Gene Variant Test Distinguishes Individuals with Ankylosing Spondylitis

Natural variations in an immune system enzyme that can leave individuals susceptible to the inflammatory rheumatic disease ankylosing spondylitis have been discovered.

Better understanding of these variations could lead to a genetic test that helps people become aware of the risk of ankylosing spondylitis earlier and improve disease prognosis. Ankylosing spondylitis (AS) is a chronic inflammatory disease that mainly affects joints in the spine and in severe cases it can lead to complete fusion and rigidity of the spine, a condition that is sometimes called "bamboo spine."


Scientists at the University of Southampton (UK) characterized the full-length coding sequence of individual endoplasmic reticulum aminopeptidase 1(ERAP1) allotypes from a cohort of AS cases and non-AS controls, revealing 13 different allotypes, and propose a standardized nomenclature reflecting the highly polymorphic nature of ERAP1. These ERAP1 allotypes revealed a level of disease distinction with the frequency of those identified in non-AS controls, significantly different from those observed in AS cases. The characterization of allotype pairs revealed stratification of AS cases and control groups because no combination was shared between groups.

The investigators isolated ERAP1 from complementary DNA (cDNA) and polymerase chain reaction (PCR) amplicons were cloned into vectors and sequenced to identify individual allotypes. ERAP1 allotype sequences were aligned and phylogenetic analysis was performed. The team also employed cell lines, T-cell activation, and major histocompatibility complex (MHC I) recovery assays to analyze the specimens. Cells were analyzed by flow cytometry with a BD FACS Canto II (BD Bioscience; Oxford, UK). Expression of ERAP1 was determined by immunoblots.

The authors concluded that their study provides a framework for understanding how ERAP1 function could impact on disease pathogenesis and how the distinct allotype combinations in AS cases may serve as biomarkers for disease stratification and a target for treatment. Tim Elliott, PhD, co-leader of the study and professor of Experimental Medicine at Southampton, said, “These natural variations in ERAP1, which are normally involved in T-cell immunity, predispose individuals to ankylosing spondylitis. We have also discovered how variations in ERAP1 change its enzyme function and this means that it might actually be a target for developing new drugs to treat ankylosing spondylitis.” The study was published on December 9, 2014, in the journal Proceedings of the National Academy of Sciences of the United States of America (PNAS).

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University of Southampton
BD Bioscience