Systemic and ocular fluid compounds as potential biomarkers in age-related macular degeneration

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 description of its function and discuss the results of the studies in relation to its usefulness as AMD biomarker. In addition, biomarkers identified by hypothesis-free techniques, including metabolomics, proteomics, and epigenomics, are covered. In summary, compounds belonging to the oxidative stress pathway, the complement system, and lipid metabolism are the most promising biomarker candidates for AMD. We hope that this comprehensive survey of the literature on systemic and ocular fluid compounds as potential biomarkers in AMD will provide a stepping stone for future research and possible implementation in clinical practice

CHCHD10 variants in amyotrophic lateral sclerosis: where Is the evidence?

Objective: After the initial report of a CHCHD10 mutation in mitochondrial disease with features resembling amyotrophic lateral sclerosis (ALS), CHCHD10 mutations have been considered to be a frequent cause for ALS. However, the exact pathogenicity and clinical significance of these mutations remain unclear. Here, we aimed to determine the role of CHCHD10 mutations in ALS. Methods: We analyzed 4,365 whole genome sequenced ALS patients and 1,832 controls from 7 different countries and examined all nonsynonymous single nucleotide variants in CHCHD10. These were tested for association with ALS, independently and in aggregate using several genetic burden tests (including sequence kernel association test [SKAT], optimal unified test [SKAT-O], and Firth logistic regression). Results: We identified 3 new variants in cases, but only 1 was ALS-specific. lso, 1 control-specific mutation was identified. There was no increased burden of rare coding mutations among ALS patients compared to controls (p=0.86, p=0.86, and p=0.88 for SKAT, SKAT-O, and Firth, respectively). The few carriers with potential pathogenic CHCHD10 mutations exhibited a slowly progressive ALS-like phenotype with atypical features such as myopathy and deafness. Interpretation: CHCHD10 mutations seem to be a far less prevalent cause of pure ALS than previously suggested, and instead appear related to more complex phenotypes. There appears to be insufficient evidence for the pathogenicity of most previously reported variants in pure ALS. This study shows that routine testing for CHCHD10 mutations in pure ALS is not recommended and illustrates the importance of sufficient genetic and functional evidence in establishing pathogenicity of genetic variants

Project MinE: study design and pilot analyses of a large-scale whole-genome sequencing study in amyotrophic lateral sclerosis

The most recent genome-wide association study in amyotrophic lateral sclerosis (ALS) demonstrates a disproportionate contribution from low-frequency variants to genetic susceptibility to disease. We have therefore begun Project MinE, an international collaboration that seeks to analyze whole-genome sequence data of at least 15 000 ALS patients and 7500 controls. Here, we report on the design of Project MinE and pilot analyses of successfully sequenced 1169 ALS patients and 608 controls drawn from the Netherlands. As has become characteristic of sequencing studies, we find an abundance of rare genetic variation (minor allele frequency < 0.1%), the vast majority of which is absent in public datasets. Principal component analysis reveals local geographical clustering of these variants within The Netherlands. We use the whole-genome sequence data to explore the implications of poor geographical matching of cases and controls in a sequence-based disease study and to investigate how ancestry-matched, externally sequenced controls can induce false positive associations. Also, we have publicly released genome-wide minor allele counts in cases and controls, as well as results from genic burden tests

The genetics of central serous chorioretinopathy

Contains fulltext : 201198.pdf (publisher's version ) (Open Access)Radboud University, 1 maart 2019Promotor : Hollander, A.I. den Co-promotor : Jong, E.K. d

The genetics of central serous chorioretinopathy

Contains fulltext : 201198.pdf (publisher's version ) (Open Access)Radboud University, 1 maart 2019Promotor : Hollander, A.I. den Co-promotor : Jong, E.K. d

No indication for increased rate of suicide attempts by SSRIs in the Netherlands.

Editor- The ongoing debate on the possible association between suicide attempts and the use of selective serotonin reuptake inhibitors (SSRIs), especially in younger patients, prompted us to look for such an association in the data collected by Dutch general practitioners (GPs). We analyzed the database of the years 1997-2003 focusing on the proportion of repeated suicide attempts in relation to the prescription by GPs of two different types of antidepressants: SSRIs and tricyclic antidepressants (TCAs). Our data do not support the notion that SSRIs trigger more suicide attempts than TCAs. (aut.ref.

