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
VL - 6
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
M1 - 7146
ER -