ALPK1 missense pathogenic variant in five families leads to ROSAH syndrome, an ocular multisystem autosomal dominant disorder.

Purpose: To identify the molecular cause in five unrelated families with a distinct autosomal dominant ocular systemic disorder we called ROSAH syndrome due to clinical features of retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and migraine headache.

Methods: Independent discovery exome and genome sequencing in families 1, 2, and 3, and confirmation in families 4 and 5. Expression of wild-type messenger RNA and protein in human and mouse tissues and cell lines.

Prevalence and correlates of bleeding and emotional harms in a national US sample of patients with venous thromboembolism: A cross-sectional structural equation model.

Introduction: Venous thromboembolism (VTE) including deep vein thrombosis (DVT) or pulmonary embolism (PE) is associated with reduced survival, poorer quality of life, and substantial health-care-costs. Limited research, primarily qualitative, suggests that those with VTE may have elevated fear of recurrence, and associated emotional dysfunction and distress.

Methods: A national online survey was administered to 907 patients who had experienced a VTE event in the past two years.

Long-term Outcomes After Proton Beam Irradiation in Patients With Large Choroidal Melanomas.

Importance: Although radiotherapy has been used more frequently in past decades for the management of large melanomas, long-term efficacy of proton beam irradiation (PBI) of large choroidal melanomas has not been reported.

Objective: To evaluate long-term outcomes in patients who underwent PBI for the treatment of large choroidal melanomas.

Design, Setting, And Participants: Data were obtained at a single Boston, Massachusetts, academic tertiary referral practice for this retrospective cohort study.

ER stress-induced aggresome trafficking of HtrA1 protects against proteotoxicity.

High temperature requirement A1 (HtrA1) belongs to an ancient protein family that is linked to various human disorders. The precise role of exon 1-encoded N-terminal domains and how these influence the biological functions of human HtrA1 remain elusive. In this study, we traced the evolutionary origins of these N-terminal domains to a single gene fusion event in the most recent common ancestor of vertebrates.

Genetics of age-related macular degeneration (AMD).

Age-related macular degeneration (AMD) is a progressive blinding disease and represents the leading cause of visual impairment in the aging population. AMD affects central vision which impairs one's ability to drive, read and recognize faces. There is no cure for this disease and current treatment modalities for the exudative form of the disease require repeated intravitreal injections which may be painful, are incompletely efficacious, and represent a significant treatment burden for both the patient and physician.

Factors predicting self-reported medication low adherence in a large sample of adults in the US general population: a cross-sectional study.

Objectives: The study objective was to determine the level and correlates of self-reported medication low adherence in the US general population.

Setting: A 30 min cross-sectional online survey was conducted with a national sample of adults.

Participants: 9202 adults (aged 18+) who had filled at least three or more prescriptions at a community pharmacy in the past 12 months.

Retinopathy of prematurity: A comprehensive risk analysis for prevention and prediction of disease.

Background: Retinopathy of prematurity (ROP) is a blinding morbidity of preterm infants. Our current screening criteria have remained unchanged since their inception and lack the ability to identify those at greatest risk.

Objectives: We sought to comprehensively analyze numerous proposed maternal, infant, and environmental ROP risk variables in a robustly phenotyped population using logistic regression to determine the most predictive model for ROP development and severity.

Adherence to Glaucoma Medications Over 12 Months in Two US Community Pharmacy Chains.

Unlabelled: This study determined the degree of adherence to medications for glaucoma among patients refilling prescriptions in community pharmacies.

Methods: Data abstracted from the dispensing records for 3615 adult patients (18 years or older, predominantly over 45) receiving glaucoma medications from two retail pharmacy chains (64 stores in total) were analyzed. From a 24-month historic data capture period, the 12-month levels of adherence were determined using standard metrics, the proportion of days covered (PDC) and the medication possession ratio (MPR).

Meta-analysis of gene-environment-wide association scans accounting for education level identifies additional loci for refractive error.

Myopia is the most common human eye disorder and it results from complex genetic and environmental causes. The rapidly increasing prevalence of myopia poses a major public health challenge. Here, the CREAM consortium performs a joint meta-analysis to test single-nucleotide polymorphism (SNP) main effects and SNP × education interaction effects on refractive error in 40,036 adults from 25 studies of European ancestry and 10,315 adults from 9 studies of Asian ancestry.

Visual Outcomes after Proton Beam Irradiation for Choroidal Melanomas Involving the Fovea.

Purpose: To report visual outcomes in patients undergoing proton beam irradiation of tumors located within 1 disc diameter of the fovea.

Design: Retrospective review.

Participants: Patients with choroidal melanoma involving the fovea treated with proton beam therapy between 1975 and 2009.

Ancestry of the Timorese: age-related macular degeneration associated genotype and allele sharing among human populations from throughout the world.

We observed that the third leading cause of blindness in the world, age-related macular degeneration (AMD), occurs at a very low documented frequency in a population-based cohort from Timor-Leste. Thus, we determined a complete catalog of the ancestry of the Timorese by analysis of whole exome chip data and haplogroup analysis of SNP genotypes determined by sequencing the Hypervariable I and II regions of the mitochondrial genome and 17 genotyped YSTR markers obtained from 535 individuals. We genotyped 20 previously reported AMD-associated SNPs in the Timorese to examine their allele frequencies compared to and between previously documented AMD cohorts of varying ethnicities.

