Longitudinal Structural and Functional Evaluation of Dark-without-Pressure Fundus Lesions in Patients with Autoimmune Diseases.

OBJECTIVES: The main objective of this study was to report and investigate the characteristics and longitudinal changes in dark-without-pressure (DWP) fundus lesions in patients with autoimmune diseases using multimodal imaging techniques. METHODS: In this retrospective observational case series, five patients affected by ocular and systemic autoimmune disorders and DWP were examined. DWP was assessed by multimodal imaging, including color fundus photography (CFP), near-infrared reflectance (NIR), blue reflectance (BR), blue autofluorescence (BAF), optical coherence tomography (OCT), OCT-angiography (OCT-A), fluorescein angiography (FA) and indocyanine green angiography (ICGA), and functional testing, including standard automated perimetry (SAP) and electroretinography (ERG). Follow-up examinations were performed for four out of five patients (range: 6 months-7 years). RESULTS: DWP fundus lesions were found in the retinal mid-periphery and were characterized by the hypo-reflectivity of the ellipsoid zone on OCT. DWP appeared hypo-reflective in NIR, BR and BAF, and exhibited hypo-fluorescence in FA in two patients while showing no signs in one patient. ICGA showed hypo-fluorescent margins in one patient. SAP and ERG testing did not show alterations attributable to the DWP lesion. Follow-up examinations documented rapid dimensional changes in DWP even in the short term (1 month). CONCLUSIONS: This study suggests a possible association between autoimmune diseases and DWP. New FA and ICGA features were described. The proposed pathogenesis hypotheses may operate as a basis for further investigation of a lesion that is still largely unknown. Large population studies would be necessary to confirm whether there is a higher incidence of DWP in this patient category.

Utilising Narrative Medicine to Identify Key Factors Affecting Quality of Life in Dry Eye Disease: An Italian Multicentre Study.

INTRODUCTION: Despite an improved understanding of its pathogenesis, dry eye disease (DED) remains relatively underestimated and its treatment challenging. A better alignment between the clinical evaluation and the patient self-assessment also requires capturing the whole patient experience of DED. This project aimed to unveil this experience through narrative medicine (NM). METHODS: The project involved 38 expert centres in Italy and one in San Marino, targeting adult patients with DED, their informal caregivers and their treating ophthalmologists. Written narratives and sociodemographic and quality of life (QoL)-related data were anonymously collected through the project's webpage. Narratives were analysed through MAXQDA (VERBI Software, Berlin, Germany), NM classifications and content analysis. RESULTS: A total of 171 patients with DED, 37 informal caregivers and 81 ophthalmologists participated in the research. DED was defined as a disabling condition by 19% of patients and 35% of caregivers; 70% of patients reported that a therapeutic alliance is an integral part of DED treatment and 32% hope for more effective therapies. Forty-four per cent of patients assessed their own QoL as good; however, DED emerged as importantly impacting work performance and social events. DED physical, emotional and economic burden and the cruciality of a trusting care relationship represent the main themes that emerged across all narratives, while empathy and effective treatment are among the factors favouring coping with DED. CONCLUSION: This project marked a pioneering initiative investigating the lived experience of patients with DED through NM, simultaneously involving all viewpoints involved in the care pathway. NM enabled the unveiling of factors favouring the ability to cope with DED and its associated QoL implications and provided valuable insights to improve the therapeutic alliance.

Short Wavelength Automated Perimetry, Standard Automated Perimetry, and Optical Coherence Tomography in Dominant Optic Atrophy.

