Genetic determinants of obesity in Korean populations: exploring genome-wide associations and polygenic risk scores.

East Asian populations exhibit a genetic predisposition to obesity, yet comprehensive research on these traits is limited. We conducted a genome-wide association study (GWAS) with 93,673 Korean subjects to uncover novel genetic loci linked to obesity, examining metrics such as body mass index, waist circumference, body fat ratio, and abdominal fat ratio. Participants were categorized into non-obese, metabolically healthy obese (MHO), and metabolically unhealthy obese (MUO) groups. Using advanced computational methods, we developed a multifaceted polygenic risk scores (PRS) model to predict obesity. Our GWAS identified significant genetic effects with distinct sizes and directions within the MHO and MUO groups compared with the non-obese group. Gene-based and gene-set analyses, along with cluster analysis, revealed heterogeneous patterns of significant genes on chromosomes 3 (MUO group) and 11 (MHO group). In analyses targeting genetic predisposition differences based on metabolic health, odds ratios of high PRS compared with medium PRS showed significant differences between non-obese and MUO, and non-obese and MHO. Similar patterns were seen for low PRS compared with medium PRS. These findings were supported by the estimated genetic correlation (0.89 from bivariate GREML). Regional analyses highlighted significant local genetic correlations on chromosome 11, while single variant approaches suggested widespread pleiotropic effects, especially on chromosome 11. In conclusion, our study identifies specific genetic loci and risks associated with obesity in the Korean population, emphasizing the heterogeneous genetic factors contributing to MHO and MUO.

Identification of genetic variants associated with diabetic kidney disease in multiple Korean cohorts via a genome-wide association study mega-analysis.

BACKGROUND: The pathogenesis of diabetic kidney disease (DKD) is complex, involving metabolic and hemodynamic factors. Although DKD has been established as a heritable disorder and several genetic studies have been conducted, the identification of unique genetic variants for DKD is limited by its multiplex classification based on the phenotypes of diabetes mellitus (DM) and chronic kidney disease (CKD). Thus, we aimed to identify the genetic variants related to DKD that differentiate it from type 2 DM and CKD. METHODS: We conducted a large-scale genome-wide association study mega-analysis, combining Korean multi-cohorts using multinomial logistic regression. A total of 33,879 patients were classified into four groups-normal, DM without CKD, CKD without DM, and DKD-and were further analyzed to identify novel single-nucleotide polymorphisms (SNPs) associated with DKD. Additionally, fine-mapping analysis was conducted to investigate whether the variants of interest contribute to a trait. Conditional analyses adjusting for the effect of type 1 DM (T1D)-associated HLA variants were also performed to remove confounding factors of genetic association with T1D. Moreover, analysis of expression quantitative trait loci (eQTL) was performed using the Genotype-Tissue Expression project. Differentially expressed genes (DEGs) were analyzed using the Gene Expression Omnibus database (GSE30529). The significant eQTL DEGs were used to explore the predicted interaction networks using search tools for the retrieval of interacting genes and proteins. RESULTS: We identified three novel SNPs [rs3128852 (P = 8.21×10-25), rs117744700 (P = 8.28×10-10), and rs28366355 (P = 2.04×10-8)] associated with DKD. Moreover, the fine-mapping study validated the causal relationship between rs3128852 and DKD. rs3128852 is an eQTL for TRIM27 in whole blood tissues and HLA-A in adipose-subcutaneous tissues. rs28366355 is an eQTL for HLA-group genes present in most tissues. CONCLUSIONS: We successfully identified SNPs (rs3128852, rs117744700, and rs28366355) associated with DKD and verified the causal association between rs3128852 and DKD. According to the in silico analysis, TRIM27 and HLA-A can define DKD pathophysiology and are associated with immune response and autophagy. However, further research is necessary to understand the mechanism of immunity and autophagy in the pathophysiology of DKD and to prevent and treat DKD.

The choroidal microvasculature of the parapapillary area as a biomarker of glaucoma development in the fellow eye of patients with unilateral glaucoma.

