Stephen G. Schwartz

Genetic Factors in Nonsmokers with Age-Related Macular Degeneration Revealed Through Genome-Wide Gene-Environment Interaction Analysis

Relatively little is known about the interaction between genes and environment in the complex etiology of age‐related macular degeneration (AMD). This study aimed to identify novel factors associated with AMD by analyzing gene‐smoking interactions in a genome‐wide association study of 1207 AMD cases and 686 controls of Caucasian background with genotype data on 668,238 single nucleotide polymorphisms (SNPs) after quality control. Participants’ history of smoking at least 100 cigarettes lifetime was determined by a self‐administered questionnaire. SNP associations modeled the effect of the minor allele additively on AMD using logistic regression, with adjustment for age, sex, and ever/never smoking. Joint effects of SNPs and smoking were examined comparing a null model containing only age, sex, and smoking against an extended model including genotypic and interaction terms. Genome‐wide significant main effects were detected at three known AMD loci: CFH (P = 7.51×10−30), ARMS2 (P = 1.94×10−23), and RDBP/CFB/C2 (P = 4.37×10−10), while joint effects analysis revealed three genomic regions with P < 10−5. Analyses stratified by smoking found genetic associations largely restricted to nonsmokers, with one notable exception: the chromosome 18q22.1 intergenic SNP rs17073641 (between SERPINB8 and CDH7), more strongly associated in nonsmokers (OR = 0.57, P = 2.73 × 10−5), with an inverse association among smokers (OR = 1.42, P = 0.00228), suggesting that smoking modifies the effect of some genetic polymorphisms on AMD risk.

Inverse Association of Female Hormone Replacement Therapy with Age-Related Macular Degeneration and Interactions with ARMS2 Polymorphisms

Purpose. To investigate whether female reproductive history and hormone replacement therapy (HRT) or birth control pills (BCPs) influence risk for age-related macular degeneration (AMD) and whether genetic factors interact with HRT to modulate AMD risk. Methods. Related and unrelated female participants (n = 799) were examined and data were analyzed with generalized estimating equations with adjustment for age and smoking. Individuals with AMD grades 1 to 2 were considered to be unaffected (n = 239) and those with grades 3 to 5 were considered affected (n = 560). Results. When comparing all cases with controls, significant inverse associations were observed for HRT (odds ratio [OR] = 0.65, 95% CI 0.48-0.90, P = 0.008) and BCPs (OR = 0.60, 95% CI 0.36-0.10, P = 0.048). When analyses were stratified by AMD severity (early versus geographic atrophy versus neovascular), the inverse association remained significant (HRT OR = 0.45, 95% CI 0.30-0.66, P < 0.0001; BCP OR = 0.55, 95% CI 0.32-0.96, P = 0.036) only when comparing neovascular AMD with the control. All pair-wise HRT-genotype and BCP-genotype interactions were examined, to determine whether HRT or BCP modifies the effect of established genetic risk factors. The strongest interactions were observed for HRT x ARMS2 coding SNP (R73H) rs10490923 (P = 0.007) and HRT x ARMS2 intronic SNP rs17623531 (P = 0.019). Conclusions. These findings provide the first evidence suggesting that ARMS2 interacts with HRT to modulate AMD risk and are consistent with previous reports demonstrating a protective relationship between exogenous estrogen use and neovascular AMD. These results highlight the genetic and environmental complexity of the etiologic architecture of AMD; however, further replication is necessary to validate them.

Pharmacogenetics and Age-Related Macular Degeneration

Pharmacogenetics seeks to explain interpatient variability in response to medications by investigating genotype-phenotype correlations. There is a small but growing body of data regarding the pharmacogenetics of both nonexudative and exudative age-related macular degeneration. Most reported data concern polymorphisms in the complement factor H and age-related maculopathy susceptibility 2 genes. At this time, the data are not consistent and no definite conclusions may be drawn. As clinical trials data continue to accumulate, these relationships may become more apparent.

