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Insights into the pathogenesis of age-related macular degeneration (AMD), a leading cause of blindness, point towards a complex interplay of genetic and lifestyle factors triggering various systemic pathways. This study aimed to... more
Insights into the pathogenesis of age-related macular degeneration (AMD), a leading cause of blindness, point towards a complex interplay of genetic and lifestyle factors triggering various systemic pathways. This study aimed to characterize metabolomic profiles for AMD and to evaluate their position in the trias with genetics and lifestyle. This study included 5923 individuals from five European studies. Blood metabolomics were assessed using a nuclear magnetic resonance platform of 146 metabolites. Associations were studied using regression analyses. A genetic risk score (GRS) was calculated using β-values of 49 AMD variants, a lifestyle risk score (LRS) using smoking and diet data, and a metabolite risk score (MRS) using metabolite values. We identified 61 metabolites associated with early-intermediate AMD, of which 94% were lipid-related, with higher levels of HDL-subparticles and apolipoprotein-A1, and lower levels of VLDL-subparticles, triglycerides, and fatty acids (false dis...
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Age-related macular degeneration (AMD) has a strong genetic basis, but environmental factors such as smoking and a healthy diet can decrease the genetic fate by up to 50%. Current guidelines for clinical management include recommendations... more
Age-related macular degeneration (AMD) has a strong genetic basis, but environmental factors such as smoking and a healthy diet can decrease the genetic fate by up to 50%. Current guidelines for clinical management include recommendations for a healthy lifestyle and antioxidant supplementation. However, many ophthalmologists do not inform their patients of this AMD-beneficial lifestyle. An important reason is the lack of trust that transition of lifestyle will be feasible in persons of advanced age and lack of methodology to measure lifestyle or its biological effects. To address these issues, we set up the lifestyle intervention study AMD-Life. It aims to investigate whether personalized risk-profiling (including genetic testing) and/or additional coaching can motivate patients to change their lifestyle. It also explores which biomarkers best reflect lifestyle change beneficial for AMD. The first year is a three-arm, self-contained open-label randomized clinical trial. A total of 1...
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Retinal structures may serve as a biomarker for dementia, but longitudinal studies examining this link are lacking. To investigate the association of inner retinal layer thickness with prevalent and incident dementia in a general... more
Retinal structures may serve as a biomarker for dementia, but longitudinal studies examining this link are lacking. To investigate the association of inner retinal layer thickness with prevalent and incident dementia in a general population of Dutch adults. From September 2007 to June 2012, participants from the prospective population-based Rotterdam Study who were 45 years and older and had gradable retinal optical coherence tomography images and at baseline were free from stroke, Parkinson disease, multiple sclerosis, glaucoma, macular degeneration, retinopathy, myopia, hyperopia, and optic disc pathology were included. They were followed up until January 1, 2015, for the onset of dementia. Inner retinal layer thicknesses (ie, retinal nerve fiber layer [RNFL]) and ganglion cell-inner plexiform layer (GC-IPL) thicknesses measured on optical coherence tomography images. Odds ratios and hazard ratios for incident dementia per SD decrease in retinal layer thickness adjusted for age, s...
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Research Interests: Ophthalmology, Genome Wide Association Studies (GWAS), Medicine, Macular Degeneration, Internal Medicine, and 11 moreCholesterol, Plasma, Proteins, Clinical Sciences, Progression, Activation, Optometry and Ophthalmology, Public health systems and services research, Odds ratio, Confidence Interval, and confounding
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Primary open angle glaucoma (POAG) is a complex disease with a major genetic contribution. Its prevalence varies greatly among ethnic groups, and is up to five times more frequent in black African populations compared to Europeans. So... more
Primary open angle glaucoma (POAG) is a complex disease with a major genetic contribution. Its prevalence varies greatly among ethnic groups, and is up to five times more frequent in black African populations compared to Europeans. So far, worldwide efforts to elucidate the genetic complexity of POAG in African populations has been limited. We conducted a genome-wide association study in 1113 POAG cases and 1826 controls from Tanzanian, South African and African American study samples. Apart from confirming evidence of association at TXNRD2 (rs16984299; OR 1.20; P = 0.003), we found that a genetic risk score combining the effects of the 15 previously reported POAG loci was significantly associated with POAG in our samples (OR 1.56; 95% CI 1.26-1.93; P = 4.79 × 10). By genome-wide association testing we identified a novel candidate locus, rs141186647, harboring EXOC4 (OR 0.48; P = 3.75 × 10), a gene transcribing a component of the exocyst complex involved in vesicle transport. The lo...
