Comprehensive Genetic Analysis Unraveled the Missing Heritability and a Founder Variant of BEST1 in a Chinese Cohort With Autosomal Recessive Bestrophinopathy.

Purpose: To describe the genetic landscape of BEST1 for a large Chinese cohort with autosomal recessive bestrophinopathy (ARB), identify the missing heritability, and report a common Chinese founder variant. Methods: We recruited 65 patients from 63 families with a clinical diagnosis of ARB. All patients underwent ophthalmic examinations and comprehensive genetic analyses, including Sanger DNA sequencing of BEST1 and whole genome sequencing (WGS). The effects of deep intronic variants (DIVs) on splicing were assessed using in vitro splicing assays in HEK293T cells and patient-derived peripheral blood mononuclear cells. Haplotype mapping was performed for 17 unrelated patients harboring variant c.867+97G>A. Results: We identified 54 distinct disease-causing variants of BEST1 in 63 pedigrees, 62 probands with biallelic variants, and one family with monoallelic variants. Sanger DNA sequencing of BEST1 initially detected 51 variants in 61 pedigrees, including 19 probands with one heterozygous variant. Subsequent WGS, combined with supplementary Sanger sequencing, revealed three missing DIVs (c.1101-491A>G, c.867+97G>A, and c.867+97G>T) in 20 families. The novel DIV c.1101-491A>G caused an abnormal splicing resulting in a 204-nt pseudoexon (PE) insertion, whereas c.867+97G>A/T relatively strengthened an alternative donor site, resulting in a 203-nt intron retention (IR). The PE and IR generated a premature termination codon downstream. Haplotype analysis identified c.867+97G>A as a common founder variant with an allele frequency of 16%. Conclusions: Our results expand the pathogenic variant spectrum of BEST1, and DIVs can explain almost all of the missing heritability. The c.867+97G>A DIV is a common founder variant for Chinese patients with ARB.

American College of Rheumatology, American Academy of Dermatology, Rheumatologic Dermatology Society, and American Academy of Ophthalmology 2020 Joint Statement on Hydroxychloroquine Use With Respect to Retinal Toxicity.

Four major medical societies involved with hydroxychloroquine (HCQ) therapy concur on the need for common principles and cooperation to minimize the risk of ocular toxicity. At a daily dosage of ≤5 mg/kg/day actual body weight, the risk of retinal toxicity from HCQ is <2% for usage up to 10 years. Widespread adoption of more sensitive testing techniques, such as optical coherence tomography and automated visual fields, by eye care providers will allow the detection of early toxicity and thus preserve the patient's visual function. Baseline testing is advised to rule out confounding disease when a patient is started on HCQ. Annual screening with sensitive tests should begin no more than 5 years after treatment initiation. Providers should be sensitive to the medical value of HCQ, and not stop the drug for uncertain indications. It is important to note that effective communication among prescribing physicians, patients, and eye care providers will optimize the utility and safety of HCQ.

UNRAVELED FRINGE-LIKE MARGINS AND BIPHASIC AUTOFLUORESCENCE OF UNILATERAL RETINAL PIGMENT EPITHELIUM DYSGENESIS.

PURPOSE: To illustrate the features of unilateral retinal pigment epithelium dysgenesis (URPED) in an African-American male patient. METHODS: Case report. RESULTS: A 47-year-old asymptomatic African-American man was referred for an atypical subretinal pigmented mass in the left eye. On examination, visual acuity was 20/20 in both eyes. The right eye was unremarkable. The left eye revealed a darkly pigmented grey-black lesion at the level of the RPE with irregular, unraveled fringe-like margins, consistent with URPED. The lesion measured 5 mm in basal dimension and was located 400 µm from the foveola. The dark portion of the lesion was grey-black and demonstrated homogeneous hypoautofluorescence, particularly at the site of grey-white peripheral fringe of fibrous metaplasia. By contrast, there was an additional, subtle lacey arrangement of normal-appearing RPE traversing over the entire lesion demonstrating isoautofluorescence. On fluorescein angiography, the lesion was generally hypofluorescent, particularly in the dark portion of the lesion, but the peripheral fringe of fibrous metaplasia displayed angiographic hyperfluorescent staining, and the subtle lacey normal RPE showed isofluorescence. Optical coherence tomography demonstrated RPE hyperplasia and shallow RPE detachment interspersed with normal-appearing RPE and thinning of outer retina and preservation of the foveola and choroid. CONCLUSION: In this case, URPED demonstrated biphasic autofluorescence implying RPE dysfunction in the hypoautofluorescent area and partial RPE function in the lacey isoautofluorescent region.

