Scheimpflug Tomographic Indices for Classifying Normal, Down Syndrome and Clinical Keratoconus in Pediatric Patients.

The study aimed to evaluate the precision of different Pentacam indices in diagnosing keratoconus (KC) in pediatric patients with and without Down Syndrome (DS) and determine suitable cutoff values. This prospective multicenter cross-sectional study evaluated 216 eyes of 131 patients aged 6-18 years (mean age 12.5 ± 3.2 years) using Pentacam. Patients were categorized into four groups: KC, forme fruste keratoconus (FK), DS, and control, excluding DS patients with topographic KC. Receiver operating characteristic curves were generated to determine the optimal cutoff points and compare the accuracy in identifying KC and FK in patients with and without DS. In DS patients, corneal morphology resembled KC features. The most effective indices for distinguishing KC in DS patients were the average pachymetric progression index (AUC = 0.961), higher-order aberration of the anterior cornea (AUC = 0.953), anterior elevation (AUC = 0.946), posterior elevation (AUC = 0.947), index of vertical asymmetry (AUC = 0.943), and Belin/Ambrosio enhanced ectasia total derivation value (AUC = 0.941). None of the indices showed good accuracy for distinguishing FK in DS patients. The thresholds of these indices differed significantly from non-DS patients. The results highlighted the need for DS-specific cutoff values to avoid false-positive or false-negative diagnoses in this population.

Amniotic Membrane-Derived Multichannel Hydrogels for Neural Tissue Repair.

In the pursuit of advancing neural tissue regeneration, biomaterial scaffolds have emerged as promising candidates, offering potential solutions for nerve disruptions. Among these scaffolds, multichannel hydrogels, characterized by meticulously designed micrometer-scale channels, stand out as instrumental tools for guiding axonal growth and facilitating cellular interactions. This study explores the innovative application of human amniotic membranes modified with methacryloyl domains (AMMA) in neural stem cell (NSC) culture. AMMA hydrogels, possessing a tailored softness resembling the physiological environment, are prepared in the format of multichannel scaffolds to simulate native-like microarchitecture of nerve tracts. Preliminary experiments on AMMA hydrogel films showcase their potential for neural applications, demonstrating robust adhesion, proliferation, and differentiation of NSCs without the need for additional coatings. Transitioning into the 3D realm, the multichannel architecture fosters intricate neuronal networks guiding neurite extension longitudinally. Furthermore, the presence of synaptic vesicles within the cellular arrays suggests the establishment of functional synaptic connections, underscoring the physiological relevance of the developed neuronal networks. This work contributes to the ongoing efforts to find ethical, clinically translatable, and functionally relevant approaches for regenerative neuroscience.

Comparative Analysis of Combined Topography-Guided Photorefractive Keratectomy and Corneal Crosslinking in Progressive Versus Stable Keratoconus.

PURPOSE: To perform a comparative analysis of visual, refractive, and tomographic outcomes of combined topography-guided photorefractive keratectomy (TG-PRK) and corneal crosslinking (CXL) in patients with progressive versus stable keratoconus. METHODS: Longitudinal retrospective case-control study. Patients with keratoconus submitted to simultaneous TG-PRK and CXL were included, with a minimum follow-up of 12 months up to 3 years. According to predefined disease progression criteria, patients were considered as progressive or stable. RESULTS: A total of 101 eyes from 93 patients were included, 62 considered progressive and 39 stable keratoconus. All baseline characteristics were similar between groups, except for age at surgery (progressive: 23.40 ± 4.22 years; stable: 35.97 ± 9.09; P < 0.001). Logarithm of the minimum angle of resolution CDVA improved significantly in progressive (baseline: 0.48 ± 0.24; 12 months: 0.33 ± 0.29; P < 0.001) and stable (baseline: 0.51 ± 0.24; 12 months: 0.28 ± 0.21; P < 0.001) patients, with no differences between groups. Maximum keratometry decreased significantly in progressive (baseline: 59.18 ± 5.63 diopters; 12 months: 54.73 ± 5.95; P < 0.001) and stable (baseline: 57.77 ± 5.02; 12 months: 53.59 ± 4.20; P < 0.001) patients, with no differences between groups. Index of surface variance significantly improved in progressive (baseline: 109.18 ± 31.74 diopters; 12 months: 94.11 ± 34.11; P < 0.001) and stable (baseline: 102.87 ± 29.52; 12 months: 86.95 ± 27.21; P < 0.001) patients, with no differences between groups. Other tomographic outcomes were also similar between groups. Pachymetry significantly decreased after surgery but remained stable throughout the follow-up. CONCLUSIONS: Combined TG-PRK and CXL is a safe and effective procedure for improving CDVA and regularizing the cornea, with comparable visual, refractive, and tomographic outcomes in both progressive and stable keratoconus. Combined TG-PRK and CXL may be added to the armamentarium of therapeutic tools for visual rehabilitation in patients with stable keratoconus.

