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1.
PLoS One ; 14(9): e0222092, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31491000

RESUMO

PURPOSE: To evaluate the incidence of Acanthamoeba keratitis in the Netherlands between 2009 and 2015 and to analyse predicting factors for treatment outcome. METHODS: Patient characteristics, diagnostic methods, diagnostic delay, therapy prior to and after diagnosis, and visual outcome were obtained from medical files of all patients diagnosed with Acanthamoeba keratitis in the Netherlands between 2009 and 2015. A logistic regression analysis on treatment failure, defined as a best corrected visual acuity of less than 20/40 Snellen decimals (i.e. >0.3 logMAR or an approximate loss of three lines of visual acuity) and/or the need for keratoplasty, was performed to determine predicting factors. RESULTS: Two hundred and twenty-four eyes of 224 patients were included. Ninety-five percent of the patients were contact lens wearers, of whom 74% wore soft contact lenses. The number of cases increased from 16 in 2009 to 49 in 2015. This resulted in an estimated incidence of 1 in 21,000 for soft contact lens wearers in 2015. Eighty-seven eyes (39%) met the criteria for treatment failure. In a multivariable regression analysis, higher age at presentation, a higher severity stage and corticosteroid use before diagnosis were positively correlated with treatment failure. Early referral to a cornea specialist was associated with better clinical outcomes. CONCLUSIONS: Although Acanthamoeba keratitis is still a relatively uncommon disease, the incidence in soft contact lens wearers has increased to reach 1 in 21,000 in 2015. Treatment failure occurred in 39% of cases, with age, higher severity stage, corticosteroid use before diagnosis and indirect referral to a cornea specialist as important risks factors.

2.
Acta Ophthalmol ; 2019 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-31161732

RESUMO

PURPOSE: To describe the learning curve for Descemet's membrane endothelial keratoplasty (DMEK) in the Rotterdam Eye Hospital and to evaluate safety and visual outcome. METHODS: This was a single-centre prospective study of 40 consecutive patients with Fuchs' endothelial dystrophy who underwent a DMEK procedure in the Rotterdam Eye Hospital. The performance of two corneal surgeons, each conducting their first series of 20 procedures, was examined with the cumulative summation test for the learning curve (LC-CUSUM). The surgical procedure was considered unsuccessful when >30% of the graft was not attached at any time during the first 12 postoperative weeks and a mixture of SF6 (20%) and air (80%) had to be injected in the anterior chamber (rebubbling) to reattach the graft. Also assessed were visual outcome, intraocular pressure and peri- and postoperative complications. RESULTS: In total, nine rebubbling procedures were performed in seven eyes. Following repeated rebubbling, two eyes did not achieve a satisfactory result and secondary surgery was required to restore visual function. Complications were usually manageable. The last 13 DMEK procedures (33%) of this series did not require rebubbling. After 3 months, 86% of the eyes had reached a Snellen visual acuity of 0.5 or more. CONCLUSION: Together with the two surgeons' personal experience, the aggregate learning curve was considered to justify incorporation of Descemet membrane endothelial keratoplasty as a regular option of the standard of care for endothelial dysfunction in the Rotterdam Eye Hospital.

