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Exfoliation syndrome (XFS) is the most common known risk factor for secondary glaucoma and a major cause of blindness worldwide. Variants in two genes, LOXL1 and CACNA1A, have previously been associated with XFS. To further elucidate the genetic basis of XFS, we collected a global sample of XFS cases to refine the association at LOXL1, which previously showed inconsistent results across populations, and to identify new variants associated with XFS. We identified a rare protective allele at LOXL1 (p.Phe407, odds ratio (OR) = 25, P = 2.9 × 10-14) through deep resequencing of XFS cases and controls from nine countries. A genome-wide association study (GWAS) of XFS cases and controls from 24 countries followed by replication in 18 countries identified seven genome-wide significant loci (P < 5 × 10-8). We identified association signals at 13q12 (POMP), 11q23.3 (TMEM136), 6p21 (AGPAT1), 3p24 (RBMS3) and 5q23 (near SEMA6A). These findings provide biological insights into the pathology of XFS and highlight a potential role for naturally occurring rare LOXL1 variants in disease biology.

Complement component 3 (C3) deficiency has recently been reported as one of the novel causes of constipation. To identify a unique gene specific to constipation caused by C3 deficiency, the total RNA extracted from the mid colon of C3 knockout (C3 KO) mice was hybridized to oligonucleotide microarrays, and the function of the candidate gene was verified in in vitro and in vivo models. C3 KO mice used for microarrays showed definite phenotypes of constipation. Overall, compared to the wild type (WT), 1237 genes were upregulated, and 1292 genes were downregulated in the C3 KO mice. Of these, the major genes included were lysine (K)-specific demethylase 5D (KDM5D), olfactory receptor 870 (Olfr870), pancreatic lipase (PNLIP), and alkaline phosphatase intestinal (ALPI). Specifically, the ALPI gene was selected as a novel gene candidate based on alterations during loperamide (Lop)-induced constipation and intestinal bowel disease (IBD). The upregulation of ALPI expression treated with acetate recovered the expression level of mucin-related genes in primary epithelial cells of C3 KO mice as well as most phenotypes of constipation in C3 KO mice. These results indicate that ALPI plays an important role as the novel gene associated with C3 deficiency-induced constipation. [ABSTRACT FROM AUTHOR]

Natural products with high antioxidant activity are considered as innovative prevention strategies to effectively prevent age-related macular degeneration (AMD) in the early stage because the generation of reactive oxygen species (ROS) leading to the development of drusen is reported as an important cause of this disease. To investigate the prevention effects of the methanol extracts of Euphorbia heterophylla L. (MEE) on AMD, its effects on the antioxidant activity, inflammatory response, apoptosis pathway, neovascularization, and retinal tissue degeneration were analyzed in N-retinylidene-N-retinylethanolamine (A2E)-landed spontaneously arising retinal pigment epithelia (ARPE)-19 cells and BALB/c mice after exposure to blue light (BL). The MEE contained 10 active components and showed high free radical scavenging activity against 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2′-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), and nitric oxide (NO) radicals. The pretreatments of high-dose MEE remarkably suppressed the production of intracellular ROS (88.2%) and NO (25.2%) and enhanced (SOD) activity (84%) and the phosphorylation of nuclear factor erythroid 2–related factor 2 (Nrf2) in A2E + BL-treated ARPE-19 cells compared to Vehicle-treated group. The activation of the inducible nitric oxide synthase (iNOS)-induced cyclooxygenase-2 (COX-2) mediated pathway, inflammasome activation, and expression of inflammatory cytokines was significantly inhibited in A2E + BL-treated ARPE-19 cells after the MEE pretreatment. The activation of the apoptosis pathway and increased expression of neovascular proteins (36% for matrix metalloproteinase (MMP)-9) were inhibited in the MEE pretreated groups compared to the Vehicle-treated group. Furthermore, the thickness of the whole retina (31%), outer nuclear layer (ONL), inner nuclear layer (INL), and photoreceptor layer (PL) were significantly increased by the MEE pretreatment of BALB/c mice with BL-induced retinal degeneration. Therefore, these results suggest that the MEE, with its high antioxidative activity, protects against BL-induced retinal degeneration through the regulation of the antioxidative system, inflammatory response, apoptosis, and neovascularization in the AMD mouse model. [ABSTRACT FROM AUTHOR]