Analysis of Genetic and Environmental Risk Factors and Their Interactions in Korean Patients with Age-Related Macular Degeneration.

Purpose: To investigate the association of genetic and environmental factors, and their interactions in Korean patients with exudative age-related macular degeneration (AMD).

Methods: A total of 314 robustly characterized exudative AMD patients, including 111 PCV (polypoidal choroidal vasculopathy) and 154 typical choroidal neovascularization (CNV), and 395 control subjects without any evidence of AMD were enrolled. Full ophthalmologic examinations including fluorescein angiography (FA), indocyanine green angiography (ICG) and optical coherence tomography (OCT) were done, according to which patients were divided into either PCV or typical CNV.

Plasma homocysteine and genetic variants of homocysteine metabolism enzymes in patients from central Greece with primary open-angle glaucoma and pseudoexfoliation glaucoma.

Background: The purpose of this study was to investigate plasma homocysteine levels and polymorphisms in genes encoding enzymes in the metabolic pathway of homocysteine in association with primary open-angle glaucoma (POAG) and pseudoexfoliation glaucoma (PXFG).

Methods: A total of 156 glaucoma patients (76 with POAG and 80 with PXFG) and 135 controls matched for age and sex were enrolled in this study. Plasma homocysteine levels were measured using a commercially available enzyme-linked immunosorbent assay kit.

Genetic variants associated with severe retinopathy of prematurity in extremely low birth weight infants.

Purpose: To determine genetic variants associated with severe retinopathy of prematurity (ROP) in a candidate gene cohort study of US preterm infants.

Methods: Preterm infants in the discovery cohort were enrolled through the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network, and those in the replication cohort were from the University of Iowa. All infants were phenotyped for ROP severity.

Rare and common variants in extracellular matrix gene Fibrillin 2 (FBN2) are associated with macular degeneration.

Neurodegenerative diseases affecting the macula constitute a major cause of incurable vision loss and exhibit considerable clinical and genetic heterogeneity, from early-onset monogenic disease to multifactorial late-onset age-related macular degeneration (AMD). As part of our continued efforts to define genetic causes of macular degeneration, we performed whole exome sequencing in four individuals of a two-generation family with autosomal dominant maculopathy and identified a rare variant p.Glu1144Lys in Fibrillin 2 (FBN2), a glycoprotein of the elastin-rich extracellular matrix (ECM).

FLT1 genetic variation predisposes to neovascular AMD in ethnically diverse populations and alters systemic FLT1 expression.

Purpose: Current understanding of the genetic risk factors for age-related macular degeneration (AMD) is not sufficiently predictive of the clinical course. The VEGF pathway is a key therapeutic target for treatment of neovascular AMD; however, risk attributable to genetic variation within pathway genes is unclear. We sought to identify single nucleotide polymorphisms (SNPs) associated with AMD within the VEGF pathway.

Seven new loci associated with age-related macular degeneration.

Age-related macular degeneration (AMD) is a common cause of blindness in older individuals. To accelerate the understanding of AMD biology and help design new therapies, we executed a collaborative genome-wide association study, including >17,100 advanced AMD cases and >60,000 controls of European and Asian ancestry. We identified 19 loci associated at P < 5 × 10(-8).

Systems biology-based analysis implicates a novel role for vitamin D metabolism in the pathogenesis of age-related macular degeneration.

Vitamin D has been shown to have anti-angiogenic properties and to play a protective role in several types of cancer, including breast, prostate and cutaneous melanoma. Similarly, vitamin D levels have been shown to be protective for risk of a number of conditions, including cardiovascular disease and chronic kidney disease, as well as numerous autoimmune disorders such as multiple sclerosis, inflammatory bowel diseases and type 1 diabetes mellitus. A study performed by Parekh et al.

Influence of ROBO1 and RORA on risk of age-related macular degeneration reveals genetically distinct phenotypes in disease pathophysiology.

ROBO1 is a strong candidate gene for age-related macular degeneration (AMD) based upon its location under a linkage peak on chromosome 3p12, its expression pattern, and its purported function in a pathway that includes RORA, a gene previously associated with risk for neovascular AMD. Previously, we observed that expression of ROBO1 and RORA is down-regulated among wet AMD cases, as compared to their unaffected siblings. Thus, we hypothesized that contribution of association signals in ROBO1, and interaction between these two genes may be important for both wet and dry AMD.

Genetic variations strongly influence phenotypic outcome in the mouse retina.

Variation in genetic background can significantly influence the phenotypic outcome of both disease and non-disease associated traits. Additionally, differences in temporal and strain specific gene expression can also contribute to phenotypes in the mammalian retina. This is the first report of microarray based cross-strain analysis of gene expression in the retina investigating genetic background effects.

Identifying subtypes of patients with neovascular age-related macular degeneration by genotypic and cardiovascular risk characteristics.

Background: One of the challenges in the interpretation of studies showing associations between environmental and genotypic data with disease outcomes such as neovascular age-related macular degeneration (AMD) is understanding the phenotypic heterogeneity within a patient population with regard to any risk factor associated with the condition. This is critical when considering the potential therapeutic response of patients to any drug developed to treat the condition. In the present study, we identify patient subtypes or clusters which could represent several different targets for treatment development, based on genetic pathways in AMD and cardiovascular pathology.