3.
Acta Ophthalmol ; 2019 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-31025804

RESUMO

PURPOSE: To evaluate the cost-effectiveness of ultrathin Descemet stripping automated endothelial keratoplasty (UT-DSAEK) versus standard DSAEK. METHODS: A cost-effectiveness analysis using data from a multicentre randomized clinical trial was performed. The time horizon was 12 months postoperatively. Sixty-four eyes of 64 patients with Fuchs' endothelial dystrophy were included and randomized to UT-DSAEK (n = 33) or DSAEK (n = 31). Relevant resources from healthcare and societal perspectives were included in the cost analysis. Quality-adjusted life years (QALYs) were determined using the Health Utilities Index Mark 3 questionnaire. The main outcome was the incremental cost-effectiveness ratio (ICER; incremental societal costs per QALY). RESULTS: Societal costs were €9431 (US$11 586) for UT-DSAEK and €9110 (US$11 192) for DSAEK. Quality-adjusted life years (QALYs) were 0.74 in both groups. The ICER indicated inferiority of UT-DSAEK. The cost-effectiveness probability ranged from 37% to 42%, assuming the maximum acceptable ICER ranged from €2500-€80 000 (US$3071-US$98 280) per QALY. Additional analyses were performed omitting one UT-DSAEK patient who required a regraft [ICER €9057 (US$11 127) per QALY, cost-effectiveness probability: 44-62%] and correcting QALYs for an imbalance in baseline utilities [ICER €23 827 (US$29 271) per QALY, cost-effectiveness probability: 36-59%]. Furthermore, the ICER was €2101 (US$2581) per patient with clinical improvement in best spectacle-corrected visual acuity (≥0.2 logMAR) and €3274 (US$4022) per patient with clinical improvement in National Eye Institute Visual Functioning Questionnaire-25 composite score (≥10 points). CONCLUSION: The base case analysis favoured DSAEK, since costs of UT-DSAEK were higher while QALYs were comparable. However, additional analyses revealed no preference for UT-DSAEK or DSAEK. Further cost-effectiveness studies are required to reduce uncertainty.

4.
Ann Clin Transl Neurol ; 6(4): 698-707, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31019994

RESUMO

Objective: To identify novel CSF biomarkers in GRN-associated frontotemporal dementia (FTD) by proteomics using mass spectrometry (MS). Methods: Unbiased MS was applied to CSF samples from 19 presymptomatic and 9 symptomatic GRN mutation carriers and 24 noncarriers. Protein abundances were compared between these groups. Proteins were then selected for validation if identified by ≥4 peptides and if fold change was ≤0.5 or ≥2.0. Validation and absolute quantification by parallel reaction monitoring (PRM), a high-resolution targeted MS method, was performed on an international cohort (n = 210) of presymptomatic and symptomatic GRN, C9orf72 and MAPT mutation carriers. Results: Unbiased MS revealed 20 differentially abundant proteins between symptomatic mutation carriers and noncarriers and nine between symptomatic and presymptomatic carriers. Seven of these proteins fulfilled our criteria for validation. PRM analyses revealed that symptomatic GRN mutation carriers had significantly lower levels of neuronal pentraxin receptor (NPTXR), receptor-type tyrosine-protein phosphatase N2 (PTPRN2), neurosecretory protein VGF, chromogranin-A (CHGA), and V-set and transmembrane domain-containing protein 2B (VSTM2B) than presymptomatic carriers and noncarriers. Symptomatic C9orf72 mutation carriers had lower levels of NPTXR, PTPRN2, CHGA, and VSTM2B than noncarriers, while symptomatic MAPT mutation carriers had lower levels of NPTXR and CHGA than noncarriers. Interpretation: We identified and validated five novel CSF biomarkers in GRN-associated FTD. Our results show that synaptic, secretory vesicle, and inflammatory proteins are dysregulated in the symptomatic stage and may provide new insights into the pathophysiology of genetic FTD. Further validation is needed to investigate their clinical applicability as diagnostic or monitoring biomarkers.

5.
Acta Neuropathol ; 137(6): 879-899, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30739198

RESUMO

Frontotemporal lobar degeneration with neuronal inclusions of the TAR DNA-binding protein 43 (FTLD-TDP) represents the most common pathological subtype of FTLD. We established the international FTLD-TDP whole-genome sequencing consortium to thoroughly characterize the known genetic causes of FTLD-TDP and identify novel genetic risk factors. Through the study of 1131 unrelated Caucasian patients, we estimated that C9orf72 repeat expansions and GRN loss-of-function mutations account for 25.5% and 13.9% of FTLD-TDP patients, respectively. Mutations in TBK1 (1.5%) and other known FTLD genes (1.4%) were rare, and the disease in 57.7% of FTLD-TDP patients was unexplained by the known FTLD genes. To unravel the contribution of common genetic factors to the FTLD-TDP etiology in these patients, we conducted a two-stage association study comprising the analysis of whole-genome sequencing data from 517 FTLD-TDP patients and 838 controls, followed by targeted genotyping of the most associated genomic loci in 119 additional FTLD-TDP patients and 1653 controls. We identified three genome-wide significant FTLD-TDP risk loci: one new locus at chromosome 7q36 within the DPP6 gene led by rs118113626 (p value = 4.82e - 08, OR = 2.12), and two known loci: UNC13A, led by rs1297319 (p value = 1.27e - 08, OR = 1.50) and HLA-DQA2 led by rs17219281 (p value = 3.22e - 08, OR = 1.98). While HLA represents a locus previously implicated in clinical FTLD and related neurodegenerative disorders, the association signal in our study is independent from previously reported associations. Through inspection of our whole-genome sequence data for genes with an excess of rare loss-of-function variants in FTLD-TDP patients (n ≥ 3) as compared to controls (n = 0), we further discovered a possible role for genes functioning within the TBK1-related immune pathway (e.g., DHX58, TRIM21, IRF7) in the genetic etiology of FTLD-TDP. Together, our study based on the largest cohort of unrelated FTLD-TDP patients assembled to date provides a comprehensive view of the genetic landscape of FTLD-TDP, nominates novel FTLD-TDP risk loci, and strongly implicates the immune pathway in FTLD-TDP pathogenesis.