Association of Retinal Microvascular Signs with Incident Atrial Fibrillation: The Multi-Ethnic Study of Atherosclerosis.

PURPOSE: Microvascular diseases may contribute to the occurrence of atrial fibrillation (AF). Retinal microvascular signs that are similar to other microvasculature in the body and can be visualized directly via ophthalmoscopy may provide insights into such a relationship. DESIGN: Prospective, longitudinal, multiethnic study. PARTICIPANTS: We examined the association between retinal microvascular signs and incident AF in 4994 participants 47 to 86 years of age and free of prior AF who underwent fundus photography from 2002 through 2004 and were followed up through 2015 in the Multi-Ethnic Study of Atherosclerosis (MESA). METHODS: Retinal microvascular signs evaluated include central retinal arteriolar equivalent and central retinal venular equivalent (CRVE) and presence of any retinopathy signs (e.g., retinal microaneurysms or hemorrhages). A multivariate Cox regression analysis was used to determine the relationship while adjusting for traditional risk factors, alcohol intake, body mass index, diabetes status, chronic kidney disease status, hemoglobin A1c level, C-reactive protein level, medications, and prevalent cardiovascular diseases or heart failure. MAIN OUTCOME AND MEASURES: Incident AF events were identified using 12-lead electrocardiographic findings, hospital discharge records, and Medicare claims data. RESULTS: During a median follow-up of 14.1 years, 643 AF events were identified. No association was found between any retinal microvascular signs and incident AF except for retinal focal arteriolar narrowing (hazard ratio, 1.75; 95% confidence interval, 1.06-2.87) in the overall population. However, in the subgroup analyses by gender, wider CRVE was associated with a higher risk of incident AF in women, but not in men (hazard ratio for every 10-µm increase in CRVE, 1.08 [95% confidence interval, 1.01-1.15] and 0.97 [95% confidence interval, 0.92-1.03], respectively; P = 0.041 for interaction). CONCLUSIONS: No consistent pattern of association was found between retinal microvascular signs and incident AF. We observed an association in women, but not in men, of wider retinal venular calibers with incidence of AF. The reasons for a possible interaction are incompletely understood.

Prevalence of Retinal Diseases and Associated Risk Factors in an African Population From Mwanza, Tanzania.

BACKGROUND AND OBJECTIVE: To determine the prevalence of retinal disease among a population in Mwanza, Tanzania, and to identify relevant risk factors for retinal disorders in this cohort. PATIENTS AND METHODS: A cross-sectional population-based study was conducted in Mwanza, Tanzania, among patients older than 18 years. Participants completed a demographics survey and underwent an ophthalmic examination that included fundus photography. RESULTS: Complete data were available for 1,007 (93.8%) of the 1,073 persons examined. The prevalence of vitreoretinal disorders was 22.8% (230/1,007). The leading retinal diseases were age-related macular degeneration (7.0%), hypertensive retinopathy (4.5%), and macular scars (2.7%). CONCLUSION: This study is the first population-based study of retinal disease in Mwanza. The findings reveal a considerable burden of retinal disease in this region, suggesting a need for trained local ophthalmic personnel and resources. [Ophthalmic Surg Lasers Imaging Retina. 2020;51:S17-S25.].

Worldwide carrier frequency and genetic prevalence of autosomal recessive inherited retinal diseases.