Metabolomic-derived endotypes of age-related macular degeneration (AMD): a step towards identification of disease subgroups.

Age-related macular degeneration (AMD) is a leading cause of blindness worldwide, with a complex pathophysiology and phenotypic diversity. Here, we apply Similarity Network Fusion (SNF) to cluster AMD patients into putative metabolomics-derived endotypes. Using a discovery cohort of 163 AMD patients from Boston, US, and a validation cohort of 214 patients from Coimbra, Portugal, we identified four distinct metabolomics-derived endotypes with varying retinal structural and functional characteristics, confirmed across both cohorts. Patients clustered into Endotype 1 exhibited a milder form of AMD and were characterized by low levels of amino acids in specific metabolic pathways. Meanwhile, patients clustered into both Endotype 3 and 4 were associated with more severe AMD and exhibited low levels of fatty acid metabolites and elevated levels of sphingomyelins and fatty acid metabolites, respectively. These preliminary findings indicate that metabolomics-derived endotyping may offer a refined strategy for categorizing AMD patients based on their specific pathophysiological underpinnings, rather than relying solely on traditional observational clinical indicators.

Advances in Microfluidic-Based Core@Shell Nanoparticles Fabrication for Cancer Applications.

Current research in cancer therapy focuses on personalized therapies, through nanotechnology-based targeted drug delivery systems. Particularly, controlled drug release with nanoparticles (NPs) can be designed to safely transport various active agents, optimizing delivery to specific organs and tumors, minimizing side effects. The use of microfluidics (MFs) in this field has stood out against conventional methods by allowing precise control over parameters like size, structure, composition, and mechanical/biological properties of nanoscale carriers. This review compiles applications of microfluidics in the production of core-shell NPs (CSNPs) for cancer therapy, discussing the versatility inherent in various microchannel and/or micromixer setups and showcasing how these setups can be utilized individually or in combination, as well as how this technology allows the development of new advances in more efficient and controlled fabrication of core-shell nanoformulations. Recent biological studies have achieved an effective, safe, and controlled delivery of otherwise unreliable encapsulants such as small interfering RNA (siRNA), plasmid DNA (pDNA), and cisplatin as a result of precisely tuned fabrication of nanocarriers, showing that this technology is paving the way for innovative strategies in cancer therapy nanofabrication, characterized by continuous production and high reproducibility. Finally, this review analyzes the technical, biological, and technological limitations that currently prevent this technology from becoming the standard.

Topical tacrolimus in high-risk corneal transplants.

PURPOSE: The purpose of this study was to assess the use of topical tacrolimus ointment in preventing rejection in high-risk corneal grafts, when added to the standard immunosuppressive regimen. METHODS: We conducted an observational, retrospective study using clinical data of high-risk patients subjected to penetrating keratoplasty, who were treated with topical tacrolimus ointment 0.2 mg/g twice a day plus topical dexamethasone 0.1 mg/ml 6 id and compared it with a similar control group treated with topical dexamethasone 0.1 mg/ml 6 id alone. High-risk status was attributed to patients with previous ipsilateral corneal graft failure, two or more quadrants with corneal neovascularization or an infectious or inflammatory corneal disease. RESULTS: We analysed 53 patients in the trial group versus 53 patients in the control group, with similar age, baseline diagnosis and risk factors, and median follow-up times of 30 and and 24 months, respectively. Survival analysis showed a higher graft survival rate at all follow-up periods for patients treated with topical tacrolimus (p < 0.01). No adverse reactions were reported. DISCUSSION: This study shows that topical tacrolimus ointment increases the survival rate of the graft if added to the previous topical steroid regimen in high-risk patients. CONCLUSION: Topical tacrolimus is safe and effective in prolonging graft survival in high-risk patients.

