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Supanji Supanji,1– 4 Dewi Fathin Romdhoniyyah,1,2 Muhammad Bayu Sasongko,1,2,4 Angela Nurini Agni,1,2,4 Firman Setya Wardhana,1,2,4 Tri Wahyu Widayanti,1,2,4 Muhammad Eko Prayogo,1,2,4 Ayudha Bahana Ilham Perdamaian,1,2 Aninditta Dianratri,1,2 Masashi Kawaichi,5 Chio Oka5 1Department of Ophthalmology, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta, Indonesia; 2Department of Ophthalmology, Dr. Sardjito General Hospital, Yogyakarta, Indonesia; 3Ophthalmology Clinic, Military Air Force Central Hospital Dr. Suhardi Hardjolukito, Yogyakarta, Indonesia; 4Ophthalmology Clinic, Dr YAP Eye Hospital, Yogyakarta, Indonesia; 5Laboratory of Gene Function in Animals, Nara Institute of Science and Technology, Ikoma, Nara, JapanCorrespondence: Supanji SupanjiDepartment of Ophthalmology, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Jalan Farmako Sekip Utara, Yogyakarta, 55281, IndonesiaTel +62 274 560300Fax +62 274 581 876Email supanji@ugm.ac.idPurpose: This study aimed to determine the association of ARMS2 A69S, ARMS2 del443ins54, and CFH Y402H polymorphisms with neovascular age-related macular degeneration (nAMD) for the first time in an Indonesian population.Patients and Methods: Our case–control study involved 104 nAMD and 100 control subjects. AMD diagnosis was evaluated by retinal specialists based on color fundus photography and optical coherence tomography. The polymorphisms on CFH Y402H and ARMS2 A69S were analyzed by PCR-restriction fragment length polymorphism (PCR-RFLP), whereas ARMS2 del443ins54 was evaluated by PCR-based assay.Results: Significant allelic associations with nAMD were detected on all polymorphisms (P< 0.05), with stronger association with the ARMS2 A69S (OR 3.13; 95% CI 2.08– 4.71; P< 0.001) and ARMS2 del443ins54 (OR 3.28; 95% CI 2.17– 4.95; P< 0.001) polymorphisms than with CFH Y402H (OR 2.08; 95% CI 1.08– 3.99; P=0.028). Genotype analysis showed a statistical difference between nAMD and the control group for all polymorphisms (P< 0.05). However, the association with nAMD was weaker for CFH Y402H (P=0.043) than for ARMS2 A69S and ARMS2 del443ins54 (P< 0.001). A significant interaction between ARMS2 A69S and hypertension was documented (OR 9.53; 95% CI 3.61– 25.1; P< 0.001).Conclusion: Our findings indicate that ARMS2 A69S and ARMS2 del443ins54 polymorphisms are strongly associated with the risk of nAMD for the first time in an Indonesian population. The risk of nAMD increased when the presence of risk alleles from ARMS2 A69S was combined with the presence of hypertension.Keywords: age-related macular degeneration, ARMS2, CFH, polymorphism

