Introduction Endoplasmic reticulum aminopeptidase-1 (ERAP1) protein is highly polymorphic with numerous missense amino acid variants. We sought to determine the naturally occurring ERAP1 protein allotypes and their contribution to Behçet's disease.
Methods Genotypes of all reported missense ERAP1 gene variants with 1000 Genomes Project EUR superpopulation frequency >1% were determined in 1900 Behçet's disease cases and 1779 controls from Turkey. ERAP1 protein allotypes and their contributions to Behçet's disease risk were determined by haplotype identification and disease association analyses.
Results One ERAP1 protein allotype with five non-ancestral amino acids was recessively associated with disease (p=3.13×10−6, OR 2.55, 95% CI 1.70 to 3.82). The ERAP1 association was absent in individuals who lacked HLA-B*51. Individuals who carry HLA-B*51 and who are also homozygous for the haplotype had an increased disease odds compared with those with neither risk factor (p=4.80×10−20, OR 10.96, 95% CI 5.91 to 20.32).
Discussion The Behçet's disease-associated ERAP1 protein allotype was previously shown to have poor peptide trimming activity. Combined with its requirement for HLA-B*51, these data suggest that a hypoactive ERAP1 allotype contributes to Behçet's disease risk by altering the peptides available for binding to HLA-B*51.
- Behcet's disease
- Gene Polymorphism
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Handling editor Tore K Kvien
Contributors MT, MJO, YK, AG, DLK and EFR: study design. BE, I-TT, ES, YO and AG: patient recruitment. MT, EFR, MJO and NW: data collection. NW and MJO: protein modelling. MT, MJO, YK, BE, I-TT, ES, YO, AG, DLK and EFR: writing and approving the paper.
Funding This study was supported by the Intramural Research Programs of the National Human Genome Research Institute and the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Dr Kirino is supported by grants from Japan Society for the Promotion of Science Grant-in-Aid for Scientific Research (Grant No. 26713036), the Naito Memorial Foundation, the Kanae Foundation for the Promotion of Medical Science and Yokohama Foundation for Advancement of Medical Science.
Competing interests None declared.
Ethics approval Istanbul Faculty of Medicine Ethics Committee.
Provenance and peer review Not commissioned; externally peer reviewed.
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