Genomic Copy Number Variations of the Complement Component C4B Gene Are Associated With Chronic Central Serous Chorioretinopathy

Contains fulltext : 155364.pdf (publisher's version ) (Open Access)PURPOSE: Chronic central serous chorioretinopathy (cCSC) has recently been associated to variants in the complement factor H gene. To further investigate the role of the complement system in cCSC, the genomic copy number variations in the complement component 4 gene (C4) were studied. METHODS: C4A and C4B copy numbers were analyzed in 197 cCSC patients and 303 healthy controls by using a Taqman copy number determination assay. Copy numbers of C4A, C4B, and the total C4 load were compared between cases and controls, by using a Fisher exact test. For this analysis Bonferroni correction was performed for three tests, and P values < 0.017 were considered to be significant. A logistic regression model was constructed to calculate the odds ratios (ORs) of each of the C4B copy numbers, using two copies as a reference. For this model P values < 0.05 were considered to be significant. RESULTS: C4B genomic copy numbers differed significantly between cCSC patients and healthy controls (P = 0.0018). Absence of C4B significantly conferred risk of cCSC (P = 0.039, OR = 2.61 [95% confidence interval (CI) = 1.05-6.52]), whereas three copies of C4B significantly decreased the risk of cCSC (P = 0.014, OR = 0.45 [95% CI = 0.23-0.85]). The C4A genomic copy numbers and total C4 load did not significantly differ between cases and controls. CONCLUSIONS: This study showed that copy numbers of C4B are significantly associated with cCSC. Carrying no copies of C4B significantly increases the risk of cCSC, whereas carrying three C4B copies is protective. These findings reinforce the hypothesis of a possible involvement of the complement system in the pathogenesis of cCSC

Suicide and suicide attempts in the Netherlands: the role of general practitioners.

Similarly as in most Western countries, suicide (S) and suicide attempts (SA) are major health problems because of many years of life lost. Many patients committing S or SA consult their GP in the period preceding S/SA, suggesting thar GPs may play a key role in prevention. Aim: We used data from the Dutch Sentinel GP Network over the period 1983-2003 to delineate typical characteristics of S/SA patients and to analyse the role of GPs with regard to care, referral and recognition of vulnerable persons. Methods: The data were derived from the Sentinel Network, which constitutes a sample of about 60 GPs, covers 1% of the Dutch population and is fairly representative with regard to age, sex, geographical distribution and urbanisation. Gps reported on the incidence of S and SA and provided additional data on sex, age, household, method, place, contact with GP, depression, medication, referral and whether the GP had foreseen S or SA. Results: From 1983-2003 the number of S steadily decreased from 11/100.000 to 6/100.000; SA declined from 53/100.000 to 27/100.000, 1998-2001 appeared a crucial turning point for decline. Most suicides were first attempts (75%). About 50% of S and 70% of SA was committed between the age of 20 and 50 years, with prominent peaks for S in the age groups 30-39 and >60. Suicides were more common in persons living alone, SA occurred more frequently in households consisting of 3 or more persons. A majority of S/SA patients was treated for depression (60%). Only 7% of them ever mentioned thoughts about committing S. Nearly all depressed patients (90%) were treated with an antidepressant; from 1993 onward SSRIs prevailed. GPs referred 65% of their depressed patients to a psychiatrist. About half of the S/SA patients had contacted their GP in the 30-day period preceding S or SA; GPs reported that they had foreseen S/SA in 31% of these cases. Conclusions: The number of S and SA occurring in Dutch general practice has declined over the years. Depression is the major underlying disease for which most patients are referred to a psychiatrist. Especially in young and older depressed persons, living alone, GPs should ask for suicidal ideation, making it debatable, to enhance recognition and improve prevention

Exome sequencing in patients with chronic central serous chorioretinopathy

Contains fulltext : 203997.pdf (publisher's version ) (Open Access

Use of the internet for monitoring of influenza-like illness (ILI).

Background: An internet-based survey of influenza-like illness (ILI)—the Great Influenza Survey or GIS—was launched in The Netherlands in the 2003–2004 influenza season. The aim of the present study was to validate the representativeness of the GIS population and to compare the GIS data with the official ILI data obtained by Dutch GPs participating in the Dutch Sentinel Practice Network. Methods: Direct mailings to schools and universities, and repeated interviews on television and radio, and in newspapers were used to kindle the enthusiasm of a broad section of the public for GIS. Strict symptomatic criteria for ILI were formulated with the assistance of expert institutes and only participants who responded at least five times to weekly e-mails asking them about possible ILI symptoms were included in the survey. Validation of GIS was done at different levels: (i) some key demographic (age distribution) and public health statistics (prevalence of asthma and diabetes, and influenza vaccination rates) for the Dutch population were compared with corresponding figures calculated from GIS; (ii) the incidence of ILI in GIS was compared with the incidence as reported by GPs participating in the Dutch Sentinel Practice Network. Results: A total of 13 300 persons (53% of total responders) were included in the survey. As expected, there was a marked underrepresentation of the age groups 0–10 years and from 81 to >90 years in the GIS population, although the similarities were remarkable for most other age groups. There were striking similarities between the GIS and the Dutch population with regard to the prevalence of asthma (6.4 versus 6.9%) and the influenza vaccination rates, and to a lesser degree for diabetes (2.4 versus 3.5%). There was also a marked similarity between the seasonal course of ILI measured by GIS and the GPs. Although the incidence in GIS was 10 times higher, the incidence curves followed an almost similar pattern, with peak incidences occurring in the same week. Conclusions: The current study demonstrates that recruitment of a high number of persons willing to participate in online health surveillance is feasible. The information gathered proved to be reliable, as it paralleled the information obtained via an undisputed route. (aut. ref.