PURPOSE: To investigate the factors associated with the development of glaucoma in the healthy eyes of unilateral glaucoma patients. MATERIALS AND METHODS: This was a retrospective observational case series study. All participants had unilateral primary open-angle glaucoma at the initial visit and were divided into two groups: one in which the fellow eyes developed glaucoma during the follow-up period and one in which the fellow eyes remained healthy. A complete ophthalmic examination, including best-corrected visual acuity testing, slit-lamp examination, intraocular pressure measurement, retinal nerve fiber layer and optic disk photographs, a 30-2 visual field test, and optical coherence tomography with angiography, was performed over a follow-up period of at least 3 years. RESULTS: A total of fifty-six patients were enrolled, and over the course of the study period, 11 patients developed glaucoma in the fellow eyes, while the fellow eyes of 45 patients remained healthy. At the baseline, the glaucomatous eye had a larger area of beta parapapillary atrophy, lower parapapillary choroidal vascular density (pCVD) within the area, and a lower prevalence of microvascular dropout than normal fellow eyes (P < 0.001, 0.013, 0.001, respectively). In the multivariate analysis, a reduced pCVD in the gamma parapapillary atrophy (γPPA) region was significantly associated with the development of glaucoma in normal eyes (odds ratio, 0.566; 95% CI, 0.342, 0.935; P = 0.026). CONCLUSIONS: The pCVD within the γPPA region at baseline is the risk factor for the development of glaucoma in the normal fellow eye of patients with unilateral glaucoma.

Trend changes and factor analysis of endometrial hyperplasia in patients with polycystic ovarian syndrome based on the Korean National Health Insurance Database.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a common endocrine disorder associated with an increased risk of other gynecological disorders, such as endometrial hyperplasia (EH). However, substantial factors in the comorbidity of EH and PCOS remain to be investigated. We analyzed trend changes in PCOS and factors related to the comorbidity of PCOS and EH using data from the Korea National Health Insurance (KNHI) claims database. METHODS: The data for this population-based study of people diagnosed with PCOS or EH in Korea from 2009 to 2016 were collected from the KNHI claims database between 2007 and 2017. We conducted a trend analysis of the prevalence and incidence of PCOS and EH. In addition, we performed a logistic regression analysis to identify risk factors associated with EH incidence in people with PCOS using the matched case-control methodology. RESULTS: The average annual growth rate of the incidence of PCOS was 14.1% from 2009 to 2016, whereas the EH rate increased by only 3.4% annually. Comorbidities, type 2 diabetes, obesity, hypertension, hyperlipidemia, and infertility, increased the risk of EH in PCOS patients. Additionally, the cumulative duration of oral contraceptive & progestin treatment for PCOS correlated highly with the comorbidity of EH and PCOS. CONCLUSIONS: We confirmed the relationship between PCOS and EH using big data suitable for time series analyses of the diagnosis and treatment of diseases. Endometrial evaluation should be done with more caution if oral contraceptives & progestins have been used for a long time.

The microbiomes of the eyelid and buccal area of patients with uveitic glaucoma.

BACKGROUND: The microbiome could trigger inflammation leading to epigenetic changes and is involved in the pathophysiology of eye diseases; however, its effect on uveitic glaucoma (UG) has not been fully investigated. This study analysed the differences in eyelid and buccal microbiomes in patients with UG using next-generation sequencing. METHODS: The eyelid and buccal specimens of 34 UG and 25 control patients were collected. The taxonomic composition of the microbiome was obtained via 16S ribosomal DNA sequencing. Diversity and differential gene expression analyses (DEG) determined taxon differences between the microbiomes of UG and control groups. RESULTS: In both the eyelid and buccal microbiomes, alpha-diversity was lower in UG patients than controls, while beta-diversity in patients with UG was higher than in controls. DEG analysis of the eyelid microbiome revealed various taxa differences, including enrichment of Paenibacillus and Dermacoccus (p-value, 1.31e-6 and 1.55e-7, respectively) and depletion of Morganella and Lactococcus (p-value, 6.26e-12 and 2.55e-6, respectively) in patients with UG. In the buccal microbiome, taxa such as Lactococcus was significantly depleted (p-value, 1.31e-17), whereas Faecalibacterium was enriched in patients with UG (p-value, 6.12e-8). CONCLUSIONS: The eyelid and buccal microbiomes in patients with UG differ from controls, which raises concerns surrounding environmental influences on the pathogenesis of UG. The reduced Lactococcus in the eyelid and buccal area suggest that microbiota dysbiosis is associated with UG.