Research Interests: Genetics, Human Genetics, Complementary and Alternative Medicine, Aging, Biology, and 15 moreMedicine, Neurodegenerative Diseases, Humans, Glaucoma, Female, Male, Aged, Middle Aged, Human Genome, Genetic Association, Neurosciences, Thioredoxin reductase, Primary Open Angle Glaucoma, Paediatrics and reproductive medicine, and Open Angle
Genome-wide association studies and targeted sequencing studies of candidate genes have identified common and rare variants that are associated with age-related macular degeneration (AMD). Whole-exome sequencing (WES) studies allow a more... more
Genome-wide association studies and targeted sequencing studies of candidate genes have identified common and rare variants that are associated with age-related macular degeneration (AMD). Whole-exome sequencing (WES) studies allow a more comprehensive analysis of rare coding variants across all genes of the genome and will contribute to a better understanding of the underlying disease mechanisms. To date, the number of WES studies in AMD case-control cohorts remains scarce and sample sizes are limited. To scrutinize the role of rare protein-altering variants in AMD cause, we performed the largest WES study in AMD to date in a large European cohort consisting of 1125 AMD patients and 1361 control participants. Genome-wide case-control association study of WES data. One thousand one hundred twenty-five AMD patients and 1361 control participants. A single variant association test of WES data was performed to detect variants that are associated individually with AMD. The cumulative eff...
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There is an urgency to find new treatment strategies that could prevent or delay the onset or progression of AMD. Different classes of lipids and lipoproteins metabolism genes have been associated with AMD in a multiple ways, but despite... more
There is an urgency to find new treatment strategies that could prevent or delay the onset or progression of AMD. Different classes of lipids and lipoproteins metabolism genes have been associated with AMD in a multiple ways, but despite the ever-increasing knowledge base, we still do not understand fully how circulating lipids or local lipid metabolism contribute to AMD. It is essential to clarify whether dietary lipids, systemic or local lipoprotein metabolismtrafficking of lipids in the retina should be targeted in the disease. In this article, we critically evaluate what has been reported in the literature and identify new directions needed to bring about a significant advance in our understanding of the role for lipids in AMD. This may help to develop potential new treatment strategies through targeting the lipid homeostasis.
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Biomarkers can help unravel mechanisms of disease and identify new targets for therapy. They can also be useful in clinical practice for monitoring disease progression, evaluation of treatment efficacy and risk assessment in... more
Biomarkers can help unravel mechanisms of disease and identify new targets for therapy. They can also be useful in clinical practice for monitoring disease progression, evaluation of treatment efficacy and risk assessment in multifactorial diseases, such as age-related macular degeneration (AMD). AMD is a highly prevalent progressive retinal disorder for which multiple genetic and environmental risk factors have been described, but the exact etiology is not yet fully understood. Many compounds have been evaluated for their association with AMD. We performed an extensive literature review of all compounds measured in serum, plasma, vitreous, aqueous humor and urine of AMD patients. Over 3600 articles were screened resulting in more than 100 different compounds analyzed in AMD studies, involved in neovascularization, immunity, lipid metabolism, extracellular matrix, oxidative stress, diet, hormones, and comorbidities (such as kidney disease). For each compound we provide a short descr...
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To assess the 5-year progression from unilateral to bilateral age-related macular degeneration (AMD) and associated risk factors. Pooled data analyses of three prospective population-based cohorts, the Blue Mountains Eye Study, Beaver Dam... more
To assess the 5-year progression from unilateral to bilateral age-related macular degeneration (AMD) and associated risk factors. Pooled data analyses of three prospective population-based cohorts, the Blue Mountains Eye Study, Beaver Dam Eye Study and Rotterdam Study. Retinal photography and interview with comprehensive questionnaires were conducted at each visit of three studies. AMD was assessed following the modified Wisconsin AMD grading protocol. Progression to bilateral any (early and late) or late AMD was assessed among participants with unilateral involvement only. Factors associated with the progression were assessed using logistic regression models while simultaneously adjusting for other significant risk factors. In any 5-year duration, 19-28% of unilateral any AMD cases became bilateral and 27-68% of unilateral late AMD became bilateral. Factors associated with the progression to bilateral involvement of any AMD were age (per year increase, adjusted OR 1.07), carrying r...
