Nancy Huynh

The NEI/NCBI dbGAP database: Genotypes and haplotypes that may specifically predispose to risk of neovascular age-related macular degeneration

BackgroundTo examine if the significantly associated SNPs derived from the genome wide allelic association study on the AREDS cohort at the NEI (dbGAP) specifically confer risk for neovascular age-related macular degeneration (AMD). We ascertained 134 unrelated patients with AMD who had one sibling with an AREDS classification 1 or less and was past the age at which the affected sibling was diagnosed (268 subjects). Genotyping was performed by both direct sequencing and Sequenom iPLEX system technology. Single SNP analyses were conducted with McNemars Test (both 2 × 2 and 3 × 3 tests) and likelihood ratio tests (LRT). Conditional logistic regression was used to determine significant gene-gene interactions. LRT was used to determine the best fit for each genotypic model tested (additive, dominant or recessive).ResultsBefore release of individual data, p-value information was obtained directly from the AREDS dbGAP website. Of the 35 variants with P < 10-6 examined, 23 significantly modified risk of neovascular AMD. Many variants located in tandem on 1q32-q22 including those in CFH, CFHR4, CFHR2, CFHR5, F13B, ASPM and ZBTB were significantly associated with AMD risk. Of these variants, single SNP analysis revealed that CFH rs572515 was the most significantly associated with AMD risk (P < 10-6). Haplotype analysis supported our findings of single SNP association, demonstrating that the most significant haplotype, GATAGTTCTC, spanning CFH, CFHR4, and CFHR2 was associated with the greatest risk of developing neovascular AMD (P < 10-6). Other than variants on 1q32-q22, only two SNPs, rs9288410 (MAP2) on 2q34-q35 and rs2014307 (PLEKHA1/HTRA1) on 10q26 were significantly associated with AMD status (P = .03 and P < 10-6 respectively). After controlling for smoking history, gender and age, the most significant gene-gene interaction appears to be between rs10801575 (CFH) and rs2014307 (PLEKHA1/HTRA1) (P < 10-11). The best genotypic fit for rs10801575 and rs2014307 was an additive model based on LRT. After applying a Bonferonni correction, no other significant interactions were identified between any other SNPs.ConclusionThis is the first replication study on the NEI dbGAP SNPs, demonstrating that alleles on 1q, 2q and 10q may predispose an individual to AMD.

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. was the first to suggest a role for vitamin D in age-related macular degeneration (AMD) and showed a correlation between reduced serum vitamin D levels and risk for early AMD. Based on this study and the protective role of vitamin D in diseases with similar pathophysiology to AMD, we examined the role of vitamin D in a family-based cohort of 481 sibling pairs. Using extremely phenotypically discordant sibling pairs, initially we evaluated the association of neovascular AMD and vitamin D/sunlight-related epidemiological factors. After controlling for established AMD risk factors, including polymorphisms of the genes encoding complement factor H (CFH) and age-related maculopathy susceptibility 2/HtrA serine peptidase (ARMS2/HTRA1), and smoking history, we found that ultraviolet irradiance was protective for the development of neovascular AMD (p = 0.001). Although evaluation of serum vitamin D levels (25-hydroxyvitamin D [25(OH)D]) was higher in unaffected individuals than in their affected siblings, this finding did not reach statistical significance.Based on the relationship between ultraviolet irradiance and vitamin D production, we employed a candidate gene approach for evaluating common variation in key vitamin D pathway genes (the genes encoding the vitamin D receptor [VDR]; cytochrome P450, family 27, subfamily B, polypeptide 1 [CYP27B1]; cytochrome P450, family 24, subfamily A, polypeptide 1 [CYP24A1]; and CYP27A1) in this same family-based cohort. Initial findings were then validated and replicated in the extended family cohort, an unrelated case-control cohort from central Greece and a prospective nested case-control population from the Nurses Health Study and Health Professionals Follow-Up Studies, which included patients with all subtypes of AMD for a total of 2,528 individuals. Single point variants in CYP24A1 (the gene encoding the catabolising enzyme of the vitamin D pathway) were demonstrated to influence AMD risk after controlling for smoking history, sex and age in all populations, both separately and, more importantly, in a meta-analysis. This is the first report demonstrating a genetic association between vitamin D metabolism and AMD risk. These findings were also supplemented with expression data from human donor eyes and human retinal cell lines. These data not only extend previous biological studies in the AMD field, but further emphasise common antecedents between several disorders with an inflammatory/immunogenic component such as cardiovascular disease, cancer and AMD.

