Candidate Gene SNP Analysis Within the Locus on Chromosome 9p With Linkage to Acute Anterior Uveitis

Abstract

Abstract: : Purpose: A genome–wide scan for acute anterior uveitis (AAU), which is associated with the spondyloarthropathies, was previously conducted (Martin, et al. Arthritis Rheum., in press). In that study, a region on chromosome 9p was found to have linkage to AAU. This region contains several genes important in immune responses and therefore are strong candidates for AAU. One of these genes is RFX3 (a transcription factor which may regulate MHC class II genes), another group of candidate genes are the type I interferons, and lastly, TEK is a candidate because it is expressed exlusively in vascular endothelium. In order to test these specific candidate genes with the linkage of chromosome 9p and AAU, we typed 35 single nucleotide polymorphism (SNP) markers that cover RFX3, the type I interferons, and TEK. Methods: The SNPs were distributed in three separate regions on chromosome 9p at ∼3, 21 and 27 Mb (physical position from the p–telomere). The cohort of AAU families included those enrolled by the group at OHSU as well as the North American Spondylitis Consortium (NASC). For inclusion by OHSU, affected family members were verified to have AAU by ophthalmology chart review. The families enrolled by the NASC were included if the affected family members both self–reported AAU and a notation of AAU was in a medical chart. The transmission disequilibrium test (TDT) was performed on those families in which parents of individuals affected with AAU were available. Results: Seven SNPs covering RFX3 (between chromosomal positions 3.2 – 3.5 Mb) were typed. None of these SNPs reached statistical significance, but one SNP was suggestive with a TDT p–value = 0.0606 (marker C__2013823_10). Twenty–four SNPs spread across the type I interferon genes, between 21.0 and 21.4 Mb, were also analyzed. Of these, marker C__141823_10 was significant, TDT p–value = 0.0065. This marker is located 2kb downstream of IFNA14. The 3^rd gene cluster included TEK at 27.5 Mb. There was no evidence of linkage at any of the 4 SNPs tested at this cluster. Conclusions: These data implicate the region of chromosome 9p responsible for linkage to AAU as the gene cluster at ∼21 Mb which contains the type I interferon genes. One SNP, C__141823_10, was found to have a significant TDT signal. Even though the closest gene to this SNP is IFNA14, additional analysis is needed to determine the actual gene responsible for the observed linkage.

Keywords: genetics • linkage analysis • inflammation