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Primary open-angle glaucoma (POAG), the most common optic neuropathy, is a heritable disease. Siblings of POAG cases have a ten-fold increase risk of developing the disease. Intraocular pressure (IOP) and optic nerve head characteristics... more
Primary open-angle glaucoma (POAG), the most common optic neuropathy, is a heritable disease. Siblings of POAG cases have a ten-fold increase risk of developing the disease. Intraocular pressure (IOP) and optic nerve head characteristics are used clinically to predict POAG risk. We conducted a genome-wide association meta-analysis of IOP and optic disc parameters and validated our findings in multiple sets of POAG cases and controls. Using imputation to the 1000 genomes (1000G) reference set, we identified 9 new genomic regions associated with vertical cup disc ratio (VCDR) and 1 new region associated with IOP. Additionally, we found 5 novel loci for optic nerve cup area and 6 for disc area. Previously it was assumed that genetic variation influenced POAG either through IOP or via changes to the optic nerve head; here we present evidence that some genomic regions affect both IOP and the disc parameters. We characterized the effect of the novel loci through pathway analysis and found...
Research Interests: Genetics, Ophthalmology, Molecular Biology, Biology, Medicine, and 15 moreBiological Sciences, Humans, Optic Nerve, Glaucoma, Female, Male, Human Molecular Genetics, Intraocular Pressure, Middle Aged, Human Genome, Optic Disk, Optic Disc, Myocilin, Primary Open Angle Glaucoma, and Medical and Health Sciences
Reticular pseudodrusen (RPD) are considered to be a distinct feature in AMD. Population studies have studied the epidemiology of RPD using standard color fundus photographs (CFP). However, recent studies have shown that RPD are better... more
Reticular pseudodrusen (RPD) are considered to be a distinct feature in AMD. Population studies have studied the epidemiology of RPD using standard color fundus photographs (CFP). However, recent studies have shown that RPD are better imaged using near-infrared (NIR) imaging. We studied the epidemiology of RPD in a large population-based study using NIR and CFP. Participants aged 65+ years from the Rotterdam Study underwent ophthalmologic examination including NIR and CFP. Both images were graded for the presence of RPD and soft indistinct drusen (SID). Associations with demographic and environmental factors, 26 genetic variants, and total genetic risk score were analyzed using logistic regression analysis. Reticular pseudodrusen were detected in 137 (4.9%) of 2774 study participants; of these, 92.7% were detected with NIR imaging and 38% on CFP. Most eyes with RPD showed presence of SID, whereas other drusen types coincided less frequently. Reticular pseudodrusen were significantly...
Research Interests: Ophthalmology, Epidemiology, Medicine, Macular Degeneration, Biological Sciences, and 15 moreProspective studies, Population, Humans, Female, Male, Netherlands, Incidence, Aged, Prevalence, Odds ratio, Risk Factors, Cross Sectional Studies, Confidence Interval, Medical and Health Sciences, and Population surveillance
Research Interests: Epidemiology, Public Health, Medicine, Humans, Europe, and 14 moreBlood Pressure, Glaucoma, Female, Male, Intraocular Pressure, Body Mass Index, Aged, Middle Aged, Public health systems and services research, Age Factors, Refractive Errors, Cross Sectional Studies, Cohort Studies, and Ocular Hypertension
Previous studies have identified many genetic loci for refractive error and myopia. We aimed to investigate the effect of these loci on ocular biometry as a function of age in children, adolescents, and adults. The study population... more
Previous studies have identified many genetic loci for refractive error and myopia. We aimed to investigate the effect of these loci on ocular biometry as a function of age in children, adolescents, and adults. The study population consisted of three age groups identified from the international CREAM consortium: 5,490 individuals aged <10 years; 5,000 aged 10-25 years; and 16,274 aged >25 years. All participants had undergone standard ophthalmic examination including measurements of axial length (AL) and corneal radius (CR). We examined the lead SNP at all 39 currently known genetic loci for refractive error identified from genome-wide association studies (GWAS), as well as a combined genetic risk score (GRS). The beta coefficient for association between SNP genotype or GRS versus AL/CR was compared across the three age groups, adjusting for age, sex, and principal components. Analyses were Bonferroni-corrected. In the age group <10 years, three loci (GJD2, CHRNG, ZIC2) wer...