Background: Blue-yellow axis dyschromatopsia is well-known in Autosomal Dominant Optic Atrophy (ADOA) patients, but there were no data on the correlation between retinal structure and short-wavelength automated perimetry (SWAP) values in this pathology. Methods: In this cross-sectional case-control study, we assessed the correlation between best corrected visual acuity (BCVA), standard automated perimetry (SAP), SWAP, and optical coherence tomography (OCT) parameters of 9 ADOA patients compared with healthy controls. Correlation analysis was performed between BCVA, mean deviation, pattern standard deviation (PSD), and fovea sensitivity (FS) values and the OCT thickness of each retinal layer and the peripapillary retinal nerve fiber layer (pRNFL). Results: The following significant and strong correlations were found: between BCVA and ganglion cell layer (GCL) and the global (G) pRNFL thicknesses; between SAP FS and GCL and the G-pRNFL thicknesses; between SWAP PSD and total retina, GCL, inner plexiform layer, inner nuclear layer, inner retinal layer and the temporal pRNFL thicknesses. We found a constant shorter duration of the SITA-SWAP compared with the SITA-STANDARD strategy. Conclusions: SWAP, SAP, and BCVA values provided relevant clinical information about retinal involvement in our ADOA patients. The perimetric functional parameters that seemed to correlate better with structure involvement were FS on SAP and PSD on SWAP.

Non-Invasive High-Resolution Imaging of In Vivo Human Myelinated Axons.

This work aims to reveal the microscopic (2-3 micrometer resolution) appearance of human myelinated nerve fibers in vivo for the first time. We analyzed the myelinated retinal nerve fibers of a male patient without other neurological disorders in a non-invasive way using the transscleral optical phase imaging method with adaptive optics. We also analyzed the fellow eye with non-myelinated nerve fibers and compared the results with traditional ocular imaging methods such as optical coherence tomography. We documented the microscopic appearance of human myelin and myelinated axons in vivo. This method allowed us to obtain better details than through traditional ocular imaging methods. We hope these findings will be useful to the scientific community to evaluate neuro-retinal structures through new imaging techniques and more accurately document nerve anatomy and the pathophysiology of this disease.

Long-Term Structural and Functional Assessment of Doyne Honeycomb Retinal Dystrophy following Nanosecond 2RT Laser Treatment: A Case Series.

Introduction: Doyne honeycomb retinal dystrophy (DHRD), or autosomal dominant radial drusen, is a genetic disease caused by pathogenic variants of the epidermal growth factor (EGF)-containing fibulin-like extracellular matrix protein 1 EFEMP1 gene and is characterized by the formation of subretinal drusenoid deposits. In a previous study, we reported the short-term beneficial effects of nanosecond laser treatment (2RT) on retinal function in DHRD. The aim of the present report was to describe the findings of a long-term follow-up of retinal structure/function in a small case series of patients with DHRD who underwent 2RT treatment. Case Presentation: Three DHRD patients (case 1, male and cases 2 and 3, two sister females, age range 41-46) with EFEMP1 pathogenic variant (c.1033C>T; p.R345W) and drusenoid deposits at the posterior pole were examined at baseline and after 2RT treatment, at regular intervals (every 2-4 months) up to 30 months. All 3 patients underwent one or two treatment sessions in one or both eyes during the follow-up period. Case 3 was treated with only the left eye (LE). Each patient underwent a full ophthalmologic examination, spectral domain optical coherence tomography (OCT), central perimetry with frequency doubling technology, and mesopic and photopic Ganzfeld electroretinograms. Compared to baseline findings, during follow-up, visual acuity improved in both eyes in case 1 and LE in case 2, while it decreased in the right eye in case 2 and LE in case 3; perimetric sensitivity was stable in case 1 and improved in both eyes in cases 2 and 3; and electroretinogram amplitude improved in cases 1 and 2 and was stable in case 3 (both eyes). OCT central macular thickness and retinal structure were stable in all cases. None of the patients had treatment-related side effects. Conclusion: This is the first report showing that in a long-term follow-up, 2RT treatment in DHRD may improve or stabilize some retinal function parameters without significant structural changes.

A Splicing Variant in RDH8 Is Associated with Autosomal Recessive Stargardt Macular Dystrophy.

