ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 1612

Ankylosing Spondylitis Is Associated with Single Nucleotide Polymorphisms in Loci Implicating Four Aminopeptidases

Philip Robinson1, Adrian Cortes1, Paul Leo1, Australian-Anglo-American Spondylitis Consortium (TASC)2, Wellcome Trust Case Control Consortium (WTCCC) .3, International Genetics of Ankylosing Spondylosis Consortium (IGAS)4, David Evans5 and Matthew A. Brown1, 1Human Genetics Group, University of Queensland Diamantina Insititute, Brisbane, Australia, 2University of Queensland Diamantina Institute, Brisbane, Australia, 3Wellcome Trust Case Control Consortium, Wellcome Trust Case Control Consortium, United Kingdom, 4IGAS, Igas, Australia, 5School of Social and Community Medicine, Bristol University, Bristol, United Kingdom

Meeting: 2012 ACR/ARHP Annual Meeting

Keywords:

Session Information

Title: Genetics and Genomics of Rheumatic Diseases

Session Type: Abstract Submissions (ACR)

Background/Purpose:

The aim of the study was to examine regions implicated in autoimmune diseases for association with AS. A previous association with AS has been described in the aminopetidase ERAP1.

Methods:

9074 European and 1550 east Asian AS cases (defined by the modified New York Criteria), and 13607 European and 1567 Asian controls were studied. Samples were genotyped on the Illumina Infinium Immunochip (196,524 SNVs), clustering performed using Opticall, and analysis performed using linear mixed modelling (FaST-LMM) to control for population stratification.

Results:

9074 European and 1550 east Asian AS cases (defined by the modified New York Criteria), and 13607 European and 1567 Asian controls were studied. Samples were genotyped on the Illumina Infinium Immunochip (196,524 SNVs), clustering performed using Opticall, and analysis performed using linear mixed modelling (FaST-LMM) to control for population stratification.

Results

After QC and removal of non-polymorphic variants, 129,030 SNPs remained. The two previously described independent associations in ERAP1 were replicated in the European cohort (rs30187, OR=0.77, p=1.3×10-41; rs10050860, OR=0.77, p=3.2×10-32), and suggestive association was noted with rs30187 in the Asian cohort (OR=0.81, p=2.1×10-5). rs10050860 was found to have low MAF (0.037) in the Asian cohort and therefore for this SNP in this ethnic group, the study had low power. In the European cohort, controlling for the association with ERAP1, SNPs in ERAP2 and LNPEP were also associated with AS (lead SNP: rs2910686, OR=1.17, p=1.3×10-16). We have previously demonstrated that at ERAP1, disease-protective variants are associated with reduced aminopeptidase function. At ERAP2, the AS-protective G allele of rs2248374 causes a complete loss of ERAP2 mRNA and no expression of ERAP2 protein. In HLA-B27 negative AS cases association was observed with the ERAP2 SNP also associated with Crohn’s disease (rs2549794, OR=1.2, p=8×10-6). Genomewide significant association was noted at chromosome 17q21 at a locus encoding the aminopeptidase NPEPPS (rs9901869, p=3.2 x10-14; OR = 0.88), a further aminopeptidase involved in peptide trimming prior to HLA Class I presentation.

Conclusion:

This study identifies robust association with three loci housing four aminopeptidases, ERAP1, ERAP2, LNPEP and NPEPPS. At ERAP1 and ERAP2, protective genetic associations are associated with reduced aminopeptidase function. This implicates peptide handling as a major mechanism in the aetiology of both HLA-B27 positive and negative AS.

Disclosure:

P. Robinson,
None;

A. Cortes,
None;

P. Leo,
None;

W. T. C. C. C. .,
None;

I. G. O. A. S. C. (IGAS),
None;

D. Evans,
None;

M. A. Brown,
None.

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