Research Interests: Genetics, Genetic Epidemiology, Biology, Myopia, Biometry, and 15 moreAdolescent, Medicine, Humans, Child, Female, Male, Risk factors, Genotype, Adult, Risk Factors, Genetic Architecture, Allele, Laminin, Connexins, and alleles
In animal models, lack of thyroid hormone is associated with cone photoreceptor preservation, while administration of high doses of active thyroid hormone leads to deterioration. The association between thyroid function and age-related... more
In animal models, lack of thyroid hormone is associated with cone photoreceptor preservation, while administration of high doses of active thyroid hormone leads to deterioration. The association between thyroid function and age-related macular degeneration (AMD) has not been investigated in the general population. Participants of age ≥55 years from the Rotterdam Study with thyroid-stimulating hormone (TSH) and/or free thyroxine (FT4) measurements and AMD assessment were included. We conducted age- and sex-adjusted Cox proportional hazards models to explore the association of TSH or FT4 with AMD, in the full range and in those with TSH (0.4-4.0 mIU/L) and/or FT4 in normal range (11-25 pmol/L). Cox proportional hazards models were performed for the association of TSH or FT4 with retinal pigment alterations (RPA), as an early marker of retinal changes. Multivariable models additionally included cardiovascular risk factors and thyroid peroxidase antibodies positivity. We also performed ...
Research Interests: Risk, Medicine, Macular Degeneration, Prospective studies, Population, and 15 moreHumans, Internal Medicine, Female, Male, Incidence, Risk factors, Age related macular degeneration, Aged, Middle Aged, Proportional hazards model, AMD, Risk Factors, Proportional Hazards Models, Cohort Studies, and Medical and Health Sciences
Genetic testing may be the next step in clinical medicine for a more personalized approach in determining risk of disease. Direct-to-consumer (DTC) personal genome tests may fulfill this role. We explored the practicability and predictive... more
Genetic testing may be the next step in clinical medicine for a more personalized approach in determining risk of disease. Direct-to-consumer (DTC) personal genome tests may fulfill this role. We explored the practicability and predictive value of DTC tests from four companies (23andMe, deCODEme, Easy DNA, Genetic Testing Laboratories) for AMD. Body specimens of three individuals were collected and sent to four companies for DNA genotyping and disease risk estimation. In addition, DNA was also genotyped using Illumina HumanOmniExpress 12v1 array in the Rotterdam Study laboratory, and risk estimates of AMD were calculated using the validated prediction model from the population-based Three Continent AMD Consortium. Genotyped results of the four DTC tests matched genotyping performed by the Rotterdam Study laboratory. The estimated risks provided by the companies varied considerably in the tested individuals, from a 1.6-fold difference for overall relative risk to an up to 12-fold dif...
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To identify genetic variants associated with refractive astigmatism in the general population, meta-analyses of genome-wide association studies were performed for: White Europeans aged at least 25 years (20 cohorts, N = 31,968); Asian... more
To identify genetic variants associated with refractive astigmatism in the general population, meta-analyses of genome-wide association studies were performed for: White Europeans aged at least 25 years (20 cohorts, N = 31,968); Asian subjects aged at least 25 years (7 cohorts, N = 9,295); White Europeans aged…
Research Interests: Genetics, Human Genetics, Complementary and Alternative Medicine, Biology, Medicine, and 15 moreRefractive Error, Humans, Female, Male, Astigmatism, Middle Aged, Adult, Age Factors, European Continental Ancestry Group, Asian Continental Ancestry Group, Genetic Association, Genetic Markers, Cohort Studies, High mobility group proteins, and Paediatrics and reproductive medicine
Age-related macular degeneration (AMD) is the most frequent cause of irreversible blindness in the elderly in developed countries. Our previous studies implicated activation of complement in the formation of drusen, the hallmark lesion of... more
Age-related macular degeneration (AMD) is the most frequent cause of irreversible blindness in the elderly in developed countries. Our previous studies implicated activation of complement in the formation of drusen, the hallmark lesion of AMD. Here, we show that factor H (HF1), the major inhibitor of the alternative complement pathway, accumulates within drusen and is synthesized by the retinal pigmented epithelium. Because previous linkage analyses identified chromosome 1q25-32, which harbors the factor H gene ( HF1 / CFH ), as an AMD susceptibility locus, we analyzed HF1 for genetic variation in two independent cohorts comprised of ≈900 AMD cases and 400 matched controls. We found association of eight common HF1 SNPs with AMD; two common missense variants exhibit highly significant associations (I62V, χ 2 = 26.1 and P = 3.2 × 10 -7 and Y402H, χ 2 = 54.4 and P = 1.6 × 10 -13 ). Haplotype analysis reveals that multiple HF1 variants confer elevated or reduced risk of AMD. One common ...