Stargardt macular dystrophy is a genetic disorder, but in many cases, the causative gene remains unrevealed. Through a combined approach (whole-exome sequencing and phenotype/family-driven filtering algorithm) and a multilevel validation (international database searching, prediction scores calculation, splicing analysis assay, segregation analyses), a biallelic mutation in the RDH8 gene was identified to be responsible for Stargardt macular dystrophy in a consanguineous Italian family. This paper is a report on the first family in which a biallelic deleterious mutation in RDH8 is detected. The disease phenotype is consistent with the expected phenotype hypothesized in previous studies on murine models. The application of the combined approach to genetic data and the multilevel validation allowed the identification of a splicing mutation in a gene that has never been reported before in human disorders.

Longitudinal Structure-Function Evaluation in a Patient with CDHR1-Associated Retinal Dystrophy: Progressive Visual Function Loss with Retinal Remodeling.

BACKGROUND: Retinal dystrophies related to damaging variants in the cadherin-related family member 1 (CDHR1) gene are rare and phenotypically heterogeneous. Here, we report a longitudinal (three-year) structure-function evaluation of a patient with a CDHR1-related retinal dystrophy. METHODS: A 14-year-old girl was evaluated between 2019 and 2022. An ophthalmological assessment, including color vision, perimetry, electroretinography, and multimodal imaging of the retina, was performed periodically every six months. Next-generation sequencing disclosed two likely pathogenic/pathogenic variants in the CDHR1 gene, in compound heterozygosity, confirmed by segregation analysis. RESULTS: At first examination, the patient showed a cone-rod pattern retinal dystrophy. Over follow-up, there was a decline of visual acuity and perimetric sensitivity (by ≥0.3 and 0.6 log units, respectively). Visual loss was associated with a progressive increase in inner retinal thickness (by 30%). Outer retina showed no detectable changes over the follow-up. CONCLUSIONS: The results indicate that, in this patient with a CDHR1-related cone-rod dystrophy, the progression to severe visual loss was paralleled by a progressive inner retinal thickening, likely a reflection of remodeling. Inner retinal changes over time may be functionally relevant in view of the therapeutic attempts based on gene therapy or stem cells to mitigate photoreceptor loss.

WARE: Wet AMD Risk-Evaluation Tool as a Clinical Decision-Support System Integrating Genetic and Non-Genetic Factors.

Given the multifactorial features characterizing age-related macular degeneration (AMD), the availability of a tool able to provide the individual risk profile is extremely helpful for personalizing the follow-up and treatment protocols of patients. To this purpose, we developed an open-source computational tool named WARE (Wet AMD Risk Evaluation), able to assess the individual risk profile for wet AMD based on genetic and non-genetic factors. In particular, the tool uses genetic risk measures normalized for their relative frequencies in the general population and disease prevalence. WARE is characterized by a user-friendly web page interface that is intended to assist clinicians in reporting risk assessment upon patient evaluation. When using the tool, plots of population risk distribution highlight a "low-risk zone" and a "high-risk zone" into which subjects can fall depending on their risk-assessment result. WARE represents a reliable population-specific computational system for wet AMD risk evaluation that can be exploited to promote preventive actions and personalized medicine approach for affected patients or at-risk individuals. This tool can be suitable to compute the disease risk adjusted to different populations considering their specific genetic factors and related frequencies, non-genetic factors, and the disease prevalence.

Genetic prescreening of a candidate for laser refractive surgery identifies risk for inadequate tissue response: a case report.

BACKGROUND: Inadequate response to corneal laser refractive surgery, e.g., ectatic corneal diseases, may not be identified by conventional examinations, hence creating therapeutic uncertainty. Herein we demonstrate the application of genetic prescreening to augment preassessment for corneal laser refractive surgery and highlight the ability to prevent the possibility of enrolling a subject at risk for developing ectatic corneal diseases. CASE PRESENTATION: Preoperative tests were performed alongside deoxyribonucleic acid (DNA) sequencing of 75 genes specific to the structure and health of the eye of a 44-year-old Caucasian male candidate for corneal laser refractive surgery. The patient had no medical, family, or psychosocial history, nor symptoms that could lead to suspect any corneal abnormalities, and conventional preoperative tests confirmed that no corneal abnormalities were present. The sequencing results uncovered rare DNA variants within the ADGRV1, PTK2, ZNF469, and KRT15 genes. These variants were considered potential risk factors for inadequate response in the patient post corneal laser refractive surgery. Subsequent reevaluation with three different last-generation corneal tomographers identified in the left eye a "warning" for a deformity of the posterior profile of the cornea. CONCLUSIONS: Genetic prescreening identifies potential risk of inadequate response to corneal laser refractive surgery where current technologies in use may lead to a hazardous predictive diagnostic uncertainty.