Association of physical activity with sarcopenia evaluated based on muscle mass and strength in older adults: 2008-2011 and 2014 - 2018 Korea National Health and Nutrition Examination Surveys.

BACKGROUND: Adequate physical activity (PA) is essential for preventing sarcopenia in older adults. However, there are insufficient epidemiological data on the intensity of PA needed to prevent age-related sarcopenia. The purpose of this study was to investigate the association of PA intensity with skeletal muscle mass and muscle strength. METHODS: This was a population-based study with a cross-sectional design that was conducted using data from the 2008 - 2011 and 2014 - 2018 Korea National Health and Nutrition Examination Surveys, which included a total of 11,162 participants aged ≥ 60 years. PA was assessed using the results of a questionnaire and organized by intensity, frequency, and duration. The study population was divided into the following groups based on PA intensity: no exercise, walking only, moderate PA, and vigorous PA. To assess sarcopenia, skeletal muscle index (SMI) and hand grip strength (HGS) were measured as indicators of muscle mass and strength, respectively. Logistic regression analysis was used to explore the relationship between PA intensity and sarcopenia. RESULTS: SMI and HGS were significantly higher in men and women engaged in moderate to vigorous PA than in those who did not exercise. The odds ratios (ORs) for sarcopenia defined based on SMI and HGS were lowest in men engaged in vigorous PA (0.444, 95% confidence interval [CI]: 0.242 - 0.818 and 0.450, 95% CI: 0.228 - 0.890, respectively). In women, the OR for sarcopenia defined based on HGS was the lowest in the group engaged in vigorous PA (0.441, 95% CI: 0.199 - 0.975), while there was no risk reduction for sarcopenia defined based on SMI. CONCLUSIONS: Moderate to vigorous PA was highly correlated with SMI and HGS in men and women. Intensive PA was positively correlated with sarcopenia prevention, which can be monitored using HGS.

Management of XEN Gel Stent Exposure with Conjunctival Erosion via Rotational Conjunctival Flap and Amniotic Membrane Transplantation-A Case Report.

Background: Despite its proven effectiveness and safety profile, the XEN gel stent (Allergan Inc., CA, USA) for minimally invasive glaucoma surgery (MIGS) has a probability of postoperative complications, including postoperative hypotony, hyphema, stent migration, stent obstruction, bleb fibrosis, and fibrin formation. In particular, the use of adjunctive Mitomycin-C (MMC) might be associated with bleb-related complications, including conjunctival erosion, XEN gel stent exposure, and blebitis. However, there are few studies on XEN gel stent exposure and its management. We describe a case of XEN gel stent exposure with conjunctival erosion 18 months postoperatively, which resolved effectively after combination treatment with a rotational conjunctival flap and amniotic membrane transplantation. Case presentation: A 74-year-old Korean male patient with diabetes and hypertension underwent uncomplicated ab interno XEN gel stent implantation with a subconjunctival injection of 0.1 cc of 0.02% MMC and presented with low intraocular pressure (IOP) with a well-functioning filtering bleb. Periocular pain and tearing developed 18 months after the initial operation, with mild deterioration of visual acuity to 20/100. Despite conservative medical treatment, the conjunctival erosion was not relieved. Anterior segment optical coherence tomography (AS-OCT) revealed an exposed XEN gel stent with conjunctival erosion. We performed bleb revision surgery using a rotational conjunctival flap and amniotic membrane transplantation. Slit-lamp examination and AS-OCT showed a well-formed moderate bleb without leakage, and IOP continued to be well controlled (14 mm Hg with latanoprost) until six months after bleb revision. Conclusions: This case report highlights the importance of careful examination, including slit-lamp examination, the Seidel test, and AS-OCT, to identify accurate anatomical positioning and to monitor ocular surface changes after XEN gel stent implantation with MMC or 5-FU. Combination treatment (rotational conjunctival flap and amniotic membrane transplantation) may be relatively safe for persistent XEN gel stent exposure.