7.
Neurobiol Aging ; 73: 229.e11-229.e18, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30314817

RESUMO

Next-generation sequencing has contributed to our understanding of the genetics of Alzheimer's disease (AD) and has explained a substantial part of the missing heritability of familial AD. We sequenced 19 exomes from 8 Dutch families with a high AD burden and identified EIF2AK3, encoding for protein kinase RNA-like endoplasmic reticulum kinase (PERK), as a candidate gene. Gene-based burden analysis in a Dutch AD exome cohort containing 547 cases and 1070 controls showed a significant association of EIF2AK3 with AD (OR 1.84 [95% CI 1.07-3.17], p-value 0.03), mainly driven by the variant p.R240H. Genotyping of this variant in an additional cohort from the Rotterdam Study showed a trend toward association with AD (p-value 0.1). Immunohistochemical staining with pPERK and peIF2α of 3 EIF2AK3 AD carriers showed an increase in hippocampal neuronal cells expressing these proteins compared with nondemented controls, but no difference was observed in AD noncarriers. This study suggests that rare variants in EIF2AK3 may be associated with disease risk in AD.

8.
Neurobiol Aging ; 74: 225-233, 2018 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-30497016

RESUMO

Knowledge about the molecular mechanisms driving Alzheimer's disease (AD) is still limited. To learn more about AD biology, we performed whole transcriptome sequencing on the hippocampus of 20 AD cases and 10 age- and sex-matched cognitively healthy controls. We observed 2716 differentially expressed genes, of which 48% replicated in a second data set of 84 AD cases and 33 controls. We used an integrative network-based approach for combining transcriptomic and protein-protein interaction data to find differentially expressed gene modules that may reflect key processes in AD biology. A total of 735 differentially expressed genes were clustered into 33 modules, of which 82% replicated in a second data set, highlighting the robustness of this approach. These 27 modules were enriched for signal transduction, transport, response to stimulus, and several organic and cellular metabolic pathways. Ten modules interacted with previously described AD genes. Our study indicates that analyzing RNA-expression data based on annotated gene modules is more robust than on individual genes. We provide a comprehensive overview of the biological processes involved in AD, and the detected differentially expressed gene modules may provide a molecular basis for future research into mechanisms underlying AD.

9.
J Alzheimers Dis ; 2018 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-30412494

RESUMO

Neuropsychiatric symptoms (NPS) are increasingly recognized as a core element of Alzheimer's disease (AD); however, clinicians still consider AD primarily as a cognitive disorder. We describe a case in which the under-recognition of NPS as part of AD resulted in substantial delay of an AD diagnosis, a wrong psychiatric diagnosis, and the organization of inappropriate care. The aim of this paper is to acknowledge NPS as an (early) manifestation of AD and to suggest features that may point toward underlying AD in older adults with late-life behavioral changes.