Mining Retrospective Data for Virtual Prospective Drug Repurposing: L-DOPA and Age-related Macular Degeneration

BACKGROUND Age-related macular degeneration (AMD) is a leading cause of visual loss among the elderly. A key cell type involved in AMD, the retinal pigment epithelium, expresses a G protein–coupled receptor that, in response to its ligand, L-DOPA, up-regulates pigment epithelia–derived factor, while down-regulating vascular endothelial growth factor. In this study we investigated the potential relationship between L-DOPA and AMD. METHODS We used retrospective analysis to compare the incidence of AMD between patients taking vs not taking L-DOPA. We analyzed 2 separate cohorts of patients with extensive medical records from the Marshfield Clinic (approximately 17,000 and approximately 20,000) and the Truven MarketScan outpatient and databases (approximately 87 million) patients. We used International Classification of Diseases, 9th Revision codes to identify AMD diagnoses and L-DOPA prescriptions to determine the relative risk of developing AMD and age of onset with or without an L-DOPA prescription. RESULTS In the retrospective analysis of patients without an L-DOPA prescription, AMD age of onset was 71.2, 71.3, and 71.3 in 3 independent retrospective cohorts. Age-related macular degeneration occurred significantly later in patients with an L-DOPA prescription, 79.4 in all cohorts. The odds ratio of developing AMD was also significantly negatively correlated by L-DOPA (odds ratio 0.78; confidence interval, 0.76–0.80; P <.001). Similar results were observed for neovascular AMD (P <.001). CONCLUSIONS Exogenous L-DOPA was protective against AMD. L-DOPA is normally produced in pigmented tissues, such as the retinal pigment epithelium, as a byproduct of melanin synthesis by tyrosinase. GPR143 is the only known L-DOPA receptor; it is therefore plausible that GPR143 may be a fruitful target to combat this devastating disease.

Vitamin A and fish oils for retinitis pigmentosa.

BACKGROUNDnRetinitis pigmentosa (RP) comprises a group of hereditary eye diseases characterized by progressive degeneration of retinal photoreceptors. It results in severe visual loss that may lead to legal blindness. Symptoms may become manifest during childhood or adulthood, and include poor night vision (nyctalopia) and constriction of peripheral vision (visual field loss). This field loss is progressive and usually does not reduce central vision until late in the disease course.The worldwide prevalence of RP is one in 4000, with 100,000 patients affected in the USA. At this time, there is no proven therapy for RP.nnnOBJECTIVESnThe objective of this review was to synthesize the best available evidence regarding the effectiveness and safety of vitamin A and fish oils (docosahexaenoic acid (DHA)) in preventing the progression of RP.nnnSEARCH METHODSnWe searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (2013, Issue 7), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to August 2013), EMBASE (January 1980 to August 2013), Latin American and Caribbean Health Sciences Literature Database (LILACS) (January 1982 to August 2013), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 20 August 2013.nnnSELECTION CRITERIAnWe included randomized controlled trials (RCTs) evaluating the effectiveness of vitamin A, fish oils (DHA) or both, as a treatment for RP. We excluded cluster-randomized trials and cross-over trials.nnnDATA COLLECTION AND ANALYSISnWe pre-specified the following outcomes: mean change from baseline visual field, mean change from baseline electroretinogram (ERG) amplitudes, and anatomic changes as measured by optical coherence tomography (OCT), at one year; as well as mean change in visual acuity at five-year follow-up. Two authors independently evaluated risk of bias for all included trials and extracted data from the publications. We also contacted study investigators for further information on trials with publications that did not report outcomes on all randomized patients.nnnMAIN RESULTSnWe reviewed 394 titles and abstracts and nine ClinicalTrials.gov records and included three RCTs that met our eligibility criteria. The three trials included a total of 866 participants aged four to 55 years with RP of all forms of genetic predisposition. One trial evaluated the effect of vitamin A alone, one trial evaluated DHA alone, and a third trial evaluated DHA and vitamin A versus vitamin A alone. None of the RCTs had protocols available, so selective reporting bias was unclear for all. In addition, one trial did not specify the method for random sequence generation, so there was an unclear risk of bias. All three trials were graded as low risk of bias for all other domains. We did not perform meta-analysis due to clinical heterogeneity of participants and interventions across the included trials.The primary outcome, mean change of visual field from baseline at one year, was not reported in any of the studies. No toxicity or adverse events were reported in these three trials. No trial reported a statistically significant benefit of vitamin supplementation on the progression of visual field loss or visual acuity loss. Two of the three trials reported statistically significant differences in ERG amplitudes among some subgroups of participants, but these results have not been replicated or substantiated by findings in any of the other trials.nnnAUTHORS CONCLUSIONSnBased on the results of three RCTs, there is no clear evidence for benefit of treatment with vitamin A and/or DHA for people with RP, in terms of the mean change in visual field and ERG amplitudes at one year and the mean change in visual acuity at five years follow-up. In future RCTs, since some of the studies in this review included unplanned subgroup analysis that suggested differential effects based on previous vitamin A exposure, investigators should consider examining this issue. Future trials should take into account the changes observed in ERG amplitudes and other outcome measures from trials included in this review, in addition to previous cohort studies, when calculating sample sizes to assure adequate power to detect clinically and statistically meaningful difference between treatment arms.