One of the major questions in human genetics is what percentage of individuals in the general population carry a disease-causing mutation. Based on publicly available information on genotypes from six main world populations, we created a database including data on 276,921 sequence variants, present within 187 genes associated with autosomal recessive (AR) inherited retinal diseases (IRDs). Assessment of these variants revealed that 10,044 were categorized as disease-causing mutations. We developed an algorithm to compute the gene-specific prevalence of disease, as well as the mutational burden in healthy subjects. We found that the genetic prevalence of AR-IRDs corresponds approximately to 1 case in 1,380 individuals, with 5.5 million people expected to be affected worldwide. In addition, we calculated that unaffected carriers of mutations are numerous, ranging from 1 in 2.26 individuals in Europeans to 1 in 3.50 individuals in the Finnish population. Our analysis indicates that about 2.7 billion people worldwide (36% of the population) are healthy carriers of at least one mutation that can cause AR-IRD, a value that is probably the highest across any group of Mendelian conditions in humans.

Evaluation of Hydroxychloroquine Retinopathy Using Ultra-Widefield Fundus Autofluorescence: Peripheral Findings in the Retinopathy.

OBJECTIVES: To investigate the application of ultra-widefield fundus autofluorescence (UWF-FAF) imaging in evaluating hydroxychloroquine (HCQ) retinopathy and to report peripheral autofluorescence findings in Asian patients with this condition. DESIGN: Retrospective case series. METHODS: Setting: institutional. PATIENT POPULATION: 58 eyes of 29 patients with HCQ retinopathy. OBSERVATION PROCEDURES: UWF-FAF imaging was performed, and the images were compared to conventional FAF images obtained using a confocal digital ophthalmoscope. The sensitivities of detecting retinopathy using the 2 modalities were compared. Peripheral autofluorescence findings in the eyes with HCQ retinopathy were assessed, and their association with the Humphrey visual field test results obtained using the 30-2 and full-field 120 (FF-120) protocols was analyzed. Main outcome measurements were abnormal FAF findings. RESULTS: In 41 of 58 eyes (70.7%) with HCQ retinopathy, abnormal FAF findings were noted in the retinal periphery outside the field of view of conventional FAF as hypoautofluorescent (23 eyes, 39.7%) and hyperautofluorescent (38 eyes, 65.5%) lesions. In 5 eyes (8.6%), differences were revealed between conventional FAF and UWF-FAF in detecting retinopathy. Most of the eyes with severe retinopathy showed the most extensive hypoautofluorescence in the nasal peripheral retina. The areas with abnormal FAF findings were significantly correlated with the number of unseen spots on FF-120 results and mean deviation and pattern standard deviation of the 30-2 test results (all P < .001). CONCLUSIONS: Peripheral autofluorescence findings varied in eyes with HCQ retinopathy according to the severity of the retinopathy. The retinal findings with UWF-FAF were functionally correlated to visual field results. UWF-FAF may be useful for evaluating HCQ retinopathy, particularly in Asian patients.

Prevalence of mutations in inherited retinal diseases: A comparison between the United States and India.

BACKGROUND: Studies evaluating next-generation sequencing (NGS) for retinal disorders may not reflect clinical practice. We report results of retrospective analysis of patients referred for clinical testing at two institutions (US and India). METHODS: This retrospective study of 131 patients who underwent clinically validated targeted NGS or exome sequencing for a wide variety of clinical phenotypes categorized results into a definitive, indeterminate, or negative molecular diagnosis. RESULTS: A definitive molecular diagnosis (52%) was more common in the India cohort (62% vs. 39%, p = .009), while an indeterminate molecular diagnosis occurred only in the US cohort (12%). In the US cohort, a lower diagnostic rate in Hispanic, non-Caucasians (23%) was seen compared to Caucasians (57%). The India cohort had a high rate of homozygous variants (61%) and different frequency of genes involved compared to the US cohort. CONCLUSION: Despite inherent limitations in clinical testing, the diagnostic rate across the two cohorts (52%) was similar to the 50%-65% diagnostic rate in the literature. However, the diagnostic rate was lower in the US cohort and appears partly explained by racial background. The high rate of consanguinity in the Indian population is reflected in the high rate of homozygosity for pathogenic mutations and may have implications for population level screening and genetic counseling. Clinical laboratories may note diagnostic rates that differ from the literature, due to factors such as heterogeneity in racial background or consanguinity rates in the populations being tested. This information may be useful for post-test counseling.