Different timing in allograft and autograft maturation after primary anterior cruciate ligament reconstruction does not influence the clinical outcome at mid-long-term follow-up.

PURPOSE: The use of allografts in primary anterior cruciate ligament reconstruction (ACLR) is increasing although they are still supposed to be associated to greater risk of re-rupture due to a slower and less efficient graft maturation. The aim of this prospective randomized controlled study was to compare the graft maturation after ACLR with allograft and autograft by MRI at 6- and 12-month follow-up and integrate these data with the functional and clinical results observed at 6-, 12- and 60-month follow-up. METHODS: Fifty patients with indication to primary ACLR were randomly and equally divided into hamstring autograft or allograft tendon groups. The graft maturation was measured at 6- and 12-month follow-up by the SNQ score and other radiological parameters on MRI scans. Clinical and functional recovery was evaluated by Lysholm score, Visual Analogues Scale, Tegner activity scale and modified Cincinnati knee rating system at 6, 12 and 60 months after surgery to estimate the predictive value of the radiological parameters for clinical outcomes. Return-to-sport (ACL-RSI) was measured 60 months after surgery. RESULTS: Three patients had retear of the neo-ligament (two from Auto group and one from Allo group). All the clinical/functional parameters significantly improved over time, with no statistically significant difference between the groups. At 6 months, the SNQ value was significantly higher in the Auto than in the Allo group (12.9 vs 7.9, p = 0.038), but at 12 months they were comparable (9.8 vs 10.4). The 6-month SNQ values did not correlate with the clinical scores, whereas the 12-month SNQ values significantly correlated with the Cincinnati score, Lysholm score and Tegner activity scale collected at 60-month follow-up. CONCLUSION: No clinical or functional differences have been found between the two treatment groups, supporting the suitability of using allograft in primary ACLR, when available. The results at MRI scans showed a different graft maturation trend in the two groups, with allografts being more reactive in the first 6 months. MRI together with the subjective evaluation allows to evaluate objectively the status of the neo-ligamentization process and therefore helps the surgeon to dictate the individual time for return-to-sport. LEVEL OF EVIDENCE: Level I.

Optical coherence tomography angiography in the multimodal assessment of the retinal posterior pole in autosomal dominant optic atrophy.

PURPOSE: To assess retinal vascular involvement in patients with autosomal dominant optic atrophy (ADOA) genetically confirmed by the presence of the OPA1 (Optic Atrophy 1) gene mutation using a multimodal protocol of investigation of retinal posterior pole. METHODS: In this cross-sectional, case-control, observational study, both eyes of 13 patients with a genetic diagnosis of ADOA were compared with both eyes of 13 healthy controls (HCs). All subjects underwent full ophthalmological examination, spectral domain-optical coherence tomography (SD-OCT), fundus perimetry (FP) and OCT angiography (OCTA). RESULTS: Vessel density (VD) of the superficial and deep macular vascular plexi and of the radial peripapillary capillary plexus were significantly decreased (p ≤ 0.001) in ADOA patients compared with HCs. The area under the receiver operating characteristics analysis also revealed high values of sensitivity and specificity of OCTA parameters in distinguish between patients and HCs. A strong correlation (Pearson Coefficient, r = 0.91) emerged between OCTA VD of the superficial retinal plexus and the average Ganglion Cell Layer (GCL) thickness as measured by SD-OCT; a slightly lower correlation (Pearson Coefficient, r = 0.89) was also found between VD of the deep plexus and the average GCL thickness of the same eyes in patients with ADOA. The correlation among values of differential light sensitivity (DLS) measured by FP with VD and GCL thickness parameters was also investigated. The correlation analysis among DLS and the VD parameters showed from low-to-moderate correlation (ranging from r = 0.29 for the deep fovea VD to r = 0.59 for the deep whole image VD). The correlation coefficient between the mean DLS and the average thickness of GCL was more significant (Pearson Coefficient, r = 0.75). A significant correlation emerged also between the VD and the visual acuity, in terms of LogMAR BCVA (best-corrected visual acuity), especially for the VD of the deep capillary plexus (Pearson Coefficient for the Deep whole Image VD and LogMAR BCVA r = -0.75; for the Deep parafovea VD and LogMAR BCVA r = -0.78). CONCLUSION: Retinal microvascular assessment by OCTA angiography can provide relevant clinical information on retinal involvement in ADOA patients. In patients with genetically confirmed OPA1-related ADOA, there is a decrease in retinal vessel density associated with GCL thinning and DLS reduction.

