Ankylosing Spondylitis
Gene Association Hints at Potential Ankylosing Spondylitis Treatment
By Maripat Corr, MD
Abstract
We have genotyped 14,436 nonsynonymous single nucleotide polymorphisms (nsSNPs) and 897 major histocompatibility complex (MHC) tag SNPs from 1,000 independent cases of ankylosing spondylitis (AS), autoimmune thyroid disease (AITD), multiple sclerosis (MS), and breast cancer (BC). Comparing these data against a common control dataset derived from 1,500 randomly selected healthy British individuals, we report initial association and independent replication in a North American sample of two new loci related to AS—ARTS1 and IL23R—and confirmation of the previously reported association of AITD with TSHR and FCRL3. These findings, enabled in part by increased statistical power resulting from the expansion of the control reference group to include individuals from the other disease groups, highlight notable new possibilities for autoimmune regulation and suggest that IL23R may be a common susceptibility factor for the major “seronegative” diseases.
Commentary
The new platforms for high-throughput genetic screening are rapidly expanding our knowledge of susceptibility loci for complex diseases. Investigators for the Wellcome Trust Case Control Consortium and the Australo-Anglo-American Spondylitis Consortium recently reported their findings from a large, genome-wide scan of four diseases. The strongest associations observed in the study were between SNPs in the major histocompatibility (MHC) encoding region and the three autoimmune diseases studied: AS, AITD, and MS. The genome-wide scan also identified and validated two new genes—ARTS1 (type 1 tumor necrosis factor receptor shedding aminopeptidase regulator) and IL23R (interleukin 23 receptor)—to be associated with AS.
Functionally, ARTS1 and IL23R represent interesting biological candidates for association with AS. The ARTS1 (also known as ERAAP, or ERAP1) gene encodes a type II integral transmembrane aminopeptidase with intra- and extracellular functions. In the endoplasmic reticulum, ARTS1 is involved in processing peptides to the optimal length for MHC class I presentation.1,2 This activity is intriguing because of the strong association of AS with the class I allele HLA-B27. A genetic association with the peptide loading process suggests a mechanistic link to HLA-B27 in developing disease. Alternatively, ARTS1 cleaves cell surface receptors for pro-inflammatory cytokines like IL-1, IL-6, and tumor necrosis factor (TNF), reducing the number of surface receptors and releasing soluble receptor antagonists.3-5 Potentially, a variant of ARTS1 with reduced ability to cleave surface receptors would prolong the interval that cells could receive signals from inflammatory cytokines.