Update on Inherited Retinal Disease in South Africa: Encouraging Diversity in Molecular Genetics.

There is a glaring disparity in the populations included in genetic research; the majority of work involves European-derived cohorts, while other global populations - including Africans - are underrepresented. This is also true for the study of inherited retinal diseases. Being the most ancient of extant populations, African samples carry more variation than others, making them valuable for novel gene and variant discovery. The inclusion of diverse populations in research is essential to gain a more comprehensive understanding of genetic variation and molecular mechanisms of disease.

Systemic Determinants of Peripapillary Vessel Density in Healthy African Americans: The African American Eye Disease Study.

PURPOSE: To determine the relationship between systemic factors and radial peripapillary capillary (RPC) vessel density (VD) in healthy African American (AA) participants of the African American Eye Disease Study. DESIGN: A population-based, cross-sectional study. METHODS: A total of 4135 eyes from 2127 AA participants aged 40 years and older in Inglewood, California, were imaged for 6×6-mm optic disc scans on a spectral-domain optical coherence tomography angiography (OCTA) device. Of these, 1029 eyes from 1029 participants who met the inclusion and exclusion criteria were analyzed, including only 1 eye per participant. Custom software was used to quantify RPC VD. Multivariate linear regression was used to identify systemic factors associated with RPC VD with a significance level set at 0.05. The contribution of each variable to the final model was estimated with the magnitude of standardized regression coefficients (SRCs). The fit of the final model was measured by R2. RESULTS: The average RPC VD was 0.346±0.045. Controlling for signal strength, the systemic variables in the final multivariate model associated with reduced RPC VD were older age (ß = -0.0123 per decade; SRC = -0.2733; P < .0001), male sex (ß = -0.0067; SRC = -0.0716; P = .0060), and longer diabetes duration (ß = -0.0022 per 5 years; SRC = -0.0527; P = .0427). The model R2 was 0.3689. CONCLUSIONS: Age, sex, and systemic influences, such as diabetes duration, need to be considered when assessing changes in RPC VD in glaucoma and other ocular diseases. Longitudinal studies are needed to investigate whether reduced RPC VD and the factors that affect it are associated with an increased risk of developing glaucomatous nerve damage.

Spectral Domain Optical Coherence Tomography in Detecting Sub-Clinical Retinal Findings in Asian Indian Children with Down Syndrome.

Purpose: Trisomy 21, also known as Down syndrome (DS), is the most common trisomy worldwide. Although ocular associations have been reported, retinal anatomy and pathology remain uninvestigated. We evaluate the role of spectral domain optical coherence tomography (SD-OCT) in analyzing foveal morphology of children with DS. Methods: Nineteen consecutive DS children and eight controls were enrolled under a cross-sectional study in an institutional practice. All subjects underwent SD-OCT imaging on a hand-held device. The morphology and thickness of central fovea, inner retinal layers, outer retina, and photoreceptor layers were measured and compared with age-group sub-analysis. Results: Mean age of the cases was 24 months (3-78 months). All cases and controls had a normal fundus on ophthalmoscopy and foveal thickness was comparable (p = 0.718). Inner retinal fusion was complete in the foveal center in only three eyes (15.8%) of cases compared to all eyes (100%) of controls (p < 0.001). The outer plexiform layer was normal in 10 eyes of cases (52.6%) compared to all eyes (100%) of the controls. Only 10 eyes of DS (52.6%) had a normal external limiting membrane, compared to all eyes of controls (100%, p = 0.01). The interdigitation zone (outer segment) was normal in one (5.3%) case compared to eight (67%) controls (p = 0.001). On subgroup analysis, in older cohorts, cases had a greater proportion of abnormal layers compared to controls. Visual acuity was found to be lower in cases when compared to controls, although not significant (p = 0.19). Conclusion: DS babies have abnormal foveal morphology and persistence of inner retinal layers. This may assist our understanding of their visual development.

