CFH, C3 and ARMS2 Are Significant Risk Loci for Susceptibility but Not for Disease Progression of Geographic Atrophy Due to AMD

Age-related macular degeneration (AMD) is a prevalent cause of blindness in Western societies. Variants in the genes encoding complement factor H (CFH), complement component 3 (C3) and age-related maculopathy susceptibility 2 (ARMS2) have repeatedly been shown to confer significant risks for AMD; however, their role in disease progression and thus their potential relevance for interventional therapeutic approaches remains unknown. Here, we analyzed association between variants in CFH, C3 and ARMS2 and disease progression of geographic atrophy (GA) due to AMD. A quantitative phenotype of disease progression was computed based on longitudinal observations by fundus autofluorescence imaging. In a subset of 99 cases with pure bilateral GA, variants in CFH (Y402H), C3 (R102G), and ARMS2 (A69S) are associated with disease (P = 1.6x10(-9), 3.2x10(-3), and P = 2.6x10(-12), respectively) when compared to 612 unrelated healthy control individuals. In cases, median progression rate of GA over a mean follow-up period of 3.0 years was 1.61 mm(2)/year with high concordance between fellow eyes. No association between the progression rate and any of the genetic risk variants at the three loci was observed (P>0.13). This study confirms that variants at CFH, C3, and ARMS2 confer significant risks for GA due to AMD. In contrast, our data indicate no association of these variants with disease progression which may have important implications for future treatment strategies. Other, as yet unknown susceptibilities may influence disease progression

Ophthalmology

OBJECTIVE: In the current study we aimed to identify metabolites associated with age-related macular degeneration (AMD) by performing the largest metabolome association analysis in AMD to date. In addition, we aimed to determine the effect of AMD-associated genetic variants on metabolite levels, and aimed to investigate associations between the identified metabolites and activity of the complement system, one of the main AMD-associated disease pathways. DESIGN: Case-control assocation analysis of metabolomics data. SUBJECTS: 2,267 AMD cases and 4,266 controls from five European cohorts. METHODS: Metabolomics was performed using a high-throughput H-NMR metabolomics platform, which allows the quantification of 146 metabolite measurements and 79 derivative values. Metabolome-AMD associations were studied using univariate logistic regression analyses. The effect of 52 AMD-associated genetic variants on the identified metabolites was investigated using linear regression. In addition, associations between the identified metabolites and activity of the complement pathway (defined by the C3d/C3 ratio) were investigated using linear regression. MAIN OUTCOME MEASURES: Metabolites associated with AMD RESULTS: We identified 60 metabolites that were significantly associated with AMD, including increased levels of large and extra-large HDL subclasses and decreased levels of VLDL, amino acids and citrate. Out of 52 AMD-associated genetic variants, seven variants were significantly associated with 34 of the identified metabolites. The strongest associations were identified for genetic variants located in or near genes involved in lipid metabolism (ABCA1, CETP, APOE, LIPC) with metabolites belonging to the large and extra-large HDL subclasses. In addition, 57 out of 60 metabolites were significantly associated with complement activation levels, and these associations were independent of AMD status. Increased large and extra-large HDL levels and decreased VLDL and amino acid levels were associated with increased complement activation. CONCLUSIONS: Lipoprotein levels were associated with AMD-associated genetic variants, while decreased essential amino acids may point to nutritional deficiencies in AMD. We observed strong associations between the vast majority of the AMD-associated metabolites and systemic complement activation levels, independent of AMD status. This may indicate biological interactions between the main AMD disease pathways, and suggests that multiple pathways may need to be targeted simultaneously for successful treatment of AMD

Macular pigment profile characteristics and stability over periods of up to 25 years

This study compares the foveal and total retinal macular pigment (MP) amount in healthy subjects and examines the stability of MP spatial distribution profiles, measured almost annually for periods of up to 25 years.Measurements of MP spatial distribution profiles were made by 51 subjects using the psychophysical technique of minimum motion photometry, utilizing a moving bichromatic grating (test 460 nm, comparison 580 nm). Two foveal fields (0.9° and 2.2° diameter) and 11 annular segments (eccentricities from 0.8° to 7.5°) were used. The total amount of MP within the central 15 degrees was estimated by numerical integration and compared with foveal values. Four subjects with widely different MP profiles underwent almost annual testing for periods of 19–25 years. Eleven of the same subjects and 19 others underwent 2‐wavelength autofluorescence (AF) assessment of MP using a scanning laser ophthalmoscope (incident radiation 488 nm and 514 nm), allowing quantification of the peak relative optical density, distribution and total complement of MP over the central 21 degrees.Detailed examinations revealed widely different MP distribution profiles using motion photometry and/or 2‐wavelength fundus autofluorescence. There was a lack of correlation between peak MP optical density at the fovea and assessments of the total complement of MP within the central 15 or 21 degrees. Serial psychophysical assessments over periods of 19–25 years in 4 cases demonstrated a high degree of stability at all macular locations including the fovea; plots of peak MP optical density against time showed minimal positive and negative gradients (<0.0003).The total amount of macular pigment cannot be accurately estimated from foveal or central values. Widely different MP distribution profiles in healthy subjects demonstrate a high degree of long‐term stability, relevant to investigations that aim to monitor MP or fundus autofluorescence in disease or in studies that aim to modify MP through dietary supplementation

Pars plana vitrectomy with intravitreal triamcinolone: effect on uveitic cystoid macular oedema and treatment limitations

OBJECTIVE: To investigate the effect of pars plana vitrectomy (PPV) in combination with intraoperative intravitreal triamcinolone acetonide injection on the course of cystoid macular oedema (CME) in patients with uveitis. METHODS: Patients with uveitis with CME (n = 19) not responding to systemic corticosteroids and/or immunosuppression combined with acetazolamide were retrospectively studied after PPV with additional intravitreal injection of 4 mg triamcinolone acetonide. Patients had chronic anterior uveitis (n = 4), intermediate uveitis (n = 9), posterior uveitis (n = 3) or panuveitis (n = 3). Visual acuity tests, tonometry, fluorescein angiographic appearance and postoperative complications were analysed. Mean follow‐up was 14 months (SD 4.6). RESULTS: CME improved in 58% of the patients within the first 6 weeks postoperatively. After 12 months, CME was further improved in 44% and worsened in another 12%. Improvement of visual acuity was noted in 42% after 3 months and in 28% after 12 months. Cataract progressed in 85% of the phacic patients postoperatively. Increased intraocular pressure was detected in 27% at 2 weeks and in 11% at 12 months after surgery. CONCLUSION: Uveitic CME that is unresponsive to systemic immunosuppression and acetazolamide may improve after PPV with additional intravitreal triamcinolone application. The effect seems to be transient in many of the patients. Frequent complications were cataract formation and ocular hypertension

Age-related Macular Degeneration

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