10.
Front Genet ; 9: 420, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30356672

RESUMO

Carotid intima-media thickness (cIMT) is an established heritable marker for subclinical atherosclerosis. In this study, we aim to identify rare variants with large effects driving differences in cIMT by performing genome-wide linkage analysis of individuals in the extremes of cIMT trait distribution (>90th percentile) in a large family-based study from a genetically isolated population in the Netherlands. Linked regions were subsequently explored by fine-mapping using exome sequencing. We observed significant evidence of linkage on chromosomes 2p16.3 [rs1017418, heterogeneity LOD (HLOD) = 3.35], 19q13.43 (rs3499, HLOD = 9.09), 20p13 (rs1434789, HLOD = 4.10), and 21q22.12 (rs2834949, HLOD = 3.59). Fine-mapping using exome sequencing data identified a non-coding variant (rs62165235) in PNPT1 gene under the linkage peak at chromosome 2 that is likely to have a regulatory function. The variant was associated with quantitative cIMT in the family-based study population (effect = 0.27, p-value = 0.013). Furthermore, we identified several genes under the linkage peak at chromosome 21 highly expressed in tissues relevant for atherosclerosis. To conclude, our linkage analysis identified four genomic regions significantly linked to cIMT. Further analyses are needed to demonstrate involvement of identified candidate genes in development of atherosclerosis.

11.
PLoS One ; 13(10): e0203993, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30289925

RESUMO

OBJECTIVE: Comparison of conventional Penetrating Keratoplasty (PKP), posterior mushroom PKP and Descemet's Stripping Automated Endothelial Keratoplasty (DSAEK) regarding overall graft survival of primary corneal transplants for Fuchs´ endothelial dystrophy (FED), best spectacle-corrected visual acuity (BSCVA) and astigmatism. METHODS: Single centre study using prospectively collected data from the national database for follow-up of corneal transplants. Main outcome parameters: 10 years graft survival, astigmatism at 24 months, pre- and post-operative BSCVA. RESULTS: In total, 721 cases were included: PKP, n = 171; posterior mushroom PKP, n = 91; and DSAEK, n = 459. There was no significant difference in graft survival between PKP, posterior mushroom PKP and the DSAEK technique (log-rank test, P = 0.12). The overall post-operative BSCVA improvement in all treatment groups was significant (paired t-test, P<0.001). Pre-operative BSCVA was better for the DSAEK group (0.68 ± 0.41 logMAR) as compared to the PKP (0.89 ± 0.53) and posterior mushroom PKP group (0.90 ± 0.58); ANOVA, P<0.001. After 24 months, BSCVA was significantly better for the DSAEK group (0.25 ± 0.26 logMAR) compared to the PKP (0.35 ± 0.29) and posterior mushroom PKP group (0.41 ± 0.42); ANOVA, P<0.001. A significant difference in astigmatism was found (median test, P<0.001) between the DSAEK (1.7 ± 1.1 D), PKP (4.6 ± 2.7 D) and posterior mushroom PKP group (4.5 ± 3.3 D). The significantly lower DSAEK-induced astigmatism was confirmed by vector analysis. CONCLUSION: There was no difference in graft survival and BSCVA improvement between conventional PKP, inverted mushroom PKP and DSAEK in this study. The significantly lower changes in astigmatism, wound stability and faster visual rehabilitation with DSAEK surgery are favourable aspects of this technique. The benefits of posterior lamellar keratoplasty warrant earlier intervention, which may contribute to preserve better vision for a prolonged period of remaining lifetime.

12.
Nat Commun ; 9(1): 4228, 2018 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-30315176

RESUMO

Elevated serum urate levels can cause gout, an excruciating disease with suboptimal treatment. Previous GWAS identified common variants with modest effects on serum urate. Here we report large-scale whole-exome sequencing association studies of serum urate and kidney function among ≤19,517 European ancestry and African-American individuals. We identify aggregate associations of low-frequency damaging variants in the urate transporters SLC22A12 (URAT1; p = 1.3 × 10-56) and SLC2A9 (p = 4.5 × 10-7). Gout risk in rare SLC22A12 variant carriers is halved (OR = 0.5, p = 4.9 × 10-3). Selected rare variants in SLC22A12 are validated in transport studies, confirming three as loss-of-function (R325W, R405C, and T467M) and illustrating the therapeutic potential of the new URAT1-blocker lesinurad. In SLC2A9, mapping of rare variants of large effects onto the predicted protein structure reveals new residues that may affect urate binding. These findings provide new insights into the genetic architecture of serum urate, and highlight molecular targets in SLC22A12 and SLC2A9 for lowering serum urate and preventing gout.

