics
Case-Control Studies
Epistasis, Genetic
Genetic Predisposition to Disease
HLA-B27 Antigen/genetics
HLA-B40 Antigen/genetics
Humans
Major Histocompatibility Complex
Minor Histocompatibility Antigens
Polymorphism, Single Nucleotide
Spondylitis, Ankylosing/etiology

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10.1038/ncomms8146Licence: CC BY

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Cite this

Cortes, A., Pulit, S. L., Leo, P. J., Pointon, J. J., Robinson, P. C., Weisman, M. H., Ward, M., Gensler, L. S., Zhou, X., Garchon, H.-J., Chiocchia, G., Nossent, J., Lie, B. A., Førre, Ø., Tuomilehto, J., Laiho, K., Bradbury, L. A., Elewaut, D., Burgos-Vargas, R., ... Brown, M. A. (2015). Major histocompatibility complex associations of ankylosing spondylitis are complex and involve further epistasis with ERAP1. Nature Communications, 6, Article 7146. https://doi.org/10.1038/ncomms8146

@article{9ed557a5bb8845e7b69e7b560e5bff0e,

title = "Major histocompatibility complex associations of ankylosing spondylitis are complex and involve further epistasis with ERAP1",

abstract = "Ankylosing spondylitis (AS) is a common, highly heritable, inflammatory arthritis for which HLA-B*27 is the major genetic risk factor, although its role in the aetiology of AS remains elusive. To better understand the genetic basis of the MHC susceptibility loci, we genotyped 7,264 MHC SNPs in 22,647 AS cases and controls of European descent. We impute SNPs, classical HLA alleles and amino-acid residues within HLA proteins, and tested these for association to AS status. Here we show that in addition to effects due to HLA-B*27 alleles, several other HLA-B alleles also affect susceptibility. After controlling for the associated haplotypes in HLA-B, we observe independent associations with variants in the HLA-A, HLA-DPB1 and HLA-DRB1 loci. We also demonstrate that the ERAP1 SNP rs30187 association is not restricted only to carriers of HLA-B*27 but also found in HLA-B*40:01 carriers independently of HLA-B*27 genotype. ",

keywords = "Aminopeptidases/genetics, Case-Control Studies, Epistasis, Genetic, Genetic Predisposition to Disease, HLA-B27 Antigen/genetics, HLA-B40 Antigen/genetics, Humans, Major Histocompatibility Complex, Minor Histocompatibility Antigens, Polymorphism, Single Nucleotide, Spondylitis, Ankylosing/etiology",

author = "Adrian Cortes and Pulit, {Sara L.} and Leo, {Paul J.} and Pointon, {Jenny J.} and Robinson, {Philip C.} and Weisman, {Michael H.} and Michael Ward and Gensler, {Lianne S.} and Xiaodong Zhou and Henri-Jean Garchon and Gilles Chiocchia and Johannes Nossent and Lie, {Benedicte A.} and {\O}ystein F{\o}rre and Jaakko Tuomilehto and Kari Laiho and Bradbury, {Linda A.} and Dirk Elewaut and Ruben Burgos-Vargas and Simon Stebbings and Louise Appleton and Claire Farrah and Jonathan Lau and Nigil Haroon and Juan Mulero and Blanco, {Francisco J.} and Gonzalez-Gay, {Miguel A.} and C Lopez-Larrea and Paul Bowness and Karl Gaffney and Hill Gaston and Gladman, {Dafna D.} and Proton Rahman and Maksymowych, {Walter P} and Crusius, {J Bart A} and {van der Horst-Bruinsma}, {Irene E} and Raphael Valle-O{\~n}ate and Consuelo Romero-S{\'a}nchez and Hansen, {Inger Myrnes} and Pimentel-Santos, {Fernando M} and Inman, {Robert D} and Javier Martin and Maxime Breban and Wordsworth, {Bryan Paul} and Reveille, {John D} and Evans, {David M} and {de Bakker}, {Paul I W} and Brown, {Matthew A}",

year = "2015",

month = may,

day = "21",

doi = "10.1038/ncomms8146",

language = "English",

volume = "6",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

}

Cortes, A, Pulit, SL, Leo, PJ, Pointon, JJ, Robinson, PC, Weisman, MH, Ward, M, Gensler, LS, Zhou, X, Garchon, H-J, Chiocchia, G, Nossent, J, Lie, BA, Førre, Ø, Tuomilehto, J, Laiho, K, Bradbury, LA, Elewaut, D, Burgos-Vargas, R, Stebbings, S, Appleton, L, Farrah, C, Lau, J, Haroon, N, Mulero, J, Blanco, FJ, Gonzalez-Gay, MA, Lopez-Larrea, C, Bowness, P, Gaffney, K, Gaston, H, Gladman, DD, Rahman, P, Maksymowych, WP, Crusius, JBA, van der Horst-Bruinsma, IE, Valle-Oñate, R, Romero-Sánchez, C, Hansen, IM, Pimentel-Santos, FM, Inman, RD, Martin, J, Breban, M, Wordsworth, BP, Reveille, JD, Evans, DM, de Bakker, PIW & Brown, MA 2015, 'Major histocompatibility complex associations of ankylosing spondylitis are complex and involve further epistasis with ERAP1', Nature Communications, vol. 6, 7146. https://doi.org/10.1038/ncomms8146

TY - JOUR

T1 - Major histocompatibility complex associations of ankylosing spondylitis are complex and involve further epistasis with ERAP1

AU - Cortes, Adrian

AU - Pulit, Sara L.