Epigenomic signatures in age-related macular degeneration: Focus on their role as disease modifiers and therapeutic targets.

Epigenetics is characterized by molecular modifications able to shape gene expression profiles in response to inner and external stimuli. Therefore, epigenetic elements are able to provide intriguing and useful information for the comprehension and management of different human conditions, including aging process, and diseases. On this subject, Age-related Macular Degeneration (AMD) represents one of the most frequent age-related disorders, dramatically affecting the quality of life of older adults worldwide. The etiopathogenesis is characterized by an interplay among multiple genetic and non-genetic factors, which have been extensively studied. Nevertheless, a deeper dissection of molecular machinery associated with risk, onset, progression and effectiveness of therapies is still missing. In this regard, epigenetic signals may be further explored to disentangle disease etiopathogenesis, the possible therapeutic avenues and the differential response to AMD treatment. This review will discuss the epigenomic signatures mostly investigated in AMD, which could be applied to improve the knowledge of disease mechanisms and to set-up novel or modified treatment options.

Genetic Determinants Highlight the Existence of Shared Etiopathogenetic Mechanisms Characterizing Age-Related Macular Degeneration and Neurodegenerative Disorders.

Age-related macular degeneration (AMD) showed several processes and risk factors in common with neurodegenerative disorders (NDDs). The present work explored the existence of genetic determinants associated with AMD, which may provide insightful clues concerning its relationship with NDDs and their possible application into the clinical practice. In this study, 400 AMD patients were subjected to the genotyping analysis of 120 genetic variants by OpenArray technology. As the reference group, 503 samples representative of the European general population were utilized. Statistical analysis revealed the association of 23 single-nucleotide polymorphisms (SNPs) with AMD risk. The analysis of epistatic effects revealed that ARMS2, IL6, APOE, and IL2RA could contribute to AMD and neurodegenerative processes by synergistic modulation of the expression of disease-relevant genes. In addition, the bioinformatic analysis of the associated miRNA variants highlighted miR-196a, miR-6796, miR-6499, miR-6810, miR-499, and miR-7854 as potential candidates for counteracting AMD and neurodegenerative processes. Finally, this work highlighted the existence of shared disease mechanisms (oxidative stress, immune-inflammatory response, mitochondrial dysfunction, axonal guidance pathway, and synaptogenesis) between AMD and NDDs and described the associated SNPs as candidate biomarkers for developing novel strategies for early diagnosis, monitoring, and treatment of such disorders in a progressive aging population.

Transtendinous approach calcaneoplasty versus endoscopic calcaneoplasty for Haglund's disease.