13.
Brain ; 141(10): 2895-2907, 2018 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-30252044

RESUMO

The G4C2-repeat expansion in C9orf72 is the most common known cause of amyotrophic lateral sclerosis and frontotemporal dementia. The high phenotypic heterogeneity of C9orf72 patients includes a wide range in age of onset, modifiers of which are largely unknown. Age of onset could be influenced by environmental and genetic factors both of which may trigger DNA methylation changes at CpG sites. We tested the hypothesis that age of onset in C9orf72 patients is associated with some common single nucleotide polymorphisms causing a gain or loss of CpG sites and thus resulting in DNA methylation alterations. Combined analyses of epigenetic and genetic data have the advantage of detecting functional variants with reduced likelihood of false negative results due to excessive correction for multiple testing in genome-wide association studies. First, we estimated the association between age of onset in C9orf72 patients (n = 46) and the DNA methylation levels at all 7603 CpG sites available on the 450 k BeadChip that are mapped to common single nucleotide polymorphisms. This was followed by a genetic association study of the discovery (n = 144) and replication (n = 187) C9orf72 cohorts. We found that age of onset was reproducibly associated with polymorphisms within a 124.7 kb linkage disequilibrium block tagged by top-significant variation, rs9357140, and containing two overlapping genes (LOC101929163 and C6orf10). A meta-analysis of all 331 C9orf72 carriers revealed that every A-allele of rs9357140 reduced hazard by 30% (P = 0.0002); and the median age of onset in AA-carriers was 6 years later than GG-carriers. In addition, we investigated a cohort of C9orf72 negative patients (n = 2634) affected by frontotemporal dementia and/or amyotrophic lateral sclerosis; and also found that the AA-genotype of rs9357140 was associated with a later age of onset (adjusted P = 0.007 for recessive model). Phenotype analyses detected significant association only in the largest subgroup of patients with frontotemporal dementia (n = 2142, adjusted P = 0.01 for recessive model). Gene expression studies of frontal cortex tissues from 25 autopsy cases affected by amyotrophic lateral sclerosis revealed that the G-allele of rs9357140 is associated with increased brain expression of LOC101929163 (a non-coding RNA) and HLA-DRB1 (involved in initiating immune responses), while the A-allele is associated with their reduced expression. Our findings suggest that carriers of the rs9357140 GG-genotype (linked to an earlier age of onset) might be more prone to be in a pro-inflammatory state (e.g. by microglia) than AA-carriers. Further, investigating the functional links within the C6orf10/LOC101929163/HLA-DRB1 pathway will be critical to better define age-dependent pathogenesis of frontotemporal dementia and amyotrophic lateral sclerosis.

14.
J Alzheimers Dis ; 65(4): 1139-1146, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30103325

RESUMO

Valosin-containing protein (VCP) is involved in multiple cellular activities. Mutations in VCP lead to heterogeneous clinical presentations including inclusion body myopathy with Paget's disease of the bone, frontotemporal dementia and amyotrophic lateral sclerosis, even in patients carrying the same mutation. We screened a cohort of 48 patients with familial frontotemporal dementia (FTD) negative for MAPT, GRN, and C9orf72 mutations for other known FTD genes by using whole exome sequencing. In addition, we carried out targeted sequencing of a cohort of 37 patients with frontotemporal lobar degeneration with Transactive response DNA-binding protein 43 (TDP-43) subtype from the Netherlands Brain bank. Two novel (p.Thr262Ser and p.Arg159Ser) and one reported (p.Met158Val) VCP mutations in three patients with a clinical diagnosis of FTD were identified, and were absence in population-match controls. All three patients presented with behavioral changes, with additional semantic deficits in one. No signs of Paget or muscle disease were observed. Pathological examination of the patient with VCP p.Arg159Ser mutation showed numerous TDP-43 immunoreactive (IR) neuronal intranuclear inclusions (NII) and dystrophic neurites (DN), while a lower number of NII and DN were observed in the patient with the VCP p.Thr262Ser mutation. Pathological findings of both patients were consistent with FTLD-TDP subtype D. Furthermore, only rare VCP-IR NII was observed in both cases. Our study expands the clinical heterogeneity of VCP mutations carriers, and indicates that other additional factors, such as genetic modifiers, may determine the clinical phenotype.