The influence of personality on the quality of vision after multifocal intraocular lens implantation.

OBJECTIVE: To assess the possible correlation between patients' personality traits and subjective perception of quality of vision (QoV), after multifocal intraocular lens (mIOL) implantation. METHODS: patients who had bilateral implantation of a non-diffractive X-WAVE or a trifocal lens were assessed 6 months postoperatively. Patients answered the NEO-Five Factor Inventory (NEO-FFI-20) questionnaire ("Big Five five-factor personality model") to examine their personality. Six months following surgery, patients were asked to fill a QoV questionnaire where they graded the frequency of 10 common visual symptoms. Primary outcomes were to evaluate the correlation between personality scores and the reported frequency of visual disturbances. RESULTS: The study comprised 20 patients submitted to bilateral cataract surgery, 10 with a non-diffractive X-WAVE lens (AcrySof® IQ Vivity) and 10 with a trifocal lens (AcrySof® IQ PanOptix). Mean age was 60.23 (7.06) years. Six months following surgery, patients with lower scores of conscientiousness and extroversion reported a higher frequency of visual disturbances (blurred vision, P = .015 and P = .009, seeing double images P = .018 and P = .006, and having difficulties focusing, P = .027 and P = .022, respectively). In addition, patients with high neuroticism scores had more difficulty focusing (P = .033). CONCLUSIONS: In this study, personality traits such as low conscientiousness and extroversion and high neuroticism significantly influenced QoV perception 6 months after bilateral multifocal lens implantation. Patients' personality questionnaires could be a useful preoperative assessment test to a mIOL.

Plasma Metabolites Associated with OCT Features of Age-Related Macular Degeneration.

Purpose: The most widely used classifications of age-related macular degeneration (AMD) and its severity stages still rely on color fundus photographs (CFPs). However, AMD has a wide phenotypic variability that remains poorly understood and is better characterized by OCT. We and others have shown that patients with AMD have a distinct plasma metabolomic profile compared with controls. However, all studies to date have been performed solely based on CFP classifications. This study aimed to assess if plasma metabolomic profiles are associated with OCT features commonly seen in AMD. Design: Prospectively designed, cross-sectional study. Participants: Subjects with a diagnosis of AMD and a control group (> 50 years old) from Boston, United States, and Coimbra, Portugal. Methods: All participants were imaged with CFP, used for AMD staging (Age-Related Eye Disease Study 2 classification scheme), and with spectral domain OCT (Spectralis, Heidelberg). OCT images were graded by 2 independent graders for the presence of characteristic AMD features, according to a predefined protocol. Fasting blood samples were collected for metabolomic profiling (using nontargeted high-resolution mass spectrometry by Metabolon Inc). Analyses were conducted using logistic regression models including the worst eye of each patient (AREDS2 classification) and adjusting for confounding factors. Each cohort (United States and Portugal) was analyzed separately and then results were combined by meta-analyses. False discovery rate (FDR) was used to account for multiple comparisons. Main Outcome Measures: Plasma metabolite levels associated with OCT features. Results: We included data on 468 patients, 374 with AMD and 94 controls, and on 725 named endogenous metabolites. Meta-analysis identified significant associations (FDR < 0.05) between plasma metabolites and 3 OCT features: hyperreflective foci (6), atrophy (6), and ellipsoid zone disruption (3). Most associations were seen with amino acids, and all but 1 metabolite presented specific associations with the OCT features assessed. Conclusions: To our knowledge, we show for the first time that plasma metabolites have associations with specific OCT features seen in AMD. Our results support that the wide spectrum of presentations of AMD likely include different pathophysiologic mechanisms by identifying specific pathways associated with each OCT feature. Financial Disclosures: Proprietary or commercial disclosure may be found after the references.

