Diagnostic SNP Markers for Primary Open Angle Glaucoma

Abstract

Abstract: : Purpose:Glaucomas are optic neuropathies that cause irreversible blindness. Primary open-angle glaucoma (POAG) is a malfunction of the aqueous outflow pathway of the eye. Data indicate that this malfunction may be due to damage caused by free radicals, aging, and other stress responses. ELAM-1 is present in glaucomatous outflow pathway cells but not in controls (Nat Med 7:304-9, 2001). As ELAM-1 is regulated by an NF-kB-mediated IL-1 autocrine feedback loop, individual variations in the response of these genes to IL-1-mediated stress may contribute to the onset and progression of POAG. This suggests inherited polymorphisms in these genes may be indicative of predisposition for POAG. We intend to determine if specific single nucleotide polymorphisms (SNPs) in these stress-response genes are diagnostic of POAG. Methods:Diagnostic ophthalmic examinations (visual fields, IOP, and optic nerve head visualization) were performed on all open angle glaucoma and normal control patients to document presence or absence of POAG, and blood samples were collected for genetic screening. Genotyping was performed using PCR-based assays for 13 SNP markers representing five genes in the stress-response pathway (ELAM-1, IL-1A, IL-1B, IL-1RN, and IL-6). Statistical tests of association were performed to determine if any of the 13 SNPs, either alone or in combination, significantly correlate with clinical symptoms of POAG. Results:We have collected clinical data on 125 glaucoma and 175 normal patients towards our goal of 250 in each group. 95 POAG and 138 normal individuals have been genotyped at 5 SNP loci representing 3 genes - ELAM-1 (positions 98 and 561); IL-1b (-511 and 3953); IL-1 receptor antagonist (VNTR). The SNP at ELAM-1 (98) was uninformative and dropped from further consideration. G tests of association showed that none of the single SNP loci had a significant association with POAG. However the genotypes IL-1b (-511 T/T; p=0.15) and (3953 C/C; p=0.098), while not quite significant, were each strongly suggestive of an association with POAG. G tests of association between pairs of loci found two suggestive (P < 0.1) associations: ELAM-1 (561 A/A) and IL1b (-511 T/T), IL1b (-511 T/T) and IL1b (3953 C/C). Conclusions:Our data suggest an increased risk for POAG among individuals who carry certain polymorphisms in IL-1 stress-response pathway genes. Genotyping of additional individuals may strengthen the statistical association between these SNP haplotypes and POAG.

Keywords: genetics • stress response • clinical (human) or epidemiologic studies: ris