Ocular Complication of Intense Pulsed Light Therapy: Iris Photoablation

Intense pulsed light (IPL) therapy is one of the most commonly performed cosmetic surgeries in the United States, with more than 500,000 IPL facial rejuvenation procedures performed in 2008. This photochemorejuvenation modality has experienced increasing popularity in dermatology and aesthetic medicine addressing skin dyspigmentation, unwanted hair, abnormal skin texture, and vascular and telangiectatic lesions. An increased awareness of the potential complications and professional errors associated with this technology has accompanied the widespread use of IPL. Side effects such as pain, erythema, hypoor hyperpigmentation, and superficial crust or vesicle formation have been reported with IPL. The potential for ocular complications has been suggested in previously reported cases, with one case of bilateral anterior uveitis after IPL treatment of bilateral upper lid pigmented lesions. Further highlighting the importance of eye protection during IPL, we report a case of permanent distorted pupillary shape and iris transillumination defects due to photoablation of the iris after IPL treatment.

New Therapeutic Approaches in Diabetic Retinopathy.

Diabetic retinopathy is a common microvascular complication of diabetes mellitus. It affects a substantial proportion of US adults over age 40. The condition is a leading cause of visual loss. Much attention has been given to expanding the role of current treatments along with investigating various novel therapies and drug delivery methods. In the treatment of diabetic macular edema (DME), intravitreal pharmacotherapies, especially anti-vascular endothelial growth factor (anti-VEGF) agents, have gained popularity. Currently, anti-VEGF agents are often used as first-line agents in center-involved DME, with recent data suggesting that among these agents, aflibercept leads to better visual outcomes in patients with worse baseline visual acuities. While photocoagulation remains the standard treatment for proliferative diabetic retinopathy (PDR), recent FDA approvals of ranibizumab and aflibercept in the management of diabetic retinopathy associated with DME may suggest a potential for pharmacologic treatments of PDR as well. Novel therapies, including small interfering RNAs, chemokines, kallikrein-kinin inhibitors, and various anti-angiogenic agents, are currently being evaluated for the management of diabetic retinopathy and DME. In addition to these strategies, novel drug delivery methods such as sustained-release implants and refillable reservoir implants are either under active evaluation or have recently gained FDA approval. This review provides an update on the novel developments in the treatment of diabetic retinopathy.

Genetic Association Analysis of Drusen Progression.

Purpose Age-related macular degeneration is a common form of vision loss affecting older adults. The etiology of AMD is multifactorial and is influenced by environmental and genetic risk factors. In this study, we examine how 19 common risk variants contribute to drusen progression, a hallmark of AMD pathogenesis. Methods Exome chip data was made available through the International AMD Genomics Consortium (IAMDGC). Drusen quantification was carried out with color fundus photographs using an automated drusen detection and quantification algorithm. A genetic risk score (GRS) was calculated per subject by summing risk allele counts at 19 common genetic risk variants weighted by their respective effect sizes. Pathway analysis of drusen progression was carried out with the software package Pathway Analysis by Randomization Incorporating Structure. Results We observed significant correlation with drusen baseline area and the GRS in the age-related eye disease study (AREDS) dataset (ρ = 0.175, P = 0.006). Measures of association were not statistically significant between drusen progression and the GRS (P = 0.54). Pathway analysis revealed the cell adhesion molecules pathway as the most highly significant pathway associated with drusen progression (corrected P = 0.02). Conclusions In this study, we explored the potential influence of known common AMD genetic risk factors on drusen progression. Our results from the GRS analysis showed association of increasing genetic burden (from 19 AMD associated loci) to baseline drusen load but not drusen progression in the AREDS dataset while pathway analysis suggests additional genetic contributors to AMD risk.