Coronary Artery Fistula as Another Cause of Acute Heart Failure.

Coronary artery fistulas (CAFs) are rare defects in the coronary circulation system that are usually diagnosed incidentally with cardiac imaging. Although the prognosis of coronary artery fistulas is highly variable, the complications to which they predispose patients are ultimately the determining factor. The authors describe a case of a 56-year-old male, a smoker, hospitalised for worsening dyspnoea on progressively smaller efforts, in the context of acute heart failure. During hospitalisation and imaging exams, a coronary-bronchial fistula was identified. LEARNING POINTS: CAFs are rare and may present with different anatomical configurations and clinical syndromes.Only 17% of CAFs reported draining into the pulmonary circulation.The optimal timing and role of CAFs intervention are not clearly defined.

New sublittoral species of Laonice (Annelida: Spionidae) from southern Asian coasts.

Four new species of Laonice (Annelida: Spionidae) are described from the southern and southeastern coasts of Asia: L. (Laonice) persica sp. nov., L. (Laonice) siamica sp. nov., L. (Sarsiana) apicelamella sp. nov. and L. (Sarsiana) andamanica sp. nov. Materials were collected within the scope of different environmental surveys performed by the consulting company Créocéan, ranging from the Persian Gulf (Indian Ocean) on the west, to the Gulf of Siam (Pacific Ocean) on the east. In addition, specimens found in the Gulf of Siam are tentatively attributed to L. (Sarsiana) sinica, and an English translation of the species description is provided for the first time. Different species subgroups within L. (Sarsiana) are also recognized based on key morphologic characters, though their phylogenetic relevance requires further confirmation. The scientific value of biological material collected during environmental surveys is emphasized, and contractors are encouraged to deposit reference collections in public natural history collections.

Cancer Models on Chip: Paving the Way to Large-Scale Trial Applications.

Cancer kills millions of individuals every year all over the world (Global Cancer Observatory). The physiological and biomechanical processes underlying the tumor are still poorly understood, hindering researchers from creating new, effective therapies. Inconsistent results of preclinical research, in vivo testing, and clinical trials decrease drug approval rates. 3D tumor-on-a-chip (ToC) models integrate biomaterials, tissue engineering, fabrication of microarchitectures, and sensory and actuation systems in a single device, enabling reliable studies in fundamental oncology and pharmacology. This review includes a critical discussion about their ability to reproduce the tumor microenvironment (TME), the advantages and drawbacks of existing tumor models and architectures, major components and fabrication techniques. The focus is on current materials and micro/nanofabrication techniques used to manufacture reliable and reproducible microfluidic ToC models for large-scale trial applications.

Comparison of outcomes between cross-linking plus topoguided excimer laser ablation and intrastromal corneal ring segments for keratoconus.

OBJECTIVE: To compare cross-linking (CXL) plus topography-guided photorefractive keratectomy (t-PRK) and intrastromal corneal ring segments (ICRS) in keratoconus patients, at 12 months of follow-up. METHODS: This was a longitudinal, retrospective multi-center study. We included a referred sample of 154 eyes from 149 patients with grade I-III Amsler-Krümeich keratoconus with insufficient corrected-distance visual acuity (CDVA). In group 1 (CXL plus t-PRK, 87 eyes), another possible indication for surgery was evidence of progression. Group 2 (ICRS, 67 eyes) included only eyes with paracentral keratoconus (thinnest point at the inferotemporal quadrant) with coincident axes, and evidence of stabilization was required. A subgroup analysis was performed regarding the disease topographic phenotype. At 12 months postoperatively, visual, refractive, and topographic outcomes were evaluated. RESULTS: Comparison of the outcomes between CXL plus t-PRK (group 1) and ICRS (group 2) showed similar improvements in CDVA (in group 1, CDVA improved 0.18 logMAR, and in group 2 0.12 logMAR, P = .18) and K2 (-2,45 [6.46] D in group 1 and -2.13 [1.67] D in group 2, P = .34) The improvement in cylinder power was greater in group 2 (-2.37 [2.07] D in group 2 versus -1.18 [2.63] D in group 1, P = .003); group 1 had a higher decrease in Kmax (- 3.26 [3.64] versus-1.74 [2.67], P = .001). CONCLUSIONS: Both CXL plus t-PRK and ICRS were equally effective in improving CDVA and topographic parameters in a similar group of keratoconus patients at 12 months.