AU - Leo, Paul J.

AU - Pointon, Jenny J.

AU - Robinson, Philip C.

AU - Weisman, Michael H.

AU - Ward, Michael

AU - Gensler, Lianne S.

AU - Zhou, Xiaodong

AU - Garchon, Henri-Jean

AU - Chiocchia, Gilles

AU - Nossent, Johannes

AU - Lie, Benedicte A.

AU - Førre, Øystein

AU - Tuomilehto, Jaakko

AU - Laiho, Kari

AU - Bradbury, Linda A.

AU - Elewaut, Dirk

AU - Burgos-Vargas, Ruben

AU - Stebbings, Simon

AU - Appleton, Louise

AU - Farrah, Claire

AU - Lau, Jonathan

AU - Haroon, Nigil

AU - Mulero, Juan

AU - Blanco, Francisco J.

AU - Gonzalez-Gay, Miguel A.

AU - Lopez-Larrea, C

AU - Bowness, Paul

AU - Gaffney, Karl

AU - Gaston, Hill

AU - Gladman, Dafna D.

AU - Rahman, Proton

AU - Maksymowych, Walter P

AU - Crusius, J Bart A

AU - van der Horst-Bruinsma, Irene E

AU - Valle-Oñate, Raphael

AU - Romero-Sánchez, Consuelo

AU - Hansen, Inger Myrnes

AU - Pimentel-Santos, Fernando M

AU - Inman, Robert D

AU - Martin, Javier

AU - Breban, Maxime

AU - Wordsworth, Bryan Paul

AU - Reveille, John D

AU - Evans, David M

AU - de Bakker, Paul I W

AU - Brown, Matthew A

PY - 2015/5/21

Y1 - 2015/5/21

N2 - Ankylosing spondylitis (AS) is a common, highly heritable, inflammatory arthritis for which HLA-B*27 is the major genetic risk factor, although its role in the aetiology of AS remains elusive. To better understand the genetic basis of the MHC susceptibility loci, we genotyped 7,264 MHC SNPs in 22,647 AS cases and controls of European descent. We impute SNPs, classical HLA alleles and amino-acid residues within HLA proteins, and tested these for association to AS status. Here we show that in addition to effects due to HLA-B*27 alleles, several other HLA-B alleles also affect susceptibility. After controlling for the associated haplotypes in HLA-B, we observe independent associations with variants in the HLA-A, HLA-DPB1 and HLA-DRB1 loci. We also demonstrate that the ERAP1 SNP rs30187 association is not restricted only to carriers of HLA-B*27 but also found in HLA-B*40:01 carriers independently of HLA-B*27 genotype.

AB - Ankylosing spondylitis (AS) is a common, highly heritable, inflammatory arthritis for which HLA-B*27 is the major genetic risk factor, although its role in the aetiology of AS remains elusive. To better understand the genetic basis of the MHC susceptibility loci, we genotyped 7,264 MHC SNPs in 22,647 AS cases and controls of European descent. We impute SNPs, classical HLA alleles and amino-acid residues within HLA proteins, and tested these for association to AS status. Here we show that in addition to effects due to HLA-B*27 alleles, several other HLA-B alleles also affect susceptibility. After controlling for the associated haplotypes in HLA-B, we observe independent associations with variants in the HLA-A, HLA-DPB1 and HLA-DRB1 loci. We also demonstrate that the ERAP1 SNP rs30187 association is not restricted only to carriers of HLA-B*27 but also found in HLA-B*40:01 carriers independently of HLA-B*27 genotype.

KW - Aminopeptidases/genetics

KW - Case-Control Studies

KW - Epistasis, Genetic

KW - Genetic Predisposition to Disease

KW - HLA-B27 Antigen/genetics

KW - HLA-B40 Antigen/genetics

KW - Humans

KW - Major Histocompatibility Complex

KW - Minor Histocompatibility Antigens

KW - Polymorphism, Single Nucleotide

KW - Spondylitis, Ankylosing/etiology

U2 - 10.1038/ncomms8146

DO - 10.1038/ncomms8146

M3 - Article

C2 - 25994336

SN - 2041-1723

VL - 6

JO - Nature Communications

JF - Nature Communications

M1 - 7146

ER -