Background: Neovascular age-related macular degeneration (nAMD) is one of the main causes of blindness in developed countries. Complement factor H (CFH) is one of the genes involved in the pathogenesis of nAMD. This study investigated the rs10737680 polymorphism in CFH and its conferred susceptibility to nAMD in Yogyakarta, Indonesia., Methods: This case-control hospital-based study recruited participants consisting of 96 patients with nAMD and 101 controls without nAMD from the Eye Polyclinic of Sardjito Hospital, YAP Eye Hospital, and Hardjolukito Hospital Yogyakarta. nAMD was diagnosed when fundus examination, fundus photographs, and optical coherence tomography revealed hard or soft drusen in the macular area measuring > 63 µm that appeared below the retinal pigment epithelium, with or without macular hypo- or hyperpigmentation, and was accompanied by choroidal neovascularization. Genomic DNA was extracted using a commercial DNA isolation kit. The restriction fragment length polymorphism technique was used to identify the rs10737680 polymorphism in CFH ., Results: The mean (standard deviation [SD]) age of the nAMD group was not homogeneous with that of the control group ( P < 0.05); 65.41 (9.74) years versus 68.24 (7.82) years. The number of patients with hypertension in the nAMD group was significantly higher than in the control group ( P < 0.05). In the nAMD group, the genotype distribution indicated homozygous risk allele in 34.38%, heterozygous risk allele in 57.29%, and homozygous non-risk allele in 8.33%. In the control group, the genotype distribution indicated homozygous risk allele in 21.78%, heterozygous risk allele in 36.63%, and homozygous non-risk allele in 41.58%. Statistical analysis between the two study groups according to homozygous risk allele genotype (odds ratio [OR], 7.87; 95% confidence interval [CI], 2.88-22.79) and heterozygous genotype (OR, 7.80; 95% CI, 3.11-21.19) showed a significant difference (both P < 0.01)., Conclusions: Homozygous risk allele was less frequent than heterogeneous risk allele in patients with nAMD; however, both increased the risk for nAMD. Although the homozygous or heterozygous risk-alleles were detected in most patients, yet other important genetic or environmental factors could be involved in the pathogenesis of nAMD. Overall, we found a significant association between rs10737680 polymorphism in CFH and the susceptibility to nAMD in Yogyakarta, Indonesia; however, future studies are needed to fully delineate the mechanism., Competing Interests: None, (© Author(s).)

Introduction: The aim of this study was to investigate the association of the HtrA1 rs11200638 polymorphism with neovascular age-related macular degeneration (nAMD) in Indonesia., Methods: This case-control study included 80 patients with nAMD and 85 controls. Demographic parameters and whole blood were collected from each participant. Genomic DNA was extracted and used to assess the rs11200638 genotype by PCR and restriction enzyme digestion. Associations between the HtrA1 rs11200638 polymorphism and other risk factors for susceptibility to nAMD were assessed using the logistic regression model., Results: Significant allelic associations between the HtrA1 polymorphism and nAMD were detected (odds ratio [OR] 8.67; 95% confidence interval [CI] 4.88-15.41; P < 0.001). Genotype analysis showed a statistical difference between the nAMD group and the control group (P < 0.001). In the multiple adjusted logistic regression model, people with the AA genotype were more likely to have nAMD although there was a wide confidence interval (OR 19.65; 95% CI 4.52-85.38; P < 0.001)., Conclusion: Our findings show that the risk of nAMD increased in the presence of risk alleles of HtrA1 rs11200638., (© 2021. The Author(s).)

Background: Currently, no generally approved medical treatment can delay the onset of age-related macular degeneration (AMD) or slow the progression of degenerative changes. Repurposing drugs with beneficial effects on AMD pathophysiology offers a route to new treatments which is faster, cost-effective, and safer for patients. Recent studies indicate a potential role for metformin in delaying AMD development and progression. In this context, we conducted a systematic review and meta-analysis to look for beneficial associations between metformin and AMD., Methods: We systematically searched Medline and Embase (via Ovid), Web of Science, and ClinicalTrials.gov databases for clinical studies in humans that examined the associations between metformin treatment and AMD published from inception to February 2021. We calculated pooled odds ratio (OR) with 95% confidence interval (CI) considering a random effect model in the meta-analysis., Results: Five retrospective studies met the inclusion criteria. There are no prospective studies that have reported the effect of metformin in AMD. The meta-analysis showed that people taking metformin were less likely to have AMD although statistical significance was not met (pooled adjusted OR = 0.80, 95% CI 0.54-1.05, I 2  = 98.8%). Subgroup analysis of the association between metformin and early and late AMD could not be performed since the data was not available from the included studies., Conclusions: Analysis of retrospective data suggests a signal that metformin may be associated with decreased risk of any AMD. It should be interpreted with caution because of the failure to meet statistical significance, the small number of studies, and the limitation of routine record data. However prospective studies are warranted in generalizable populations without diabetes, of varied ethnicities, and AMD stages. Clinical trials are needed to determine if metformin has efficacy in treating early and late-stage AMD.