Differences in the eyelid and buccal microbiome of glaucoma patients receiving long-term administration of prostaglandin analog drops.

PURPOSE: To investigate the differences in the eyelid and buccal microbiomes between patients receiving long-term prostaglandin analogs for open-angle glaucoma (PG-OAG) and naïve-OAG patients by using metagenomics. METHODS: Eyelid and buccal samples were collected from 30 PG-OAG and 32 naïve-OAG patients. The taxonomic composition of the microbiome was obtained via 16S rRNA gene sequencing, operational taxonomic unit analysis, and diversity analysis. Differential gene expression analysis (DEG) and Bland-Altman (MA) plots were used to determine taxon differences between the microbiomes of PG-OAG and naïve-OAG patients. RESULTS: The eyelid microbiome showed marginally significant differences, while the alpha-diversity of the buccal microbiome showed significant differences between PG-OAG and naïve-OAG patients. However, the beta-diversity of both eyelid and buccal microbiomes was higher in PG-OAG patients than in naïve-OAG patients. The MA plot showed cluster differences in the eyelid microbiome. DEG analysis of the eyelid microbiome revealed various taxa differences, including enrichment of Azomonas, Pseudomonas, and Granulicatella in PG-OAG patients over naïve-OAG patients, as well as significant depletion of Delftia and Rothia. In the buccal microbiome in PG-OAG patients, taxa such as Rikenella and Stenotrophomonas were significantly enriched. CONCLUSION: Our findings suggest that the eyelid microbiome differs between PG-OAG and naïve-OAG patients, raising concerns regarding the eyelid environment in patients receiving these drugs. The overexpressed microbiome in the eyelid area suggests that microbiota may change after the administration of glaucoma medications in OAG.

Comparison of risk allele frequencies of single nucleotide polymorphisms associated with age-related macular degeneration in different ethnic groups.

BACKGROUND: The prevalence of age-related macular degeneration (AMD) varies from 6.8 to 18.3% for all forms of AMD and from 0.6 to 2.6% for late AMD according to race, suggesting the existence of genetic differences among races. The purpose of this study was to determine the genetic causes of differences in the prevalence of AMD among individuals of different races. METHODS: We collected 138 AMD-associated single nucleotide polymorphisms (SNPs) from a genome-wide association studies catalog. Their population-level allele frequencies were derived based on the 1000 Genomes Project and Korean Reference Genome Database. We used Fisher's exact tests to assess whether the effect allele at a given SNP was significantly enriched or depleted in the database. RESULTS: European, American, and South Asian populations showed similar heatmap patterns, whereas East Asian, and Korean populations had distinct patterns. Korean populations exhibited patterns that were different from those of the other groups; rs5754227 (SYN3), rs1626340 (TGFBR1/COL15A1), rs3750846(ARMS2/HTRA1), and rs9564692 (B3GALTL) were enriched, whereas rs2230199 (C3) and rs73036519 (EXOC3L2/MARK4) were depleted in Koreans; these SNPs are associated with late AMD. The genetic risk score calculated from allele frequencies was not less in East Asians than in Europeans. CONCLUSION: The prevalence of AMD is lower in Asians than in Europeans. However, our study showed that genetic risk scores in East Asians were similar to those in Europeans, which may explain why the global projected number of people with AMD by 2040 is in largest for East Asians, including Koreans.

Comparison of conjunctival vascularity changes using optical coherence tomography angiography after trabeculectomy and phacotrabeculectomy.