PURPOSE: In this study, we performed a comparison between open calcaneoplasty through transtendinous approach and endoscopic calcaneoplasty for Haglund's disease. METHODS: A retrospective review was performed of patients who had undergone either a calcaneoplasty with transtendinous approach or endoscopic for Haglund's disease from three centres. Inclusion criteria were patients with Haglund's disease confirmed radiographically, neutral alignment of the hindfoot and at least one year of follow-up. Patients were excluded in case of ipsilateral ankle osteoarthritis or other neighbouring joints, previous foot surgery, hindfoot malalignment and marked calcific insertional Achilles tendinosis. A chart review was performed to collect demographic data, including age, sex and body mass index (BMI). Functional outcome analysis included the Foot Function Index, AOFAS score and VAS for pain pre-operatively and post-operatively at the last follow-up. This patient-reported outcome scores were used in the native language of each patient (Italian). RESULTS: Clinical and functional outcomes were collected from 54 patients (28 heels treated by open technique and 26 heels treated by endoscopic technique). In the open group, the AOFAS score improved from a pre-operative value of 65.67 ± 10.09 points to a value of 91.78 ± 9.67 points at the last follow-up (P < 0.05). In the endoscopic group, the AOFAS score improved from a pre-operative value of 66.69 ± 7.19 points to a value of 93.69 points ± 10.04 at the last follow-up (P < 0.05). The VAS and the FFI (Disability and Pain) scores were also improved significantly in both groups at the final follow-up evaluation (P < 0.001). Comparing the final follow-up post-operative clinical scores between the two groups, there was no difference in the AOFAS, VAS or the FFI scores between the two groups. No major complications were recorded, except for one Achilles tendon tear after open calcaneoplasty. The satisfaction rate was similar for both techniques. CONCLUSIONS: Both techniques provided good clinical outcomes with a low rate of complications.

The Interplay between miRNA-Related Variants and Age-Related Macular Degeneration: EVIDENCE of Association of MIR146A and MIR27A.

The complex interplay among genetic, epigenetic, and environmental variables is the basis for the multifactorial origin of age-related macular degeneration (AMD). Previous results highlighted that single nucleotide polymorphisms (SNPs) of CFH, ARMS2, IL-8, TIMP3, SLC16A8, RAD51B, VEGFA, and COL8A1 were significantly associated with the risk of AMD in the Italian population. Given these data, this study aimed to investigate the impact of SNPs in genes coding for MIR146A, MIR31, MIR23A, MIR27A, MIR20A, and MIR150 on their susceptibility to AMD. Nine-hundred and seventy-six patients with exudative AMD and 1000 controls were subjected to an epigenotyping analysis through real-time PCR and direct sequencing. Biostatistical and bioinformatic analysis was performed to evaluate the association with susceptibility to AMD. These analyses reported that the SNPs rs11671784 (MIR27A, G/A) and rs2910164 (MIR146A, C/G) were significantly associated with AMD risk. Interestingly, the bioinformatic analysis showed that MIR27A and MIR146A take part in the angiogenic and inflammatory pathways underlying AMD etiopathogenesis. Thus, polymorphisms within the pre-miRNA sequences are likely to affect their functional activity, especially the interaction with specific targets. Therefore, our study represents a step forward in the comprehension of the mechanisms leading to AMD onset and progression, which certainly include the involvement of epigenetic modifications.

Doyne honeycomb retinal dystrophy - functional improvement following subthreshold nanopulse laser treatment: a case report.