Surgical Management of Bilateral Limbal Stem Cell Deficiency.

At the age of 43 years-old, a man was left with bilateral limbal stem cell deficiency after an ocular alkaline burn with lime, which resulted in corneal opacification. After multiple unsuccessful surgical attempts to restore vision, including penetrating keratoplasties and Boston keratoprosthesis, visual acuity was counting fingers in the left eye. At 73 years of age, the patient underwent another surgery in his left eye. Cauterization of neovessels and removal of the vascular pannus were followed by partial excision of Tenon's capsule. Penetrating keratoplasty was followed by an intrastromal injection of anti-VEGF (vascular endothelial growth factor), and the ocular surface was covered with amniotic membrane. Postoperatively, the graft was clear with no signs of inflammation; vision improved to 20/50 and remained stable throughout the following two years. Herein we describe some adjunctive procedures that might have delayed failure and rejection of the corneal graft. This case demonstrates the difficulties in treating bilateral limbal stem cell deficiency in a tertiary eye care center with no capacity to perform stem cell therapy.

Customized corneal crosslinking with excimer laser-assisted epithelium removal for progressive keratoconus: 1-year results.

PURPOSE: To evaluate the 1-year visual and tomographic results of customized crosslinking using excimer laser-assisted epithelium removal and topography-guided irradiation in the treatment of progressive keratoconus. SETTING: Coimbra Ophthalmology Unit, Private Practice, Coimbra, Portugal. DESIGN: Prospective nonrandomized clinical trial. METHODS: Eyes with documented progressive keratoconus were enrolled. After de-epithelialization with phototherapeutic keratectomy, customized UV irradiation was performed, designed as 3 concentric circular areas centered on the thinnest point (Mosaic System). Energy exposure was 5.4 J/cm 2 in the outer circle and then increased centripetally to 7.2 J/cm 2 and 10 J/cm 2 . Corrected distance visual acuity (CDVA), refractive outcomes, and Scheimpflug tomographies (Allegro Oculyzer) were assessed at baseline, and 6 months, and 12 months postoperatively. RESULTS: 37 eyes of 32 patients were enrolled in this prospective study. The mean diameter for treated areas was 6.17 ± 0.80 mm, 4.45 ± 0.47 mm, and 2.58 ± 0.14 mm for the outer, medium, and inner circle, respectively. At the 1-year follow-up, the mean CDVA improved significantly from 0.38 ± 0.19 to 0.20 ± 0.16 logMAR ( P < .01), with 34 (91.89%) of the 37 eyes retaining or improving CDVA. The mean preoperative minimum pachymetry decreased from 449.26 ± 41.62 to 443.26 ± 41.06 µm ( P = .02). The maximum keratometry decreased significantly from 58.50 ± 7.84 to 57.05 ± 7.27 diopters ( P < .01). After 1 year, 34 eyes (91.89%) showed no signs of progression. CONCLUSIONS: 1 year postoperatively, patients showed a significant improvement in visual acuity while achieving stabilization of disease progression.

Description of the new species Sigambra nkossa (Annelida, Pilargidae), with an analysis of the distribution patterns of polychaetes associated with artificially hydrocarbon-enriched bottoms.

