title: ERAP1 association with ankylosing spondylitis is attributable to common genotypes rather than rare haplotype combinations.
abstract: We investigated the proposal that ankylosing spondylitis (AS) is associated with unusual ERAP1 genotypes. ERAP1 haplotypes were constructed for 213 AS cases and 46 rheumatoid arthritis controls using family data. Haplotypes were generated from five common ERAP1 single nucleotide polymorphisms (SNPs)-rs2287987 (M349V), rs30187 (K528R), rs10050860 (D575N), rs17482078 (R725Q), and rs27044 (Q730E). Haplotype frequencies were compared using Fisher's exact test. ERAP1 haplotypes imputed from the International Genetics of AS Consortium (IGAS) Immunochip study were also studied. In the family study, we identified only four common ERAP1 haplotypes ("VRNQE," "MKDRQ," "MRDRE," and "MKDRE") in both AS cases and controls apart from two rare (<0.5%) previously unreported haplotypes. There were no examples of the unusual ERAP1 haplotype combination ("*001/*005") previously reported by others in 53% of AS cases. As expected, K528-bearing haplotypes were increased in the AS family study (AS 43% vs. control 35%), due particularly to an increase in the MKDRQ haplotype (AS 35% vs. control 25%, P = 0.01). This trend was replicated in the imputed Immunochip data for the two K528-bearing haplotypes MKDRQ (AS 33% vs. controls 27%, P = 1.2 × 10-24) and MKDRE (AS 8% vs. controls 7%, P = 0.004). The ERAP1 association with AS is therefore predominantly attributable to common ERAP1 haplotypes and haplotype combinations.
authors.affiliation: Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford OX3 7LD, United Kingdom.|National Institute for Health Research Oxford Comprehensive Biomedical Research Centre, Oxford OX3 7LE, United Kingdom.
authors.forename: Amity R
authors.initials: AR
authors.lastname: Roberts
authors.affiliation: Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford OX3 7LD, United Kingdom.|National Institute for Health Research Oxford Comprehensive Biomedical Research Centre, Oxford OX3 7LE, United Kingdom.
authors.forename: Louise H
authors.initials: LH
authors.lastname: Appleton
authors.affiliation: Nuffield Department of Clinical Neurosciences, Division of Clinical Neurology, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, United Kingdom.|Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, United Kingdom.
authors.forename: Adrian
authors.initials: A
authors.lastname: Cortes
authors.affiliation: Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford OX3 7LD, United Kingdom.|National Institute for Health Research Oxford Comprehensive Biomedical Research Centre, Oxford OX3 7LE, United Kingdom.
authors.forename: Matteo
authors.initials: M
authors.lastname: Vecellio
authors.affiliation: Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford OX3 7LD, United Kingdom.|National Institute for Health Research Oxford Comprehensive Biomedical Research Centre, Oxford OX3 7LE, United Kingdom.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Lau
authors.affiliation: Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford OX3 7LD, United Kingdom.|National Institute for Health Research Oxford Comprehensive Biomedical Research Centre, Oxford OX3 7LE, United Kingdom.
authors.forename: Laura
authors.initials: L
authors.lastname: Watts
authors.affiliation: Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, QLD 4102, Australia.|Translational Research Institute, Princess Alexandra Hospital, Woolloongabba, QLD 4102, Australia.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Brown
authors.affiliation: Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford OX3 7LD, United Kingdom; paul.wordsworth@ndorms.ox.ac.uk.|National Institute for Health Research Oxford Comprehensive Biomedical Research Centre, Oxford OX3 7LE, United Kingdom.
authors.forename: Paul
authors.initials: P
authors.lastname: Wordsworth
mesh_terms: D000626:Aminopeptidases / Q000235:genetics*; D001172:Arthritis, Rheumatoid / Q000235:genetics; D016022:Case-Control Studies; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D015796:HLA-B27 Antigen / Q000235:genetics; D006239:Haplotypes; D006801:Humans; D008297:Male; D015778:Minor Histocompatibility Antigens / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D013167:Spondylitis, Ankylosing / Q000201:enzymology / Q000235:genetics* / Q000276:immunology
chemical_list: D015796:HLA-B27 Antigen; D015778:Minor Histocompatibility Antigens; D000626:Aminopeptidases; C464841:ERAP1 protein, human
keywords: ERAP1; ankylosing spondylitis; haplotypes