Progression of Myopic Maculopathy in Highly Myopic Chinese Eyes.

Purpose: To evaluate the 2-year changes in myopic maculopathy and its associations in highly myopic eyes. Methods: This was a longitudinal, observational cohort study involving 657 Chinese participants with bilateral high myopia (≤ -6.00 diopters spherical power), who were followed for 2 years. The worst eye of each participant was considered for the analysis. Myopic maculopathy was graded based on fundus photographs, using the International Photographic Classification and Grading System for Myopic Maculopathy. Results: The mean baseline age was 21.6 ± 12.2 years (range, 6.8-69.7 years). Myopic maculopathy progressed in 97 (14.8%) of 657 eyes, of which 24 eyes progressed to a higher category of myopic maculopathy, including from no maculopathy to tessellated fundus in 17 eyes, from tessellated fundus to diffuse atrophy in 6 eyes, and from diffuse to patchy atrophy in 1 eye. Among 122 lesion changes identified, the most common changes were enlargement of diffuse atrophy (n = 50, 41.0%), appearance of lacquer cracks (n = 28, 23.0%), enlargement of patchy atrophy (n = 10, 8.2%) and development of additional lacquer cracks (n = 7, 5.8%). In addition, we identified 1 eye with enlargement of a Fuch's spot, and 1 eye with active choroidal neovascularization. In multiple logistic regression analysis, myopic maculopathy progression was associated with older age, longer axial length, greater change in myopic spherical equivalent and more severe myopic maculopathy at baseline. Conclusions: Myopic maculopathy progressed in approximately 15% of highly myopic eyes over a 2-year period. Further studies with longer follow up periods are required to confirm identified risk factors for progression.

Variable reduction in Norrin signaling activity caused by novel mutations in FZD4 identified in patients with familial exudative vitreoretinopathy.

Purpose: To identify novel mutations in FZD4 and to investigate their pathogenicity in a cohort of Chinese patients with familial exudative vitreoretinopathy (FEVR). Methods: Next-generation sequencing was performed in patients with a clinical diagnosis of FEVR. Wide-field angiography was performed in probands and family members if available. Clinical data were collected from patient charts. The effect of the mutations in FZD4 on its biologic activity in the Norrin/ß-catenin signaling pathway was analyzed with the luciferase reporter assay. Results: Four novel mutations in FZD4 (c.1188_1192del/p.F396fs, c.1220delC/p.A407Vfs*24, c.905G>A/p.C302Y, c.1325T>A/p.V442E) were identified in four unrelated families. The mutations were not detected in 200 healthy individuals. The variability of the ocular phenotypes was not only observed in the probands and parents harboring the same mutation but also between two eyes in one individual. All four novel mutations introduced reduction in luciferase activity. Compared with the wild-type, the FZD4 level of the four mutants also decreased variably. Conclusions: Four novel mutations in FZD4 were identified in Chinese patients with FEVR. No correlation in the reduced luciferase activity and the ocular phenotype was observed in this study. This study further emphasized the complexity of the FEVR-causing machinery.

Funduscopic examination and SD-OCT in detecting sickle cell retinopathy among pediatric patients.

