Genotype-phenotype associations of IL6 and PRG4 with conjunctival fibrosis after glaucoma surgery

Abstract

IMPORTANCE: Postsurgical fibrosis is a critical determinant of the long-term success of glaucoma surgery, but no reliable biomarkers are currently available to stratify the risk of scarring. OBJECTIVE: To compare the clinical phenotype of patients with conjunctival fibrosis after glaucoma surgery with candidate gene expression tissue biomarkers of fibrosis. DESIGN, SETTING, AND PARTICIPANTS: In this cross-sectional study, 42 patients were recruited at the time of glaucoma surgery at the Moorfields Eye Hospital from September 1, 2014, to September 1, 2016. The participants were divided into those with fibrosis and those without fibrosis. MAIN OUTCOMES AND MEASURES: Genotype-phenotype correlations of the IL6 or PRG4 gene and detailed clinical phenotype. The IL6 and PRG4 protein expression in conjunctival tissues was also assessed using in situ immunohistochemical analysis. Central bleb area, maximal bleb area, and bleb height were graded on a scale of 1 to 5 (1 indicating 0%; 2, 25%; 3, 50%; 4, 75%; and 5, 100%). Bleb vascularity was graded on a scale of 1 to 5 (1 indicating avascularity; 2, normal; 3, mild; 4, moderate; and 5, severe hyperemia). RESULTS: A total of 42 patients were recruited during the study period; 28 participants (67%) had previously undergone glaucoma surgery (fibrotic group) (mean [SD] age, 43.8 [3.6 years]; 16 [57%] female; 22 [79%] white), and 14 participants (33%) had not previously undergone glaucoma surgery (nonfibrotic group) (mean [SD] age, 47.7 [6.9] years; 4 [29%] female; 9 [64%] white). The fibrotic group had marked bleb scarring and vascularization and worse logMAR visual acuity. The mean (SD) grades were 1.4 (0.1) for central bleb area, 1.4 (0.1) for bleb height, and 3.4 (0.2) for bleb vascularity. The IL6 gene was upregulated in fibrotic cell lines (mean, 0.040) compared with nonfibrotic cell lines (mean, 0.011) (difference, 0.029; 95% CI, 0.015-0.043; P = .003). The PRG4 gene was also downregulated in fibrotic cell lines (0.002) compared with nonfibrotic cell lines (mean, 0.109; difference, 0.107; 95% CI, 0.104-0.110; P = .03). The study found a strong correlation between the IL6 gene and the number of glaucoma operations (r = 0.94, P < .001) and logMAR visual acuity (r = 0.64, P = .03). A moderate correlation was found between the PRG4 gene and the number of glaucoma operations (r = −0.72, P = .005) and logMAR visual acuity (r = −0.62, P = .03). CONCLUSIONS AND RELEVANCE: IL6 and PRG4 represent potential novel tissue biomarkers of disease severity and prognosis in conjunctival fibrosis after glaucoma surgery. Future longitudinal studies with multiple postoperative measures are needed to validate the effect of these potential biomarkers of fibrosis.