Elevated transforming growth factor ß1 in plasma of primary open-angle glaucoma patients.

PURPOSE: To test the hypothesis that primary open-angle glaucoma (POAG) patients have a systemic elevation of transforming growth factor ß1 (TGFß1). METHODS: Plasma was prepared from blood samples drawn from patients of the Vanderbilt Eye Institute during clinic visits. Concentrations of total TGFß1 and thrombospondin-1 (TSP1) in plasma were determined by ELISA. Statistical significance of differences between POAG and control samples was evaluated by Mann-Whitney test. Regression analysis was used to evaluate correlations between plasma TGFß1 and patient age and between plasma TGFß1 and TSP1. RESULTS: Plasma samples were obtained from 148 POAG patients and 150 controls. Concentration of total TGFß1 in the plasma of POAG patients (median = 3.25 ng/mL) was significantly higher (P < 0.0001) than in controls (median = 2.46 ng/mL). Plasma TGFß1 was not correlated with age of patient (P = 0.17). Thrombospondin-1 concentration was also significantly higher (P < 0.0001) in POAG patients (median = 0.774 µg/mL) as compared to controls (median = 0.567 µg/mL). Plasma total TGFß1 and TSP1 concentrations were linearly correlated (P < 0.0001). CONCLUSIONS: Plasma samples from POAG patients display elevated total TGFß1 compared to controls, consistent with elevated systemic TGFß1 in POAG patients.

Screening ADAMTS10 in dog populations supports Gly661Arg as the glaucoma-causing variant in beagles.

PURPOSE: Previously, we mapped the disease locus in the beagle model of autosomal recessive primary open angle glaucoma (POAG) to a 4-Mb interval on chromosome 20, and identified a Gly661Arg variant in ADAMTS10 as the candidate disease-causing variant. The purpose of this study was to test the hypothesis that the Gly661Arg variant of ADAMTS10 causes glaucoma by genotyping dogs of various breeds affected and unaffected by primary glaucoma. METHODS: Dogs of various breeds, affected or unaffected with primary glaucoma, were genotyped for the Gly661Arg variant of ADAMTS10, as well as 7 other nonsynonymous single nucleotide polymorphisms (SNPs) in other genes in the beagle POAG locus that segregate with disease. Alternate allele frequencies were calculated with 95% confidence intervals and comparisons made to expected allele frequency relative to disease prevalence or between cases and controls. RESULTS: For the nonsynonymous SNPs other than the ADAMTS10 variant, control dogs were identified that were homozygous for the alternative alleles, ruling out those variants as causative. None of the nonsynonymous SNPs were found associated with primary glaucoma in American cocker spaniels. The Gly661Arg variant of ADAMTS10 was the only variant with minor allele frequency consistent with the prevalence of primary glaucoma in the general beagle population. The only dog found homozygous for the Gly661Arg variant of ADAMTS10 was an affected beagle, unrelated to the POAG colony. CONCLUSIONS: These findings support the Gly661Arg mutation of ADAMTS10 as the likely cause of POAG in beagles.