PURPOSE: To compare bleb vascularity changes using optical coherence tomography angiography (OCT-A) between mitomycin-C (MMC)-augmented trabeculectomy and phacotrabeculectomy and to determine whether bleb vascularity measurements during preoperative and early postoperative periods could act as surrogate parameters to predict surgical outcomes. METHODS: We retrospectively reviewed data for 72 eyes from 72 glaucoma patients who underwent MMC-augmented trabeculectomy with/without cataract surgery. Bleb area scans were obtained using OCT-A during the preoperative period; 1, 2, 4, and 6 weeks postoperatively; and 2, 4, and 6 months postoperatively. For conjunctival vascularity analysis, a semi-automated program was used to calculate color and brightness densities of the selected area. RESULTS: Color and brightness densities were decreased in the trabeculectomy group during all periods but not in the phacotrabeculectomy group at 4 and 6 weeks, as well as 2, 4, and 6 months postoperatively. Color and brightness densities were significantly higher in the phacotrabeculectomy group than in the trabeculectomy group after 6 weeks and 2, 4, and 6 months postoperatively. A Kaplan-Meier survival graph indicated that intraocular pressure differed according to glaucoma type but not surgery type. Logistic regression analysis revealed that brightness density 1 week postoperatively was correlated with reoperation. CONCLUSIONS: Changes in conjunctival vascularity density measured by OCT-A differed according to the surgical method. Following trabeculectomy with MMC, brightness density 1 week postoperatively may be a predictive index for surgical outcomes.

Comparison of glaucoma diagnostic ability of ganglion cell-inner plexiform layer according to the range around the fovea.

BACKGROUND: To compare the glaucoma diagnostic ability of the ganglion cell-inner plexiform layer (GCIPL) thickness depending on the range around the fovea using wide-angle, swept-source optical coherence tomography (SS-OCT). METHODS: We compared the glaucoma diagnostic utility of GCIPL parameters across multiple regions while centered on the fovea. In a wide-angle scan, the GCIPL for each 1-mm2 grid square of a 12 × 9 mm2 scan resulted in 108 data points. With respect to the range of the GCIPL measurements around the macula, the wide-angle scan images were classified into three zones. Zone 1 was defined as a narrow area; zone 2 was defined as a mid-sized area; and zone 3 was defined as a wide area. We recorded the quadrant GCIPL thickness, average, and minimum quadrant GCIPL within each zone. The areas under the receiver operating characteristic (AUROCs) curves were calculated to evaluate the glaucoma diagnostic utility. RESULTS: Sixty-one eyes with glaucoma and 59 normal eyes were assessed. The minimum and average GCIPL measurements in zones 1-3 in eyes with glaucoma were significantly lower than those in normal eyes (P <  0.001). The AUROCs for the minimum and inferotemporal GCIPL in zone 1 and the inferotemporal GCIPL thickness in zone 2 were greater than 0.9 (0.945, 0.931, and 0.918, respectively). CONCLUSIONS: Wide-angle scanning using SS-OCT will contribute to improvements in the detection of glaucomatous damage. The minimum and inferotemporal GCIPL in zone 1 may be more useful for detecting glaucoma than those in the conventional area.

Short-term change in higher-order aberrations after mitomycin-C-augmented trabeculectomy.

PURPOSE: To investigate the changes in ocular higher-order aberrations (HOA) after trabeculectomy using mitomycin-C (MMC). METHODS: We retrospectively reviewed data for 63 eyes from 63 glaucoma patients who had undergone MMC augmented trabeculectomy. We measured intraocular pressure (IOP), refractive errors, anterior chamber depth (ACD), and HOA before surgery and 1, 2, and 4 weeks postoperatively. The patients were divided into two groups on the basis of preoperative lens status: phakic and pseudophakic group. We used a paired t test to compare preoperative and postoperative HOA values. Regression analysis was used to compare higher-order total (HOT) change and factors including ACD and age. RESULTS: For entire eye aberrations, coma-like and total HOT were significantly increased postoperatively at 1 week (P = 0.029, P = 0.005, respectively), but not after 2 or 4 weeks in the phakic group and were not significant at any time in the pseudophakic group. Corneal HOA were significantly increased postoperatively after 1, 2 weeks, but not after 4 weeks in the phakic group and were not significant in the pseudophakic group. For internal optics aberrations, HOA were significantly increased postoperatively at 1, 2, and 4 weeks in the phakic group, but were not significant at any time in the pseudophakic group. However, HOT aberration change showed no correlation with age, ACD, IOP change in either group. CONCLUSION: Following trabeculectomy, HOA changes were significantly increased postoperatively at 1, 2 weeks in the phakic group. Therefore, visual complaint-related HOA changes after trabeculectomy may be more profound in phakic patients.

The effects of vascular endothelial growth factor (VEGF) on human orbital preadipocyte.