Ophthalmology in North America: Early Stories (1491-1801)

New World plants, such as tobacco, tomato, and chili, were held to have beneficial effects on the eyes. Indigenous healers rubbed or scraped the eyes or eyelids to treat inflammation, corneal opacities, and even eye irritation from smoke. European settlers used harsh treatments, such as bleeding and blistering, when the eyes were inflamed or had loss of vision with a normal appearance (gutta serena). In New Spain, surgery for corneal opacity was performed in 1601 and cataract couching in 1611. North American physicians knew of contralateral loss of vision after trauma or surgery (sympathetic ophthalmia), which they called “sympathy.” To date, the earliest identified cataract couching by a surgeon trained in the New World was performed in 1769 by John Bartlett of Rhode Island. The American Revolution negatively affected ophthalmology, as loyalist surgeons were expelled and others were consumed with wartime activities. After the war, cataract extraction was imported to America in earnest and academic development resumed. Charles F Bartlett, the son of John, performed cataract extraction but was also a “rapacious privateer.” In 1801, a doctor in the frontier territory of Kentucky observed anticholinergic poisoning by Datura stramonium (Jimsonweed) and suggested that this agent be applied topically to dilate the pupil before cataract extraction. John Warren at Harvard preferred couching in the 1790s, but, after his son returned from European training, recommended treating angle closure glaucoma by lens extraction. Other eye procedures described or advertised in America before the 19th century included enucleation, resection of conjunctival lesions or periocular tumors, treatment of lacrimal fistula, and fitting of prosthetic eyes.

A Family of Early English Oculists (1600-1751), With a Reappraisal of John Thomas Woolhouse (1664-1733/1734):

Introduction: John Thomas Woolhouse (1666-1733/1734), who practiced in Paris, was part of a family with 5 generations of English oculists. Some historians have derided him as a “charlatan” and have criticized him for adhering to the old notion that a cataract was a membrane anterior to the lens. Methods: We reviewed treatises and digital records related to Woolhouse and his family and the handwritten notes of his 1721 lecture series at the Royal Society of Medicine. Results: We have identified 5 generations of oculists in Woolhouse’s family, by the names of Atwood, Stepkins, Ivy, and Beaumont. Woolhouse taught students from across Europe. He was one of the early proponents in Europe, inspired by Asian medical practices, to perform paracentesis to release aqueous for a new condition called hydrophthalmia. In Woolhouse’s system, some of these cases probably described angle-closure glaucoma. He was the first to attach the name glaucoma to the palpably hard eye in 1707. He may also have been the first to teach that a soft eye was unlikely to recover vision. Credit for these teachings has traditionally gone to one of his students, Johannes Zacharias Platner, in 1745. Some historians have stated that he proposed iridectomy as a theoretical procedure, which was later performed by Cheselden. In fact, Woolhouse described techniques he had performed which today would be called pupilloplasty, synechiolysis, or pupillary membrane lysis. He was also a pioneer in dacryocystectomy for chronic dacryocystitis and in congenital cataract surgery. His writings from 1716 onward repeatedly (and correctly) stressed that most of the patients with visual disorders required depression of the crystalline lens (for what he called glaucoma), as opposed to removal of an anterior membrane (which he called cataract). Conclusions: Woolhouse was a bold ophthalmic innovator and teacher who made major contributions which have lasted to this day. Although he did not admit it, he ultimately adopted much of the evolving understanding of the nature of lens opacities. However, his stubborn refusal to adopt the newer semantics has detracted from a full appreciation of his contributions.