15.
PLoS One ; 13(8): e0202022, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30148849

RESUMO

Genetic Generalized Epilepsy (GGE) and benign epilepsy with centro-temporal spikes or Rolandic Epilepsy (RE) are common forms of genetic epilepsies. Rare copy number variants have been recognized as important risk factors in brain disorders. We performed a systematic survey of rare deletions affecting protein-coding genes derived from exome data of patients with common forms of genetic epilepsies. We analysed exomes from 390 European patients (196 GGE and 194 RE) and 572 population controls to identify low-frequency genic deletions. We found that 75 (32 GGE and 43 RE) patients out of 390, i.e. ~19%, carried rare genic deletions. In particular, large deletions (>400 kb) represent a higher burden in both GGE and RE syndromes as compared to controls. The detected low-frequency deletions (1) share genes with brain-expressed exons that are under negative selection, (2) overlap with known autism and epilepsy-associated candidate genes, (3) are enriched for CNV intolerant genes recorded by the Exome Aggregation Consortium (ExAC) and (4) coincide with likely disruptive de novo mutations from the NPdenovo database. Employing several knowledge databases, we discuss the most prominent epilepsy candidate genes and their protein-protein networks for GGE and RE.

16.
IEEE Trans Med Imaging ; 37(10): 2278-2289, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29993573

RESUMO

Corneal endothelium images obtained by in vivo specular microscopy provide important information to assess the health status of the cornea. Estimation of clinical parameters, such as cell density, polymegethism, and pleomorphism, requires accurate cell segmentation. State-of-the-art techniques to automatically segment the endothelium are error-prone when applied to images with low contrast and/or large variation in cell size. Here, we propose an automatic method to segment the endothelium. Starting with an oversegmented image comprised of superpixels obtained from a stochastic watershed segmentation, the proposed method uses intensity and shape information of the superpixels to identify and merge those that constitute a cell, using support vector machines. We evaluated the automatic segmentation on a data set of in vivo specular microscopy images (Topcon SP-1P), obtaining 95.8% correctly merged cells and 2.0% undersegmented cells. We also evaluated the parameter estimation against the results of the vendor's built-in software, obtaining a statistically significant better precision in all parameters and a similar or better accuracy. The parameter estimation was also evaluated on three other data sets from different imaging modalities (confocal microscopy, phase-contrast microscopy, and fluorescence confocal microscopy) and tissue types (ex vivo corneal endothelium and retinal pigment epithelium). In comparison with the estimates of the data sets' authors, we achieved statistically significant better accuracy and precision in all parameters except pleomorphism, where a similar accuracy and precision were obtained.

17.
Ophthalmology ; 125(9): 1433-1443, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29706360

RESUMO

PURPOSE: 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. DESIGN: Genome-wide case-control association study of WES data. PARTICIPANTS: One thousand one hundred twenty-five AMD patients and 1361 control participants. METHODS: A single variant association test of WES data was performed to detect variants that are associated individually with AMD. The cumulative effect of multiple rare variants with 1 gene was analyzed using a gene-based CMC burden test. Immunohistochemistry was performed to determine the localization of the Col8a1 protein in mouse eyes. MAIN OUTCOME MEASURES: Genetic variants associated with AMD. RESULTS: We detected significantly more rare protein-altering variants in the COL8A1 gene in patients (22/2250 alleles [1.0%]) than in control participants (11/2722 alleles [0.4%]; P = 7.07×10-5). The association of rare variants in the COL8A1 gene is independent of the common intergenic variant (rs140647181) near the COL8A1 gene previously associated with AMD. We demonstrated that the Col8a1 protein localizes at Bruch's membrane. CONCLUSIONS: This study supported a role for protein-altering variants in the COL8A1 gene in AMD pathogenesis. We demonstrated the presence of Col8a1 in Bruch's membrane, further supporting the role of COL8A1 variants in AMD pathogenesis. Protein-altering variants in COL8A1 may alter the integrity of Bruch's membrane, contributing to the accumulation of drusen and the development of AMD.