PURPOSE: To compare the results of fundus examination and spectral domain optic coherence tomography (SD-OCT) in detecting retinal changes in pediatric patients with sickle cell disease at a single center. METHODS: In this prospective study, conducted over a period of 19 months, consecutive African American patients with sickle cell disease underwent complete ophthalmologic examination, and SD-OCT images of the maculas of both eyes were obtained. RESULTS: A total of 69 (37 males) patients aged 5-20 years (mean 12.89 ± 4.09; range, 2-20) with sickle cell disease (SC, 26; SS, 36; Sß+, 5; Sß0 thalassemia, 2) were examined. Patients' visual acuity range was 20/20 to 20/40. On funduscopic examination, 11 of 69 showed signs of retinopathy, whereas 47 of 68 showed inner retina thinning in the watershed zone temporal to the fovea on SD-OCT. On average, SD-OCT diagnosed disease 1.78 years earlier than fundus examination. Of patients <10 years of age, 1 was diagnosed with retinopathy by funduscopy, whereas retinal changes were evident on SD-OCT in 12 of 22. Fundus examination showed no significant difference in retinal findings between SS/Sß0 and SC genotypes. On SD-OCT, SS/Sß0 showed worse disease process than SC in frequency of diagnosis (82% vs 56%), bilateral involvement (87% vs 43%), and foveal involvement (18% vs 0). CONCLUSIONS: The peripheral retina could be visualized on fundus examination but not easily imaged on SD-OCT, which, however, had a higher detection rate and offered earlier diagnosis. In our patient cohort SD-OCT showed that the severity of retinal change was associated with more severe sickle cell disease genotypes (SS and Sß0).

[Variability of chloroquine and hydroxychloroquine retinopathy among various ethnicities]. / Différences ethniques parmi les patients souffrant de toxicité maculaire aux antipaludéens de synthèse.

INTRODUCTION: Current screening recommendations for chloroquine (CQ) and hydroxychloroquine (HCQ) retinopathy are based on central 10°C static perimetry and a high-resolution SD-OCT with a special attention to the inferior part of the macula where the toxicity usually starts by ellipsoid zone disruption. However, Melles and Marmor, have recently shown a great variability in the topography of the initial toxicity observed among various ethnicities, which is important to keep in mind so as not to miss early toxicity in certain subgroups of patients. METHODS: Review of the literature. RESULTS: Ethnic differences have been shown regarding the topography of the initial retinal toxicity of CQ and HCQ, particularly between Caucasian and Asian subjects. In Caucasians, the first signs of toxicity are more often localized in the inferior para-foveal area associated with a decrease in retinal sensitivity in the upper 10°C visual field. However, in Asian subjects, the first signs of toxicity appear more pericentral (still inferior) with an extramacular pattern that could be missed by the usual 10°C visual field screening. DISCUSSION/CONCLUSION: The pathophysiology of these ethnic differences is unknown and may be due to distinct genetic predisposition to CQ and HCQ toxicity. Screening strategies should be adjusted to the ethnicity and performed in Asian subjects with larger visual fields (30°C), along with SD-OCT, looking for ellipsoid disruption≥8°C from the fovea. The recognition of this pericentral topography and an adjusted screening protocol should avoid late diagnosis in Asians treated with CQ and HCQ.

Prevalence and causes of blindness, visual impairment among different ethnical minority groups in Xinjiang Uygur autonomous region, China.

BACKGROUND: The aim of this cross-sectional study is to ascertain the prevalence and causes of blindness, visual impairment, uptake of cataract surgery among different ethnic groups in Xinjiang Uygur Autonomous Region, China. METHODS: Four thousand one hundred fifty people at 50 years and above from different minority ethnic groups were randomly selected for an eye examination. The four trained eye teams collected data using tumbling E visual chart, torch, portable slit lamp and direct ophthalmoscope in 2015. The World Health Organization's definition of blindness and visual impairment (VI) was used to classify patients in each ethnic group. Data were analyzed by different minority groups and were compared with Han Chinese. RESULTS: 3977 (95.8%) out of 4150 people were examined. The prevalence of blindness from the study population was 1.7% (95% confidence interval: 1.3-2.2%).There was no significant difference in prevalence of blindness between Han Chinese and people of Khazak and other minority ethnic groups, nor, between male and female. Cataract was the leading course (65.5%) of blindness and uncorrected refractive error was the most common cause of VI (36.3%) followed by myopic retinopathy. The most common barrier to cataract surgery was lack of awareness of service availability. CONCLUSIONS: This study documented a low blindness prevalence among people aged 50 years and over comparing to prevalence identified through studies of other regions in China. It still indicates blindness and un-operated cataract as the significant public health issue, with no evidence of eye health inequalities, but some inequities in accessing to cataract surgery amongst ethnic minority groups in Xinjiang.