BACKGROUND: Based on phenotypic similarities between age-related macular degeneration and the autosomal disorder Doyne honeycomb retinal dystrophy, we report on a single nanolaser treatment of a patient with genotype Doyne honeycomb retinal dystrophy confirmation and evidence of disease progression over 12 months. The case study is the first report of short-term results of subthreshold nanolaser treatment in a patient with Doyne honeycomb retinal dystrophy. CASE PRESENTATION: A 43-year-old Caucasian man with moderate loss of visual acuity in his left eye (20/40) and normal visual acuity in his right eye (20/20), with clinical Doyne honeycomb retinal dystrophy diagnosis and genetic confirmation of the common heterozygous mutation (EFEMP1) by genetic testing, underwent nanopulse subthreshold laser treatment in his left eye. A safety examination, carried out 7 days after treatment, and clinical follow-up, conducted 60 days following laser treatment, showed improvement of visual acuity from baseline by two letters and a subjective improvement of blurring. While no apparent morphological changes were found on fundoscopy, increased autofluorescence in the treated eye was observed on imaging. In addition, 2 months after nanopulse subthreshold laser treatment, rod-mediated and cone-mediated full-field electroretinography b-wave amplitudes showed an increase from baseline in both the treated eye (300%) and untreated eye (50%). At 2 months after nanopulse subthreshold laser treatment, multifocal electroretinograms showed improvement. Acuity and full-field electroretinography improvement persisted at 6-month follow-up. CONCLUSIONS: Sustained improvements in retinal function on electroretinography persisted in both eyes 6 months after treatment, suggesting an enhancement of phototransduction and retinoid recycling induced by nanopulse subthreshold laser treatment. The functional improvement observed in the untreated eye is hypothesized to arise from an increased expression and release of metalloproteinases that circulate systemically.

Uncovering genetic and non-genetic biomarkers specific for exudative age-related macular degeneration: significant association of twelve variants.

Age-related Macular Degeneration (AMD) represents one of the most sight-threatening diseases in developed countries that substantially impacts the patients' lifestyle by compromising everyday activities, such as reading and driving. In this context, understanding the prevalence, burden, and population-specific risk/protective factors of AMD is essential for adequate health care planning and provision. Our work aimed to characterize exudative AMD in Italian population and to identify the susceptibility/protective factors (genetic variants, age, sex, smoking and dietary habits) which are specific for the onset of disease. Our study involved a cohort of 1976 subjects, including 976 patients affected with exudative AMD and 1000 control subjects. In particular, the sample cohort has been subjected to a large genotyping analysis of 20 genetic variants which are known to be associated with AMD among European and Asiatic populations. This analysis revealed that 8 genetic variants (CFH, ARMS2, IL-8, TIMP3, SLC16A8, RAD51B, VEGFA and COL8A1) were significantly associated with AMD susceptibility. Successively, we performed a multivariate analysis, considering both genetic and non-genetic data available for our sample cohort. The multivariate analysis showed that age, smoking, dietary habits and sex, together with the genetic variants, were significantly associated with AMD in our population. Altogether, these data represent a starting point for the set-up of adequate preventive and personalized strategies aimed to decrease the burden of disease and improve the patients' quality of life.

Towards the application of precision medicine in Age-Related Macular Degeneration.

The review essentially describes genetic and non-genetic variables contributing to the onset and progression of exudative Age-related Macular Degeneration (AMD) in Italian population. In particular, AMD susceptibility within Italian population is contributed to by genetic variants, accounting for 23% of disease and non-genetic variants, accounting for 10% of AMD. Our data highlighted prominent differences concerning genetic and non-genetic contributors to AMD in our cohort with respect to worldwide populations. Among genetic variables, SNPs of CFH, ARMS2, IL-8, TIMP3, SLC16A8, RAD51B, VEGFA and COL8A1 were significantly associated with the risk of AMD in the Italian cohort. Surprisingly, other susceptibility variants described in European, American and Asiatic populations, did not reach the significance threshold in our cohort. As expected, advanced age, smoking and dietary habits were associated with the disease. In addition, we also describe a number of gene-gene and gene-phenotype interactions. In fact, AMD-associated genes may be involved in the alteration of Bruch's membrane and induction of angiogenesis, contributing to exacerbate the damage caused by aging and environmental factors. Our review provides an overview of genetic and non-genetic factors characterizing AMD susceptibility in Italian population, outlining the differences with respect to the worldwide populations. Altogether, these data reflect historical, geographic, demographic and lifestyle peculiarities of Italian population. The role of epigenetics, pharmacogenetics, comorbities and genetic counseling in the management of AMD patients have been described, in the perspective of the application of a "population-specific precision medicine" approach addressed to prevent AMD onset and improve patients' quality of life.