Aims/hypothesis. Kallikrein-binding protein (KBP) is a serine proteinase inhibitor (serpin). It specifically binds to tissue kallikrein and inhibits kallikrein activity. Our study was designed to test its effects on retinal neovascularization and vascular permeability. Angiogenesis in the retina is controlled by a delicate balance between angiogenic stimulators (e.g., vascular endothelial growth factor, VEGF) and angiogenic inhibitors (e.g., pigment epithelium-derived factor, PEDF) [1,2,3]. Under certain pathological conditions such as diabetic retinopathy and retinopathy of prematurity (ROP), the retinal cells increase the production of angiogenic stimulators while decreasing angiogenic inhibitors in response to local hypoxia [4,5]. These changes break the balance in angiogenesis control and consequently, resulting in over-proliferation of capillary endothelial cells and retinal neovascularization which is a common cause of blindness [2,3,6]. The molecular mechanism leading to retinal neovascularization is presently not known. Methods. Endothelial cell proliferation was deter

The ICAM-1 gene K469E polymorphism is associated with diabetic retinopathy in Chinese patients with Type 2 diabetes. Patients with the K469K genotype were more likely to have diabetic retinopathy than patients with the K469E or E469E genotype.

BackgroundMetformin is a first-line therapeutic agent for the treatment of type 2 diabetes, and despite its widespread long-term use in type 2 diabetes, the A variety of specific mechanisms of action of metformin are still being elucidated. Metformin is able to regulate cellular metabolism, proliferation, growth and autophagy, so it may have disease-modifying effects under a variety of other conditions. Metformin has been reported to improve a number of autoimmune diseases. Metformin has anti-inflammatory effects through a variety of mechanisms, including inhibition of tumour necrosis α (TNF-α)- induced synovial cell inflammation and angiogenesis[1]. Previously, observational studies have demonstrated the ability of metformin to ameliorate the pathogenesis of rheumatoid arthritis (RA). However, the causality from metformin related targets on the risk of RA remains unknown.ObjectivesThe aim of this study was to assess the causal effect of metformin related targets (AMPK, MCI, MG3, GDF15 and GLP1/GCG) on the risk of RA using a two-sample Mendelian randomization (MR) study.MethodsGenetic proxies for the effects of metformin drug targets were identified as variants in the gene for the corresponding target that associated with HbA1c level. we selected genetic variants within 1 megabase pairs downstream and upstream of the genes encoding the five targets, and low-linkage disequilibrium (r2< 0.3) variants associated with HbA1c at a nominal level of statistical significance (p ≤ 0.05) in the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC)，restricted to people of European ancestry to minimise population stratification (n = 88355). Data on RA have been obtained from the NHGRI-EBI Catalog of human genome-wide association studies (14361 cases and 42923 healthy controls)[2]. Two-sample Mendelian randomization (MR) study was conducted to examine the association of metformin related targets and the risk of RA, including the inverse-variance weighted (IVW) method, MR-Egger, and Weighted median (WM), which was followed by sensitivity analyses. In addition, we also performed Cochran’s Q test, MR pleiotropy residual sum and outlier (MR-PRESSO), leave-one-out sensitivity test to test for heterogeneity, horizontal multiplicity and stability of results.ResultsGenetically predicted 5 targets were not associated with RA with odds ratio (AMPK [OR=1.21, 95% CI=0.61, 2.39, p = 0.58], MCI [OR=1.16, 95% CI=0.92,1.48, p = 0.20], MG3[OR=1.76, 95% CI=0.49, 6.31, p = 0.14], GDF15 [OR=0.63, 95% CI=0.19, 2.05, p = 0.31], GLP1/GCG [OR=0.97, 95% CI=0.80, 1.16, p = 0.78])(Figure1). In addition, no apparent heterogeneity and no horizontal pleiotropy were observed in the sensitivity analysis.ConclusionOur study using MR herein indicated that the metformin related targets is not causally associated with the risk of RA. Future studies shall further systematically explore other potential pathways that metformin may affect to explore the association.References[1]Tomczynska M, Bijak M, Saluk J. Metformin - The Drug for the Treatment of Autoimmune Diseases; A New Use of a Known Anti-Diabetic Drug. Current topics in medicinal chemistry. 2016;16(19):2223-30.[2]Okada Y, Wu D, Trynka G, Raj T, Terao C, Ikari K, et al. Genetics of rheumatoid arthritis contributes to biology and drug discovery. Nature. 2014;506(7488):376-81.Acknowledgements:NIL.Disclosure of InterestsNone Declared.

BackgroundOsteoarthritis (OA) and cardiovascular disease (CVD) are common and often coexist in the aging population[1]. In addition to aging and biomechanical factors, OA is associated with many cardiovascular risk factors, including diabetes, hypertension, obesity, and low-grade systemic inflammation. However, whether OA is an independent risk factor for CVD has yet to be determined.ObjectivesThis bidirectional two-sample Mendelian random(MR) analysis aimed to delve into the effects of genetically predicted OA on atrial fibrillation(AF), hypertension, and pulmonary embolism(PE).MethodsFrom the genome-wide association study of European ancestry, we selected the single nucleotide polymorphisms(SNPs) of OA, knee osteoarthritis(KOA), and hip osteoarthritis(HOA) as instrumental variables(IVs). We obtained the data related to AF, PE, and hypertension from the large genome-wide meta-analysis, the FinnGen project, and the UK BioBank, respectively. The primary MR analysis was conducted by the inverse variance weighted (IVW) method. MR-Egger regression, weighted median, Cochran Q statistic, and leave-one-out analysis approach were leveraged as supplements.ResultsIVW analysis showed that the genetic responsibility of OA was closely related to hypertension. Compared with the control group, the logarithmic OR of OA increased by one unit, and the risk of hypertension increased by 1.14%(OR=1.011,95%CI: 1.005-1.018, p<0.001). Both KOA and HOA were significantly associated with an increased risk of AF(HOA: OR=1.063, 95%CI:1.014-1.015, p=0.011; KOA: OR=1.091, 95%CI:1.046-1.137, p<0.001;) and hypertension(HOA: OR=1.006, 95%CI:1.002-1.002, p=0.007; KOA: OR=1.012, 95%CI:1.008-1.017, p<0.001). We only observed that PE would decrease the risk of HOA(OR=0.944, 95%CI:0.910-0.979, p=0.002) in reverse MR.ConclusionUnder MR assumptions, our findings suggested a positive effect for OA with a risk-increasing impact of CVD. On the contrary, the genetic responsibility of HOA will reduce the risk of PE. More studies should be conducted to detect the specific causal relationship between OA and CVD.Reference[1]Kuusalo, L. et al. Metabolic osteoarthritis - relation of diabetes and cardiovascular disease with knee osteoarthritis. Osteoarthritis Cartilage 29, 230-234, doi:10.1016/j.joca.2020.09.010 (2021).Acknowledgements:NIL.Disclosure of InterestsNone Declared.