Prevalence and Associations of Retinal Emboli With Ethnicity, Stroke, and Renal Disease in a Multiethnic Asian Population: The Singapore Epidemiology of Eye Disease Study.

Importance: To our knowledge, population-based data on retinal emboli are limited in Asia. Besides its associations with traditional cardiovascular risk factors and stroke, associations between retinal emboli and renal disease and function remain unclear. Objective: To examine the prevalence of and risk factors for retinal emboli in a large, contemporary, multiethnic Asian population. Design, Setting, and Participants: This population-based cross-sectional study was conducted from 2004 to 2011 and included a total of 10 033 Chinese, Malay, and Indian persons aged 40 to 80 years residing in the general communities of Singapore. Analyses were performed from November 2016 to February 2017. Interventions or Exposures: Retinal emboli were ascertained from retinal photographs obtained from both eyes of all participants according to a standardized protocol. Age-standardized prevalence of retinal emboli was calculated using the 2010 Singapore adult population. Risk factors were assessed from comprehensive systemic and ophthalmic examinations, interviews, and laboratory investigations. Main Outcomes and Measures: Retinal emboli. Results: Of the 10 033 participants, 9978 (99.5%) had gradable retinal photographs. Of these, 5057 (50.7%) were female, and 3375 (33.8%) were Indian. We identified 88 individuals (0.9%) with retinal emboli; the overall person-specific, age-standardized prevalence of retinal emboli was 0.75% (95% CI, 0.60-0.95), with the highest prevalence seen in the Indian cohort (0.98%), followed by the Chinese (0.73%) and Malay (0.44%) cohorts (P = .03). In multivariable-adjusted analysis, factors associated with prevalent retinal emboli included older age (per 5-year increase; odds ratio [OR], 1.22; 95% CI, 1.05-1.41), Indian ethnicity (compared with Malay ethnicity; OR, 3.58; 95% CI, 1.95-6.60), hypertension (OR, 1.95; 95% CI, 1.03-3.70), chronic kidney disease (OR, 2.05; 95% CI, 1.15-3.64), creatinine level (per SD increase; OR, 1.13; 95% CI, 1.05-1.21), glomerular filtration rate (per SD increase; OR, 0.67; 95% CI, 0.51-0.86), and history of stroke (OR, 3.45; 95% CI, 1.70-6.99). Conclusions and Relevance: Based on 88 individuals among 9978 participants of 3 major Asian ethnic populations, retinal emboli were most commonly seen in Indian persons and associated with conventional cardiovascular risk factors, stroke, and chronic kidney disease. Therefore, its presence may signal vascular embolic event and damage not only in the brain but also in the kidneys. If these data are confirmed in longitudinal studies, they would suggest that persons with retinal emboli may require both general cardiovascular and renal assessment.

Serum Phosphate and Retinal Microvascular Changes: The Multi-Ethnic Study of Atherosclerosis and the Beaver Dam Eye Study.