PURPOSE: To investigate the presence of the Vascular Endothelial Growth Factor (VEGF) and its receptor (VEGFR) in human orbital preadipocytes, and to evaluate the effect of VEGF on human orbital preadipocyte differentiation and adipogenesis in vitro. RESULTS: Four isoforms of VEGF (VEGF121, 155, 189, and 206), VEGFR-1, VEGF-2, and neuropilin-1 were expressed in human orbital preadipocytes. Treatment with 100 ng/ml VEGF induced higher expressions of C/EBPα and LPL than the non-treated control (p = 0.03 and p = 0.01) or treatment with 50ng/ml (p = 0.04 for both). At both concentrations VEGF enhanced the accumulation of intra-cytoplasmic lipid versus the control, and treatment with 100 ng/ml VEGF induced more lipid accumulation than treatment with 50 ng/ml VEGF (p = 0.03). CONCLUSIONS: VEGF and VEGFR were observed in human orbital preadipocytes, and exogenous VEGF enhanced adipogenesis in these cells. These results suggest that VEGF plays a role as an autocrine or paracrine growth factor during human orbital preadipocyte differentiation.

Evaluation of Retinal Nerve Fiber Layer in Patients with Idiopathic Optic Perineuritis using Optical Coherence Tomography.

The aim of this study was to assess the effect of idiopathic Optic perineuritis on the retinal nerve fiber layer, and determine the ability of optical coherence tomography to evaluate retinal nerve fiber loss after idiopathic Optic perineuritis. Four patients were assessed in this study. In all cases, average retinal nerve fiber layer was significantly thinner in the affected eye in comparison with the normal reference value and with the value for the contralateral normal eye at 12 months after the onset of optic perineuritis. Our study revealed that retinal nerve fiber layer loss occurs in idiopathic optic nerve sheath inflammation.

Possible Causal Association between Type 2 Diabetes and Glycaemic Traits in Primary Open-Angle Glaucoma: A Two-Sample Mendelian Randomisation Study.

Existing literature suggests a controversial relationship between type 2 diabetes mellitus (T2D) and glaucoma. This study aimed to examine the potential causal connection between T2D and glycaemic traits (fasting glucose [FG] and glycated haemoglobin [HbA1c] levels) as exposures to primary open-angle glaucoma (POAG) in multi-ethnic populations. Single-nucleotide polymorphisms associated with exposure to T2D, FG, and HbA1c were selected as instrumental variables with significance (p < 5.0 × 10-8) from the genome-wide association study (GWAS)-based meta-analysis data available from the BioBank Japan and the UK Biobank (UKB). The GWAS for POAG was obtained from the meta-analyses of Genetic Epidemiology Research in Adult Health and Aging and the UKB. A two-sample Mendelian randomisation (MR) study was performed to assess the causal estimates using the inverse-variance weighted (IVW) method, and MR-Pleiotropy Residual Sum and Outlier test (MR-PRESSO). Significant causal associations of T2D (odds ratio [OR] = 1.05, 95% confidence interval [CI] = [1.00-1.10], p = 0.031 in IVW; OR = 1.06, 95% CI = [1.01-1.11], p = 0.017 in MR-PRESSO) and FG levels (OR = 1.19, 95% CI = [1.02-1.38], p = 0.026 in IVW; OR = 1.17, 95% CI = [1.01-1.35], p = 0.041 in MR-PRESSO) with POAG were observed, but not in HbA1c (all p > 0.05). The potential causal relationship between T2D or FG and POAG highlights its role in the prevention of POAG. Further investigation is necessary to authenticate these findings.

Causal Associations of Glaucoma and Age-Related Macular Degeneration with Cataract: A Bidirectional Two-Sample Mendelian Randomisation Study.