Primary angle closure glaucoma (PACG) is a major cause of blindness worldwide. We conducted a genome-wide association study (GWAS) followed by replication in a combined total of 10,503 PACG cases and 29,567 controls drawn from 24 countries across Asia, Australia, Europe, North America, and South America. We observed significant evidence of disease association at five new genetic loci upon meta-analysis of all patient collections. These loci are at EPDR1 rs3816415 (odds ratio (OR) = 1.24, P = 5.94 × 10(-15)), CHAT rs1258267 (OR = 1.22, P = 2.85 × 10(-16)), GLIS3 rs736893 (OR = 1.18, P = 1.43 × 10(-14)), FERMT2 rs7494379 (OR = 1.14, P = 3.43 × 10(-11)), and DPM2-FAM102A rs3739821 (OR = 1.15, P = 8.32 × 10(-12)). We also confirmed significant association at three previously described loci (P < 5 × 10(-8) for each sentinel SNP at PLEKHA7, COL11A1, and PCMTD1-ST18), providing new insights into the biology of PACG.

Purpose: To compare the efficacy and safety of omidenepag isopropyl (OMDI) 0.002% with latanoprost 0.005% once daily in Asian subjects with open-angle glaucoma (OAG)/ocular hypertension (OHT). Methods: In this Phase III randomized, observer-masked, active-controlled, multinational trial (NCT02981446), subjects aged ≥ 18 years with OAG/OHT in both eyes and baseline intraocular pressure (IOP) ≥ 22 mmHg and ≤ 34 mmHg were randomized 1:1 to OMDI or latanoprost. IOP was measured at 9AM, 1PM, and 5PM at baseline, 1 week, 6 weeks, and 3 months. Adverse events (AEs) were recorded. Non-inferiority of OMDI to latanoprost was tested for primary and key secondary endpoints. Results: Each group included 185 subjects. Mean diurnal IOP from baseline to month 3 was reduced 7.1 mmHg (28.8%) with OMDI and 7.8 mmHg (31.3%) with latanoprost, with the least-squares mean difference (OMDI minus latanoprost) being 0.6 mmHg (95% CI: 0.0, 1.2 mmHg; p = 0.0366), indicating non-inferiority. Mean IOP reductions at the nine timepoints were − 5.8 to − 7.3 mmHg (23.5– 29.5%) for OMDI and − 6.1 to − 7.9 mmHg (24.3– 31.7%) for latanoprost. Non-inferiority per FDA criteria was also met. Rates of all AEs, ocular AEs, and ocular AEs associated with treatment were 40.0%, 36.8%, and 23.2%, respectively, for OMDI and 29.7%, 21.1%, and 11.9%, respectively, for latanoprost. Conjunctival hyperemia rates were higher with OMDI than latanoprost (11.9% vs 5.4%). Most AEs were mild, with no serious ocular AEs. Conclusion: OMDI safely and effectively reduces IOP in Asian subjects with OAG/OHT, with mean diurnal IOP at Month 3 and per-timepoint IOP reductions non-inferior to those of latanoprost. Plain Language Summary: PEONY Study: Testing How Well and How Safely Omidenepag Isopropyl Eye Drops Treat People with Glaucoma or Ocular Hypertension Compared with Latanoprost. Who took part in the study? Three hundred and seventy participants average age of 57 years, from 34 centers across four Asian countries who had glaucoma or high pressure in both eyes were randomly divided into two groups. One group (185 people; 50%) was given OMDI, and the other group (185 people; 50%) latanoprost for 3 months. The intraocular pressure of both eyes was measured in all participants at three time points (9 AM, 1 PM, and 5 PM) after 1 week, 6 weeks, and 3 months of treatment. The primary endpoint was the average of the daily eye pressure after 3 months of treatment. The safety of OMDI was also assessed. Study results. After 3 months of treatment, OMDI decreased the eye pressure by 29%. This was similar to latanoprost, which decreased the eye pressure by 31% over the same time period. OMDI was safe and well tolerated by those participants who received it. The most common side-effect in people receiving OMDI or latanoprost was conjunctival hyperemia (red eye) (experienced by 22 people receiving OMDI, and 10 people receiving latanoprost). Conclusions After 3 months of use, OMDI was found to safely reduce high eye pressure to a similar level as latanoprost in Asian people with glaucoma or high eye pressure. [ABSTRACT FROM AUTHOR]