PURPOSE: Higher levels of serum phosphate are strongly linked to increased risk of cardiovascular disease and therapies aimed to lower serum phosphate are employed in the management of patients with chronic kidney disease (CKD). Data are limited, however, on serum phosphate as a risk factor for microvascular disease in community-based populations. It is important to determine the impact of novel risk factors, such as phosphate, on the microvasculature. METHODS: We conducted a prospective study of 3919 individuals in the Multi-Ethnic Study of Atherosclerosis (MESA) and 3544 individuals in the Beaver Dam Eye Study (BDES) to test the associations of serum phosphate with retinopathy and retinal vessel caliber, and change in retinopathy severity and change in retinal vessel caliber. RESULTS: Mean (standard deviation) serum phosphate was 3.66 (0.52) mg/dl in the MESA and 3.77 (0.55) mg/dl in the BDES. In multivariable adjusted models, phosphate was significantly associated with prevalent retinopathy in the MESA (Odds Ratio [OR] per 1 mg/dl increase in phosphate, 1.22; Confidence Interval [CI] 1.02-1.47) and the BDES (OR 1.06; CI 1.01-1.11). In stratified analyses, these relationships were even stronger and only seen in individuals with diabetes in both the MESA (OR 1.81; CI 1.30-2.53) and the BDES (OR 1.16; CI 1.05-1.29). Phosphate was not associated with incident or change in retinopathy severity, nor any retinal caliber outcome. CONCLUSIONS: Among community-living individuals with low prevalence of CKD, higher serum phosphate was associated with prevalent retinopathy in individuals with diabetes. Further longitudinal assessments in patients with diabetes necessitate further investigation.

Identification and population history of CYP4V2 mutations in patients with Bietti crystalline corneoretinal dystrophy.

To identify known and novel CYP4V2 mutations in patients with Bietti crystalline cornea (BCD), expand the spectrum of CYP4V2 mutations, and characterize the population history of the c.802-8_810del17insGC mutation common in Asian populations, genomic DNA was isolated from peripheral blood samples from 58 unrelated patients with clinical diagnoses of BCD. Exons and flanking intronic regions of the CYP4V2 gene were dideoxy DNA sequenced. Nonpathogenic polymorphisms were excluded and known mutations were identified by sequencing 192 unaffected individuals from similar ethnic backgrounds and examination of online databases. The age of the c.802-8_810del17insGC mutation was estimated using three independent approaches. A total of 28 CYP4V2 mutations, 9 of which were novel, were detected in the 58 patients with BCD. These included 19 missense, 4 nonsense, 2 deletion, 2 splice site, and 1 insertion-deletion mutations. Two missense variants of uncertain significance were also detected. The age of the c.802-8_810del17insGC mutation was estimated to be 1040-8200 generations in the Chinese and 300-1100 generations in the Japanese populations. These results expand the mutation spectrum of CYP4V2, and provide insight into the origin of the c.802-8_810del17insGC mutation in the Chinese population and its transmission to the Japanese population.

Prognostic value of T786C and G894T eNOS polymorphisms in sickle cell disease.

Endothelial Nitric Oxide Synthase (eNOS) is crucial for vascular homeostasis. Polymorphisms T786C and G894T affect eNOS regulation and have been related to various diseases. Sickle Cell Disease (SCD), a clinically diverse chronic hemolytic anemia, implies impaired nitric oxide bioavailability. Our aim was to determine eNOS genotype for T786C and G894T polymorphisms in Greek patients with SCD and to elucidate its consequences and effects if any on clinical phenotype. Seventy nine steady state cases, mostly compound heterozygous for Sickle Cell anemia/beta thalassemia and 48 controls were measured. Peripheral blood DNA was extracted and genotyped with PCR-RFLPs and Sanger sequencing. Total RNA was extracted from 18 patients and 9 controls and eNOS mRNA levels were determined by real-time PCR. Genotypes, allele distribution and eNOS mRNA levels did not differ between patients and controls, or among patients with different beta globin gene mutations. The 786CC genotype was more common in S/S and ß0/S patients with retinopathy. Moreover, 894TT S/S and ß0/S patients tended to have a higher hematocrit than 894GG and GT ones. However, the T786C eNOS genotype does not seem to affect peripheral blood cell-derived eNOS mRNA levels, at least in steady state conditions. This work is the first one describing the effects of eNOS polymorphisms on different forms of SCD, the first enrolling SCD patients of Caucasian origin and the first determining eNOS mRNA levels in peripheral blood from steady-state SCD patients.