Common age-related eye disorders include glaucoma, cataract, and age-related macular degeneration (AMD); however, little is known about their relationship with age. This study investigated the potential causal relationship between glaucoma and AMD with cataract using genetic data from multi-ethnic populations. Single-nucleotide polymorphisms (SNPs) associated with exposure to cataract were selected as instrumental variables (IVs) from genome-wide association studies using meta-analysis data from BioBank Japan and UK Biobank. A bidirectional two-sample Mendelian randomisation (MR) study was conducted to assess the causal estimates using inverse variance weighted, MR-Egger, and MR pleiotropy residual sum and outlier tests. SNPs with (p < 5.0 × 10-8) were selected as IVs for cataract, primary open-angle glaucoma, and AMD. We found no causal effects of cataract on glaucoma or AMD (all p > 0.05). Furthermore, there were no causal effects of AMD on cataract (odds ratio [OR] = 1.02, p = 0.400). However, glaucoma had a substantial causal effect on cataract (OR = 1.14, p = 0.020). Our study found no evidence for a causal relationship of cataract on glaucoma or AMD and a casual effect of AMD on cataract. Nonetheless, glaucoma demonstrates a causal link with cataract formation, indicating the need for future investigations of age-related eye diseases.

Potential Causal Association between C-Reactive Protein Levels in Age-Related Macular Degeneration: A Two-Sample Mendelian Randomization Study.

Researchers have proposed a possible correlation between age-related macular degeneration (AMD) and inflammation or C-reactive protein (CRP) levels. We investigated the potential causal relationship between CRP levels and AMD. Single-nucleotide polymorphisms (SNPs) associated with CRP exposure were selected as the instrumental variables (IVs) with significance (p < 5 × 10-8) from the genome-wide association study (GWAS) meta-analysis data of Biobank Japan and the UK Biobank. GWAS data for AMD were obtained from 11 International AMD Genomics Consortium studies. An evaluation of causal estimates, utilizing the inverse-variance-weighted (IVW), weighted-median, MR-Egger, MR-Pleiotropy-Residual-Sum, and Outlier tests, was conducted in a two-sample Mendelian randomization (MR) study. We observed significant causal associations between CRP levels and AMD (odds ratio [OR] = 1.13, 95% CI = [1.02-1.24], and p = 0.014 in IVW; OR = 1.18, 95% CI = [1.00-1.38], and p = 0.044 in weight median; OR = 1.31, 95% CI = [1.13-1.52], and p < 0.001 in MR-Egger). The causal relationship between CRP and AMD warrants further research to address the significance of inflammation as a risk factor for AMD.

Associations between Disc Hemorrhage and Primary Open-Angle Glaucoma Based on Genome-Wide Association and Mendelian Randomization Analyses.

Background/Objectives: We aimed to investigate the genetic loci related to disc hemorrhage (DH) and the relationship of causation between DH and primary open-angle glaucoma (POAG) using a genome-wide association study (GWAS) in East Asian individuals. Methods: The GWAS included 8488 Koreans who underwent ocular examination including fundus photography to determine the presence of DH and POAG. We performed a GWAS to identify significant single-nucleotide polymorphisms (SNPs) associated with DH and analyzed the heritability of DH and genetic correlation between DH and POAG. The identified SNPs were utilized as instrumental variables (IVs) for two-sample Mendelian randomization (MR) analysis. The POAG outcome dataset was adopted from Biobank Japan data (n = 179,351). Results: We found that the rs62463744 (TMEM270;ELN), rs11658281 (CCDC42), and rs77127203 (PDE10A;LINC00473) SNPs were associated with DH. The SNP heritability of DH was estimated to be 6.7%, with an absence of a genetic correlation with POAG. MR analysis did not reveal a causal association between DH and POAG for East Asian individuals. Conclusions: The novel loci underlying DH in the Korean cohort revealed SNPs in the ELN, CCDC41, and LINC00473 genes. The absence of a causal association between DH and POAG implies that DH is a shared risk factor, rather than an independent culprit factor, and warrants further investigation.

COL8A2 Activation Enhances Function of Corneal Endothelial Cells through HIPPO Signaling/Mitochondria Pathway.