The monitoring of the N'Kossa offshore oil and gas fields in the Republic of Congo allowed us to assess the ecological traits of two polychaete species belonging to Sigambra (Annelida, Pilargidae). Sigambra parva occur in very low densities in all bottoms, except the most impacted, where it is totally absent; it is an undescribed species that reached >4,000 ind/m2 in hydrocarbon-enriched sediments. Their distribution patterns are compared with those of other polychaetes, showing a range of affinities for hydrocarbon-enriched sediments in the N'Kossa region. Our results suggest that S. parva would be a representative of the original local fauna, while the species associated with artificial hydrocarbon-enriched sediments, including the other Sigambra, six more polychaetes and a bivalve, could be natively associated with natural hydrocarbon-enriched sediments, using the former as alternative habitats and as dispersal stepping stones. This ecological segregation, together with a careful morphological and morphometric analyses led us to describe the latter as a new species, namely Sigambra nkossa sp. nov. Moreover, morphometric analysis allowed us to discuss on the taxonomic robustness of the key morphological characters of S. nkossa sp. nov., as well as to emend the generic diagnosis of Sigambra to accommodate the new species.

Urinary Mass Spectrometry Profiles in Age-Related Macular Degeneration.

We and others have shown that patients with different severity stages of age-related macular degeneration (AMD) have distinct plasma metabolomic profiles compared to controls. Urine is a biofluid that can be obtained non-invasively and, in other fields, urine metabolomics has been proposed as a feasible alternative to plasma biomarkers. However, no studies have applied urinary mass spectrometry (MS) metabolomics to AMD. This study aimed to assess urinary metabolomic profiles of patients with different stages of AMD and a control group. We included two prospectively designed, multicenter, cross-sectional study cohorts: Boston, US (n = 185) and Coimbra, Portugal (n = 299). We collected fasting urine samples, which were used for metabolomic profiling (Ultrahigh Performance Liquid chromatography-Mass Spectrometry). Multivariable logistic and ordinal logistic regression models were used for analysis, accounting for gender, age, body mass index and use of AREDS supplementation. Results from both cohorts were then meta-analyzed. No significant differences in urine metabolites were seen when comparing patients with AMD and controls. When disease severity was considered as an outcome, six urinary metabolites differed significantly (p < 0.01). In particular, two of the metabolites identified have been previously shown by our group to also differ in the plasma of patients of AMD compared to controls and across severity stages. While there are fewer urinary metabolites associated with AMD than plasma metabolites, this study identified some differences across stages of disease that support previous work performed with plasma, thus highlighting the potential of these metabolites as future biomarkers for AMD.

Berardinelli-Seip Congenital Lipodystrophy Discovered Following a STEMI Event.

A 60-year-old man, with a history of familial lipodystrophy, hypertriglyceridaemia, hepatic steatosis and bone cysts, was admitted due an acute coronary event. Coronary angiography showed significant stenosis in the left anterior descending artery, which was treated. Transthoracic echocardiography showed a slightly dilated left ventricle with diffuse and heterogeneous thickening of its walls, slightly decreased left ventricular function and reduced global longitudinal strain. Due to these echocardiographic findings, cardiac magnetic resonance imaging was requested, which identified intramyocardial diffuse fibrosis of the basal septum and points of insertion of the left and right ventricles, without oedema, microvascular obstruction or myocardial infarction. Owing to the constellation of symptoms and distinctive features on cardiac imaging, a diagnosis of Berardinelli-Seip congenital lipodystrophy (BSCL) was suspected, which was confirmed through genetic testing of the pathogenic variants in BSCL2 and AGPAT2. BSCL is a rare autosomal recessive syndrome characterized by the congenital absence of adipose tissue and triglyceride deposition in other tissues, such as muscle, liver and heart. LEARNING POINTS: Berardinelli-Seip congenital lipodystrophy (BSCL) is a rare congenital lipodystrophy, with an incidence of 1-9 per million population, which is usually diagnosed at birth and is associated with pathogenic variants of the BSCL2 and AGPAT2 genes.Due to the absence of functional adipocytes, lipid storage occurs in other tissues, including skeletal muscle and liver.Diagnosis is based on the presence of three major or two major and two minor characteristics.