Research Interests: Genetics, Biology, Immunohistochemistry, Medicine, Multidisciplinary, and 15 moreMacular Degeneration, Humans, General, Developing Country, Haplotypes, Age related macular degeneration, Aged, Middle Aged, Genotype, European Continental Ancestry Group, Genetic variation, Complement Factor H, Confidence Interval, Haplotype, and DNA mutational analysis
Research Interests: Evolutionary Biology, Genetics, Epidemiology, Genetic Epidemiology, Human Genetics, and 15 moreBiology, Biological Sciences, Clinical immunology, Female, Genetic Association Studies, Heritability, Aged, Genotype, Degeneration, Genetic Polymorphism, Genetic variation, Amino Acid Substitution Rates, Genetic Screens, Case Control Studies, and alleles
Research Interests: Ophthalmology, Biology, Medicine, Macular Degeneration, Humans, and 15 moreFemale, Male, Heritability, Proteins, Risk factors, Genes, Clinical Sciences, Concordance, Optometry and Ophthalmology, Genotype, Public health systems and services research, Genotyping, Risk Factors, Choroidal Neovascularization, and Geographic atrophy
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The aim of the European Eye Epidemiology (E3) consortium was to develop a spectral-domain optical coherence tomography (SD-OCT)-based classification for macular diseases to standardize epidemiological studies. A European panel of... more
The aim of the European Eye Epidemiology (E3) consortium was to develop a spectral-domain optical coherence tomography (SD-OCT)-based classification for macular diseases to standardize epidemiological studies. A European panel of vitreoretinal disease experts and epidemiologists belonging to the E3 consortium was assembled to define a classification for SD-OCT imaging of the macula. A series of meeting was organized, to develop, test and finalize the classification. First, grading methods used by the different research groups were presented and discussed, and a first version of classification was proposed. This first version was then tested on a set of 50 SD-OCT images in the Bordeaux and Rotterdam centres. Agreements were analysed and discussed with the panel of experts and a final version of the classification was produced. Definitions and classifications are proposed for the structure assessment of the vitreomacular interface (visibility of vitreous interface, vitreomacular adhes...
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Primary open-angle glaucoma (POAG) is the most common chronic optic neuropathy worldwide. Epidemiological studies show a robust positive relation between intraocular pressure (IOP) and POAG and modest positive association between IOP and... more
Primary open-angle glaucoma (POAG) is the most common chronic optic neuropathy worldwide. Epidemiological studies show a robust positive relation between intraocular pressure (IOP) and POAG and modest positive association between IOP and blood pressure (BP), while the relation between BP and POAG is controversial. The International Glaucoma Genetics Consortium (n=27 558), the International Consortium on Blood Pressure (n=69 395), and the National Eye Institute Glaucoma Human Genetics Collaboration Heritable Overall Operational Database (n=37 333), represent genome-wide data sets for IOP, BP traits and POAG, respectively. We formed genome-wide significant variant panels for IOP and diastolic BP and found a strong relation with POAG (odds ratio and 95% confidence interval: 1.18 (1.14-1.21), P=1.8 × 10(-27)) for the former trait but no association for the latter (P=0.93). Next, we used linkage disequilibrium (LD) score regression, to provide genome-wide estimates of correlation between...
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To examine human performance and agreement on reticular pseudodrusen (RPD) detection and quantification by using single- and multimodality grading protocols and to describe and evaluate a machine learning system for the automatic... more
To examine human performance and agreement on reticular pseudodrusen (RPD) detection and quantification by using single- and multimodality grading protocols and to describe and evaluate a machine learning system for the automatic detection and quantification of reticular pseudodrusen by using single- and multimodality information. Color fundus, fundus autofluoresence, and near-infrared images of 278 eyes from 230 patients with or without presence of RPD were used in this study. All eyes were scored for presence of RPD during single- and multimodality setups by two experienced observers and a developed machine learning system. Furthermore, automatic quantification of RPD area was performed by the proposed system and compared with human delineations. Observers obtained a higher performance and better interobserver agreement for RPD detection with multimodality grading, achieving areas under the receiver operating characteristic (ROC) curve of 0.940 and 0.958, and a κ agreement of 0.91...
Research Interests: Computer Science, Algorithms, Artificial Intelligence, Photography, Medicine, and 10 moreBiological Sciences, Prospective studies, Humans, Near Infrared Spectroscopy, Multimodal imaging, ROC Curve, Observer Variation, Receiver Operating Characteristic, Cohort Studies, and Medical and Health Sciences
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Advanced age-related macular degeneration (AMD) is the leading cause of blindness in the elderly, with limited therapeutic options. Here we report on a study of…