Corneal endothelial cells (CECs) are essential for maintaining corneal transparency and hydration through their barrier and pump functions. The COL8A2 gene encodes a component of the extracellular matrix of the cornea, which is crucial for the normal functioning of these cells. Mutations in COL8A2 are linked to corneal dystrophies, emphasizing the gene's importance in corneal health. The purpose of this research is to explore the effects of COL8A2 activation within CECs, to understand its contribution to cellular behavior and health. COL8A2 CRISPR/dCas9 activation system (aCOL8A2) was used to activate the COL8A2. In rats, wound healing and mitochondrial function were assessed after COL8A2 activation. As a result, aCOL8A2 promoted wound healing of rat corneal endothelium by increasing mitochondrial membrane potential. In cultured human CECs, proteomic analysis was performed to screen and identify the differential protein profiles between control and aCOL8A2 cells. Western blot was used to validate the differential proteins from both cells. Mitochondrial function and intracellular distribution were assessed by measuring ATP production and mitochondrial membrane potential. In cultured human CECs, aCOL8A2 increased COL8A2 and phospho-YAP levels. Transendothelial electrical resistance (TEER) was increased and actin cytoskeleton was attenuated by aCOL8A2. Gene ontology analysis revealed that the proteins were mainly involved in the regulation of folate biosynthesis, ECM-receptor interaction, cell differentiation, NADP activity and cytoskeleton. ATP production was increased, mitochondrial membrane potential was polarized and mitochondrial distribution was widespread in the aCOL8A2 group. In conclusion, aCOL8A2 induces a regulatory cascade affecting mitochondrial positioning and efficiency, mediated by alterations in the cytoskeletal architecture and the YAP signaling pathway. This sequence of events serves to bolster the functional capacities of corneal endothelial cells, including their pump and barrier functions, essential for corneal health and transparency.

Sphingolipid metabolites as potential circulating biomarkers for sarcopenia in men.

BACKGROUND: Sarcopenia is an age-related progressive loss of muscle mass and function. Sarcopenia is a multifactorial disorder, including metabolic disturbance; therefore, metabolites may be used as circulating biomarkers for sarcopenia. We aimed to investigate potential biomarkers of sarcopenia using metabolomics. METHODS: After non-targeted metabolome profiling of plasma from mice of an aging mouse model of sarcopenia, sphingolipid metabolites and muscle cells from the animal model were evaluated using targeted metabolome profiling. The associations between sphingolipid metabolites identified from mouse and cell studies and sarcopenia status were assessed in men in an age-matched discovery (72 cases and 72 controls) and validation (36 cases and 128 controls) cohort; women with sarcopenia (36 cases and 36 controls) were also included as a discovery cohort. RESULTS: Both non-targeted and targeted metabolome profiling in the experimental studies showed an association between sphingolipid metabolites, including ceramides (CERs) and sphingomyelins (SMs), and sarcopenia. Plasma SM (16:0), CER (24:1), and SM (24:1) levels in men with sarcopenia were significantly higher in the discovery cohort than in the controls (all P < 0.05). There were no significant differences in plasma sphingolipid levels for women with or without sarcopenia. In men in the discovery cohort, an area under the receiver-operating characteristic curve (AUROC) of SM (16:0) for low muscle strength and low muscle mass was 0.600 (95% confidence interval [CI]: 0.501-0.699) and 0.647 (95% CI: 0.557-0.737). The AUROC (95% CI) of CER (24:1) and SM (24:1) for low muscle mass in men was 0.669 (95% CI: 0.581-0.757) and 0.670 (95% CI: 0.582-0.759), respectively. Using a regression equation combining CER (24:1) and SM (16:0) levels, a sphingolipid (SphL) score was calculated; an AUROC of the SphL score for sarcopenia was 0.712 (95% CI: 0.626-0.798). The addition of the SphL score to HGS significantly improved the AUC from 0.646 (95% CI: 0.575-0.717; HGS only) to 0.751 (95% CI: 0.671-0.831, P = 0.002; HGS + SphL) in the discovery cohort. The predictive ability of the SphL score for sarcopenia was confirmed in the validation cohort (AUROC = 0.695, 95% CI: 0.591-0.799). CONCLUSIONS: SM (16:0), reflecting low muscle strength, and CER (24:1) and SM (16:0), reflecting low muscle mass, are potential circulating biomarkers for sarcopenia in men. Further research on sphingolipid metabolites is required to confirm these results and provide additional insights into the metabolomic changes relevant to the pathogenesis and diagnosis of sarcopenia.