Taxonomic review of Gallardonerisnonatoi (Ramos, 1976) comb. nov. (Annelida, Lumbrineridae), and description of a new species of Lumbrineris from the Gulf of Mexico.

The small LumbrineridaeGallardonerisiberica Martins, Carrera-Parra, Quintino & Rodrigues, 2012 was first described as new to science based on specimens from Portuguese waters. Then, it was successively reported from several south European areas, including Spain, Italy, Greece, and Cyprus. Here evidence is presented that G.iberica should be placed in synonymy with Lumbrinerisnonatoi Ramos, 1976, originally described from NW Mediterranean waters, a species that fits with the diagnosis of Gallardoneris. Based on specimens from the French coasts of the NW Mediterranean, this paper (1) redescribes the species using the new combination Gallardonerisnonatoi (Ramos, 1976) and (2) provides a morphometric analysis of its main morphological characters. The lack of recent reports of G.nonatoi comb. nov. in Mediterranean waters is presumably due to the recent redescription of the species as L.nonatoi based on specimens from the Gulf of Mexico. However, these specimens belong to Lumbrineris, as currently defined. By assessing their morphological differences, it is concluded that the specimens from the Gulf of Mexico represent a different and new species, namely Lumbrinerisjan sp. nov. Also discussed is the possible assignation of Lumbrinerislongipodiata Cantone, 1990, a poorly known species seldom recorded since its original description from the Gulf of Catania (Mediterranean Sea) to Gallardoneris, as well as on whether it is a valid species or may be an additional junior synonym of G.nonatoi comb. nov.

Genomic-Metabolomic Associations Support the Role of LIPC and Glycerophospholipids in Age-Related Macular Degeneration.

PURPOSE: Large-scale genome-wide association studies (GWAS) have reported important single nucleotide polymorphisms (SNPs) with significant associations with age-related macular degeneration (AMD). However, their role in disease development remains elusive. This study aimed to assess SNP-metabolite associations (i.e., metabolite quantitative trait loci [met-QTL]) and to provide insights into the biological mechanisms of AMD risk SNPs. DESIGN: Cross-sectional multicenter study (Boston, Massachusetts, and Coimbra, Portugal). PARTICIPANTS: Patients with AMD (n = 388) and control participants (n = 98) without any vitreoretinal disease (> 50 years). METHODS: Age-related macular degeneration grading was performed using color fundus photographs according to the Age-Related Eye Disease Study classification scheme. Fasting blood samples were collected and evaluated with mass spectrometry for metabolomic profiling and Illumina OmniExpress for SNPs profiling. Analyses of met-QTL of endogenous metabolites were conducted using linear regression models adjusted for age, gender, smoking, 10 metabolite principal components (PCs), and 10 SNP PCs. Additionally, we analyzed the cumulative effect of AMD risk SNPs on plasma metabolites by generating genetic risk scores and assessing their associations with metabolites using linear regression models, accounting for the same covariates. Modeling was performed first for each cohort, and then combined by meta-analysis. Multiple comparisons were accounted for using the false discovery rate (FDR). MAIN OUTCOME MEASURES: Plasma metabolite levels associated with AMD risk SNPs. RESULTS: After quality control, data for 544 plasma metabolites were included. Meta-analysis of data from all individuals (AMD patients and control participants) identified 28 significant met-QTL (ß = 0.016-0.083; FDR q-value < 1.14 × 10-2), which corresponded to 5 metabolites and 2 genes: ASPM and LIPC. Polymorphisms in the LIPC gene were associated with phosphatidylethanolamine metabolites, which are glycerophospholipids, and polymorphisms in the ASPM gene with branched-chain amino acids. Similar results were observed when considering only patients with AMD. Genetic risk score-metabolite associations further supported a global impact of AMD risk SNPs on the plasma metabolome. CONCLUSIONS: This study demonstrated that genomic-metabolomic associations can provide insights into the biological relevance of AMD risk SNPs. In particular, our results support that the LIPC gene and the glycerophospholipid metabolic pathway may play an important role in AMD, thus offering new potential therapeutic targets for this disease.