Genotype Analysis of Polymorphisms in the Ankylosing Spondylitis (AS) Susceptibility Gene ERAP1 (ARTS1) in an Acute Anterior Uveitis (AAU) Cohort

Abstract

Purpose: : ERAP1 is a gene located on human chromosome 5q15. The protein is an aminopeptidase involved in trimming peptides for MHC class 1 presentation and in cleaving cell surface cytokine receptors such as the type I TNF receptor. Single nucleotide polymorphisms (SNPs) in ERAP1 have been associated with susceptibility to AS. In this study, we assessed four ERAP1 SNPs in AAU, the most common form of immune-mediated uveitis.

Methods: : This research was conducted under human subjects protocols approved by the investigators’ ethics committees. The diagnostic validation of AAU was based on chart review by an ophthalmologist. Genomic DNA was extracted from whole blood. Genotyping of the SNPs was performed by denaturing HPLC and/or direct sequencing of DNA amplified by SSP-PCR. Minor allele frequencies (MAFs) were analyzed using the chi2 test.

Results: : The AAU cohort consisted of 167 subjects (94 female, 73 male), with 159 identified as Caucasian. Of the 167 with AAU, 85 were without history of AS, while 24 had a diagnosis of AS and 56 subjects were considered to have probable or early signs of AS; in 2 subjects the AS status was unknown. The healthy control cohort represented 112 subjects (66 female, 46 male), 103 of whom were Caucasian. In 2 of the 4 analyzed SNPs, statistically significant differences in the MAFs were found. The rs30187 and rs27044 MAFs were 47.0% and 38.3% in the AAU group, and 36.4% and 29.1% in the control group (uncorrected p=0.02 and 0.03 respectively). The other 2 SNPs, rs2287987 and rs17482078 were found to be in linkage. Although we noted a higher MAF in the AAU group (56.0% vs.46.4% in the control group), the difference was not statistically significant (p=0.14). The SNP MAFs in the control group were in agreement with other published Caucasian cohorts. Sub-analyses with only the subjects without history of AS or only the AS subjects compared to the healthy controls showed similar results (uncorrected p=0.03 and 0.04 for rs30187, respectively; p=0.05 in both subgroups for rs27044; and p> 0.05 in both subgroups for the two SNPs in linkage).

Conclusions: : These results suggest that polymorphisms in ERAP1 may contribute to the risk of AAU, independent of the presence of AS. Concerning rs2287987 and rs17482078, a larger cohort would be needed to determine if our observation of a trend towards a relationship is significant.

Keywords: genetics • autoimmune disease • uveitis-clinical/animal model