Date: Tuesday, November 10, 2015
Session Title: Spondylarthropathies and Psoriatic Arthritis Pathogenesis, Etiology Poster I
Session Type: ACR Poster Session C
Session Time: 9:00AM-11:00AM
Background/Purpose: Polymorphisms in the endoplasmic reticulum aminopeptidase genes ERAP1 and/or ERAP2 are strongly associated with the diseases AS, psoriasis, IBD and Behcet’s disease. Robust genetic interaction exists between ERAP1 and the HLA Class I alleles HLA-B27 and –B40 (associated with AS), -Cw6 (in psoriasis), and -B*51 (in Behcet’s disease). In AS, two ERAP1 haplotypes are disease associated, tagged either by rs30187 (thought to be directly disease-associated) or rs10050860 (which lies on a disease-associated haplotype). Protective alleles of rs30187 are associated with reduced peptidase activity. We hypothesized that other AS-associated ERAP1 and ERAP2 genetic variants would also either lead to reduced function or expression of the respective gene.
Methods: RNA sequencing was performed on PBMC derived total RNA from 54 AS cases and 70 healthy controls. This data was analysed to investigate the gene and isoform expression profiles of ERAP1 and ERAP2. The consequences of ERAP1 variants on the protein level were then validated by mass spectrometry.
Results: Considering markers in linkage disequilibrium with rs30187, multiple showed effects on expression of ERAP1 (P=5.27×10-7 for lead variant rs39840), with protective variants invariably leading to reduced ERAP1 expression. The same property was noted for multiple protective ERAP2 variants associated with ERAP2 expression (lead SNP rs2910686, P=1.71×10-6, after correction for rs2248374 which leads to nonsense mediated decay of ERAP2 transcripts). On the second ERAP1 haplotype tagged by the SNP rs10050860, a subset of variants alter the expression of two isoforms of the gene. The risk allele at the lead putative splice altering polymorphism, rs7063, correlated with a significant increase in expression of the canonical 19-exon ERAP1 isoform (P=8.7×10-12, expression level 2x greater in AS-risk genotype carriers), and a significant decrease in the expression of a second 20-exon isoform (P=1.0×10-17, expression level 0.47x lower in risk genotype carriers). The proportion of the 19-exon isoform was also significantly greater in cases than controls (P=0.047). The correlation between ERAP1 disease risk genotype and isoform profile was replicated at the protein level. Protein expression of the second isoform was greatly reduced, rendering individual carrying the protective genotype at rs7063, with predominant production of this transcript variant, with significantly less total ERAP1 overall (P =1.58×10-6).
Conclusion: ERAP1 and ERAP2 genetic variants operate by effects on protein function, expression and sequence to influence the risk of developing AS and related diseases.
To cite this abstract in AMA style:Hanson A, Haynes K, Thomas G, Cuddihy T, Leo P, Brown MA. Genetic Variants at Chromosome 5q15 Associated with Immune-Mediated Diseases Influence Gene Expression and Isoform Profile of the Endoplasmic Reticulum Aminopeptidase [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). https://acrabstracts.org/abstract/genetic-variants-at-chromosome-5q15-associated-with-immune-mediated-diseases-influence-gene-expression-and-isoform-profile-of-the-endoplasmic-reticulum-aminopeptidase/. Accessed March 21, 2023.
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