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

Prevalence of Age-Related Macular Degeneration in Europe: The Past and the Future

Purpose Age-related macular degeneration (AMD) is a frequent, complex disorder in elderly of European ancestry. Risk profiles and treatment options have changed considerably over the years, which may have affected disease prevalence and outcome. We determined the prevalence of early and late AMD in Europe from 1990 to 2013 using the European Eye Epidemiology (E3) consortium, and made projections for the future. Design Meta-analysis of prevalence data. Participants A total of 42 080 individuals 40 years of age and older participating in 14 population-based cohorts from 10 countries in Europe. Methods AMD was diagnosed based on fundus photographs using the Rotterdam Classification. Prevalence of early and late AMD was calculated using random-effects meta-analysis stratified for age, birth cohort, gender, geographic region, and time period of the study. Best-corrected visual acuity (BCVA) was compared between late AMD subtypes; geographic atrophy (GA) and choroidal neovascularization (CNV). Main Outcome Measures Prevalence of early and late AMD, BCVA, and number of AMD cases. Results Prevalence of early AMD increased from 3.5% (95% confidence interval [CI] 2.1%–5.0%) in those aged 55–59 years to 17.6% (95%

Semi-Quantitative Multiplex Profiling of the Complement System Identifies Associations of Complement Proteins with Genetic Variants and Metabolites in Age-Related Macular Degeneration

Age-related macular degeneration (AMD) is a major cause of vision loss among the elderly in the Western world. The complement system has been identified as one of the main AMD disease pathways. We performed a comprehensive expression analysis of 32 complement proteins in plasma samples of 255 AMD patients and 221 control individuals using mass spectrometry-based semi-quantitative multiplex profiling. We detected significant associations of complement protein levels with age, sex and body-mass index (BMI), and potential associations of C-reactive protein, factor H related-2 (FHR-2) and collectin-11 with AMD. In addition, we confirmed previously described associations and identified new associations of AMD variants with complement levels. New associations include increased C4 levels for rs181705462 at the C2/CFB locus, decreased vitronectin (VTN) levels for rs11080055 at the TMEM97/VTN locus and decreased factor I levels for rs10033900 at the CFI locus. Finally, we detected significant associations between AMD-associated metabolites and complement proteins in plasma. The most significant complement-metabolite associations included increased high density lipoprotein (HDL) subparticle levels with decreased C3, factor H (FH) and VTN levels. The results of our study indicate that demographic factors, genetic variants and circulating metabolites are associated with complement protein components. We suggest that these factors should be considered to design personalized treatment approaches and to increase the success of clinical trials targeting the complement system

Common haplotypes at the CFH locus and low-frequency variants in CFHR2 and CFHR5 associate with systemic FHR concentrations and age-related macular degeneration

Age-related macular degeneration (AMD) is the principal cause of blindness in the elderly population. A strong effect on AMD risk has been reported for genetic variants at the CFH locus, encompassing complement factor H (CFH) and the complement-factor-H-related (CFHR) genes, but the underlying mechanisms are not fully understood. We aimed to dissect the role of factor H (FH) and FH-related (FHR) proteins in AMD in a cohort of 202 controls and 216 individuals with AMD. We detected elevated systemic levels of FHR-1 (p = 1.84 × 10−6), FHR-2 (p = 1.47 × 10−4), FHR-3 (p = 1.05 × 10−5) and FHR-4A (p = 1.22 × 10−2) in AMD, whereas FH concentrations remained unchanged. Common AMD genetic variants and haplotypes at the CFH locus strongly associated with FHR protein concentrations (e.g., FH p.Tyr402His and FHR-2 concentrations, p = 3.68 × 10−17), whereas the association with FH concentrations was limited. Furthermore, in an International AMD Genomics Consortium cohort of 17,596 controls and 15,894 individuals with AMD, we found that low-frequency and rare protein-altering CFHR2 and CFHR5 variants associated with AMD independently of all previously reported genome-wide association study (GWAS) signals (p = 5.03 × 10−3 and p = 2.81 × 10−6, respectively). Low-frequency variants in CFHR2 and CFHR5 led to reduced or absent FHR-2 and FHR-5 concentrations (e.g., p.Cys72Tyr in CFHR2 and FHR-2, p = 2.46 × 10−16). Finally, we showed localization of FHR-2 and FHR-5 in the choriocapillaris and in drusen. Our study identifies FHR proteins as key proteins in the AMD disease mechanism. Consequently, therapies that modulate FHR proteins might be effective for treating or preventing progression of AMD. Such therapies could target specific individuals with AMD on the basis of their genotypes at the CFH locus

Genetic Predisposition to Coronary Artery Disease in Type 2 Diabetes Mellitus

BACKGROUND: Coronary artery disease (CAD) is accelerated in subjects with type 2 diabetes mellitus (T2D). METHODS: To test whether this reflects differential genetic influences on CAD risk in subjects with T2D, we performed a systematic assessment of genetic overlap between CAD and T2D in 66 643 subjects (27 708 with CAD and 24 259 with T2D). Variants showing apparent association with CAD in stratified analyses or evidence of interaction were evaluated in a further 117 787 subjects (16 694 with CAD and 11 537 with T2D). RESULTS: None of the previously characterized CAD loci was found to have specific effects on CAD in T2D individuals, and a genome-wide interaction analysis found no new variants for CAD that could be considered T2D specific. When we considered the overall genetic correlations between CAD and its risk factors, we found no substantial differences in these relationships by T2D background. CONCLUSIONS: This study found no evidence that the genetic architecture of CAD differs in those with T2D compared with those without T2D.Peer reviewe