Ocular Involvement in Hospitalized Patients with Candidemia: Analysis at a Boston Tertiary Care Center

Purpose: To study the prevalence, microbial profile, and risk factors for ocular involvement in patients with candidemia. Methods: The records of all inpatient consultations requested at the Brigham and Women’s Hospital from October 2009 to June 2011 to evaluate for ocular involvement in patients with candidemia were retrospectively reviewed. Results: Forty-nine consults were requested to rule out ocular involvement in patients with candidemia. The mean patient age was 55 years. In decreasing frequency, the organisms isolated were Candida albicans (42%), Candida parapsilosis (23%), Candida glabrata (17%), Candida tropicalis (8%), Candida dublinensis (5%), Candida krusei (3%), and Candida lusitaniae (3%). All patients were on antifungal treatment at the time of their initial ophthalmologic examination. One patient had evidence of chorioretinitis, and 3 patients had nonspecific fundus findings. Common risk factors included presence of an intravenous catheter, malignancy, and abdominal surgery. Conclusions: Ocular involvement is rare among patients with systemic Candida infection.

Dilated fundus exam and associated findings in spontaneous subconjunctival haemorrhage.

projected on a wall-mounted operating suite display for real-time surgeon feedback. The MIOCT imaging protocol consisted of 6 9 7.5 9 7.5 mm scans acquired during array positioning, tack placement and post-tacking. Specific advantages were noted in each step: Preretinal tack placement:Microscopeintegrated swept-source optical coherence tomography (MIOCT) permitted realtime confirmation of appropriate array positioning prior to proceeding with tack placement (Fig. 1A shows the array tilted in relation to the retina as it is lowered to the retinal surface). Microscope-integrated swept-source optical coherence tomography (MIOCT) can also determine the adequacy of epiretinal membrane peel, if performed (Rizzo et al. 2014). Retinal tack placement: Microscopeintegrated swept-source optical coherence tomography (MIOCT) allowed real-time visualization of retinal tack placement (Video S1) (Fig. 1B–F). When using the tack forceps to secure the electrode array over the macula, pressure is applied perpendicular to the retinal surface to penetrate the tack through the sclera (Sight 2013). On B-scan images, array boundaries were visualized as hyper-reflective surfaces and the array handle as a hyper-reflective oval. As pressure was applied with the tack forceps, array apposition was directly visualized on OCT. Postretinal tack placement: After release of the tack forceps, MIOCT permitted intra-operative confirmation of electrode-inner retinal surface apposition (Fig. 1E–G) and centration over the foveal pit. Electrode-inner retinal surface distances, which have been shown to correlate with threshold levels of electrode stimulation, were determined by manually creating a distance map that also confirmed array centration over the foveal pit (Fig. 1H) (Ahuja et al. 2013). Array position variability in the intra-operative prone position and the postoperative standing or sitting position has been questioned (Rizzo et al. 2014). We confirmed this stability by comparing intra-operative and postoperative OCT scans (Fig. 1I). Dislodged or improperly positioned retinal tacks were reported in 2/30 (6.7%) eyes during clinical trials. Improper positioning was not noted in either case intra-operatively and both required revision surgeries (Ho et al. 2015). Microscope-integrated swept-source optical coherence tomography (MIOCT)-based intra-operative confirmation of array position can potentially avoid this scenario. Microscope-integrated swept-source optical coherence tomography (MIOCT) allows near real-time capture of volumetric data and the ability to view individual B-scans in any area of interest. This is in contrast to spectraldomain-based intra-operative OCT systems, wherein an area of interest needs to be identified prior to image acquisition, and maintained in the same plane intra-operatively, which is challenging. In conclusion, Argus II implantation with a prototype MIOCT device was successfully performed, enabling intra-operative cross-sectional visualization. MIOCT allowed real-time confirmation of array position pre-, intraand post-tack placement and confirmed the adequacy of tacking in securing the array in close contact with the retina. This may help optimize outcomes and prevent known complications of Argus II implantation, and further investigation into its utility is warranted.