The Sarcoidosis Candidate Gene, CR1, Is Associated With Uveitis in Sarcoidosis Patients

Abstract

Abstract: : Purpose: Sarcoidosis is a multi–system inflammatory disease that often involves the eye. Uveitis, which may result in visual loss, is the most common ocular manifestation. The Complement Receptor 1 (CR1) gene has been implicated in the genetic predisposition to sarcoidosis. CR1 has a role in the clearance of immune complexes. Deficient clearance is thought to precipitate granulomatous inflammation that is seen in sarcoidosis. The CR1 gene contains a long homologous repeat in intron 27 giving rise to 2 alleles that exhibit low or high levels of cell surface expression of CR1, respectively. This repeat polymorphism is in linkage disequilibrium with a single nucleotide polymorphism (SNP) in exon 33 (NCBI reference SNP rs3811381), a C to G change encoding the Pro1827Arg substitution. This SNP was significantly associated with sarcoidosis in an Italian patient cohort (Am J Respir Cell Mol Biol 27:17, 2002). In the present study, we sought to determine if the Pro1827Arg SNP was present specifically in patients with sarcoidosis who developed uveitis. Methods: Healthy controls and patients provided informed consent. Medical records were reviewed to validate the diagnoses of sarcoidosis and sarcoidosis–associated uveitis. Genomic DNA was extracted from anticoagulated blood using standard techniques. Genotypes were determined by direct DNA sequencing of an amplicon flanking the SNP in exon 33, which was generated by the polymerase chain reaction using specific primers. Allele frequencies were determined and statistical comparisons were made by the Fisher’s exact test. Results: Forty controls and 47 sarcoidosis patients were enrolled; with approximately half of the sarcoidosis group also having a history of uveitis. Both groups were predominantly Caucasians residing in the U.S. and Canada. The variant allele frequency (G) was found to be 11% in the control group compared to 26% in the sarcoidosis group (p = 0.0198). Furthermore, the presence of this variant allele was skewed toward patients with both sarcoidosis and uveitis, where its frequency was 35%. This was highly significant compared to the control group (p= 0.0023). Conclusions: The Pro1827Arg SNP may be associated with an increased risk of sarcoidosis in our predominantly Caucasian cohort, particularly in those who also had a history of uveitis. This association supports previous findings and suggests that the CR1 gene may also influence the pattern of sarcoid presentation.

Keywords: gene/expression • uveitis-clinical/animal model • autoimmune disease