18.
J Ophthalmol ; 2018: 7320816, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29713526

RESUMO

Purpose: To investigate the long-term anatomical and functional outcomes of Descemet stripping automated endothelial keratoplasty (DSAEK). Methods: Prospective follow-up of 114 eyes (95 subjects) after DSAEK for endothelial dysfunction. Measurements included best spectacle-corrected visual acuity (BSCVA), straylight, endothelial cell density (ECD), and graft thickness. Results: The mean follow-up time was 5.1 ± 1.5 years. Four grafts ultimately failed (after 5 to 7 years). From baseline up to 1 year after DSAEK, mean BSCVA improved by 0.30 logMAR. This beneficial effect remained until the last follow-up (LFU). After DSAEK, straylight was reduced. ECD sharply dropped by 900 cells/mm2 (33%) immediately after surgery and, thereafter, steadily decreased at a rate of 11 cells/mm2 per month. No significant correlation was observed between graft thickness at 3 years and BSCVA. Conclusions: We observed a low graft failure rate and a normalization of graft thickness. Postoperative straylight remained elevated relative to the normal population. The sharp initial and the subsequent more gradual ECD decline are consistent with other studies. A significant and prolonged functional gain can be achieved by posterior lamellar grafting for endothelial dysfunction.

19.
J Hum Genet ; 63(4): 431-446, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29382920

RESUMO

Genome-wide association studies (GWAS) have identified many susceptibility loci for cardiometabolic disorders. Most of the associated variants reside in non-coding regions of the genome including long non-coding RNAs (lncRNAs), which are thought to play critical roles in diverse biological processes. Here, we leveraged data from the available GWAS meta-analyses on lipid and obesity-related traits, blood pressure, type 2 diabetes, and coronary artery disease and identified 179 associated single-nucleotide polymorphisms (SNPs) in 102 lncRNAs (p-value < 2.3 × 10-7). Of these, 55 SNPs, either the lead SNP or in strong linkage disequilibrium with the lead SNP in the related loci, were selected for further investigations. Our in silico predictions and functional annotations of the SNPs as well as expression and DNA methylation analysis of their lncRNAs demonstrated several lncRNAs that fulfilled predefined criteria for being potential functional targets. In particular, we found evidence suggesting that LOC157273 (at 8p23.1) is involved in regulating serum lipid-cholesterol. Our results showed that rs4841132 in the second exon and cg17371580 in the promoter region of LOC157273 are associated with lipids; the lncRNA is expressed in liver and associates with the expression of its nearby coding gene, PPP1R3B. Collectively, we highlight a number of loci associated with cardiometabolic disorders for which the association may act through lncRNAs.


Assuntos
Estudos de Associação Genética , Predisposição Genética para Doença , Cardiopatias/genética , Doenças Metabólicas/genética , RNA Longo não Codificante/genética , Biologia Computacional/métodos , Metilação de DNA , Epigênese Genética , Epistasia Genética , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Variação Genética , Estudo de Associação Genômica Ampla , Humanos , MicroRNAs/genética , Anotação de Sequência Molecular , Conformação de Ácido Nucleico , Interferência de RNA , RNA Longo não Codificante/química
20.
Front Genet ; 8: 151, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29093733

RESUMO

Obstructive sleep apnea (OSA) is a common sleep breathing disorder associated with an increased risk of cardiovascular and cerebrovascular diseases and mortality. Although OSA is fairly heritable (~40%), there have been only few studies looking into the genetics of OSA. In the present study, we aimed to identify genetic variants associated with symptoms of sleep apnea by performing a whole-exome sequence meta-analysis of symptoms of sleep apnea in 1,475 individuals of European descent. We identified 17 rare genetic variants with at least suggestive evidence of significance. Replication in an independent dataset confirmed the association of a rare genetic variant (rs2229918; minor allele frequency = 0.3%) with symptoms of sleep apnea (p-valuemeta = 6.98 × 10-9, ßmeta = 0.99). Rs2229918 overlaps with the 3' untranslated regions of ERCC1 and CD3EAP genes on chromosome 19q13. Both genes are expressed in tissues in the neck area, such as the tongue, muscles, cartilage and the trachea. Further, CD3EAP is localized in the nucleus and mitochondria and involved in the tumor necrosis factor-alpha/nuclear factor kappa B signaling pathway. Our results and biological functions of CD3EAP/ERCC1 genes suggest that the 19q13 locus is interesting for further OSA research.

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