Background/Purpose: We recently performed a genome-wide association study in 1215 patients with Behçet’s disease (BD) and 1278 controls from Turkey and found disease-associated variants within the class I region of the MHC, and in the IL10 and IL23R loci.  However, the combined effects of these loci account for less than 10% of the estimated disease heritability, suggesting other loci are yet to be identified.

Methods: To limit disease heterogeneity, we performed an analysis of the subset of patients with uveitis. In this subset we expanded the association analysis to include 3 genetic models, additive, dominant, and recessive, correcting the threshold for genome-wide significance for the 3 models examined.  Confirmatory studies were conducted in our combined GWAS and replication sets of 2017 BD cases and 1875 controls, and in this sample an interaction between two loci was evaluated with a logistic likelihood ratio test comparing a full model (including a multiplicative interaction term) with a reduced model (without the interaction term).

Results: A genome-wide analysis, applying a recessive model, in 420 BD patients with uveitis and 1278 controls revealed one variant located 5’ of ERAP1, with near genome-wide significance (rs2927615, p = 1.02 x 10^-7).  This effect was not observed with an additive or dominant model.  ERAP1 encodes an endoplasmic reticulum expressed aminopeptidase that plays an important role in trimming and loading intracellular peptides for class I MHC presentation.  Fine-mapping with the same samples and replication in an independent collection of 370 Turkish BD cases with uveitis and 630 controls identified two disease-associated non-synonymous variants in ERAP1, with the most significant combined p value for rs17482078 (R725Q) = 4.73 x 10^-11, OR = 4.56, 95%CI: 2.88-7.22).  Focusing solely on the recessive model, the effect of the variant was corroborated by meta-analysis of the combined 2017 BD cases (including those with and without uveitis) and 1875 controls (p = 4.35 x 10^-8).  Furthermore, we identified a genetic interaction between the BD-associated MHC class I allele, HLA-B*51, and ERAP1 (p < 0.0009) in the combined Turkish GWAS and replication samples.  ERAP1 R725Q homozygosity compared with non-homozygosity was associated with an OR for BD of 3.78 (95% CI = 1.94-7.35) in HLA- B*51 positive individuals versus an OR of 1.48 (95% CI =0.78-2.80) in HLA-B*51 negative individuals.

Conclusion: A coding variant of ERAP1, encoding endoplasmic reticulum expressed amino peptidase 1, recessively confers risk for BD preferentially to individuals carrying the disease-associated HLA-B*51 allele.  Genetic similarity with two other MHC class I associated diseases, ankylosing spondylitis and psoriasis (shared loci include MHC class I, IL23R, ERAP1 and the MHC-ERAP1 interaction), suggest shared pathogenic pathways among these diseases.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/genome-wide-analysis-reveals-a-recessive-association-of-erap1-variants-with-behcets-disease-and-epistasis-between-erap1-and-hla-b51/