Time filter

Source Type

Grassi M.A.,University of Chicago | Grassi M.A.,University of Illinois at Chicago | Tikhomirov A.,University of Chicago | Ramalingam S.,Molecular Therapeutics | And 7 more authors.
Investigative Ophthalmology and Visual Science

PURPOSE. The purpose of this study is to attempt to replicate the top single nucleotide polymorphism (SNP) associations from a previous genome-wide association study (GWAS) for the sight-threatening complications of diabetic retinopathy in an independent cohort of diabetic subjects from the Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR). METHODS. This study included 469 type 1 diabetic, Caucasian subjects from WESDR. Cases (n = 208) were defined by prior laser treatment for either proliferative diabetic retinopathy or diabetic macular edema. Controls (n = 261) were all other subjects in the cohort. Three hundred eighty-nine SNPs were tested for association using the Illumina GoldenGate custom array. A retinopathy-only subanalysis was conducted in 437 subjects by removing those with end-stage renal disease. Evaluation for association between cases and controls was conducted by using chi-square tests. A combined analysis incorporated the results from WESDR with the prior GWAS. RESULTS. No associations were significant at a genome-wide level. The analysis did identify SNPs that can be pursued in future replication studies. The top association was at rs4865047, an intronic SNP, in the gene CEP135 (P value 2.06×10 -5). The top association from the subanalysis was at rs1902491 (P value 2.81 ×10 -5), a SNP that sits upstream of the gene NPY2R. CONCLUSIONS. This study nominates several novel genetic loci that may be associated with severe diabetic retinopathy. In order to confirmthese findings, replication and extension in additional cohorts will be necessary as susceptibility alleles for diabetic retinopathy appear to be of modest effect. © 2012 The Association for Research in Vision and Ophthalmology, Inc. Source

Nguyen D.Q.,Bristol Eye Hospital | Hosseini M.,Genetics and Genome Biology Program | Billingsley G.,Genetics and Genome Biology Program | Heon E.,Genetics and Genome Biology Program | And 2 more authors.
Acta Ophthalmologica

Purpose: To describe the clinical phenotype in a family with posterior polymorphous corneal dystrophy (PPCD) and a novel mutation in the ZEB1 gene. Methods: Clinical examination, anterior segment photography, specular microscopy and electrophysiological investigations were performed and quantified. Genomic DNA extracted from peripheral blood was sequenced for ZEB1 exons. Cosegregation of identified mutation with the disease status in the family was confirmed using polymerase chain reaction and restriction fragment length polymorphism. Results: Ocular examination was performed on five family members from two generations. Three had anomalies of the corneal endothelium that were consistent with PPCD. Endothelial cell counts ranged from 2306 to 2987 mm2 (ref. 2000-4000 cells/mm2). No evidence of glaucoma or retinal abnormalities was observed. Extraocular abnormalities such as inguinal herniation, hydrocoele and possible bony or connective tissue anomalies were part of the disease spectrum in this family. Mutation analysis revealed a novel change in exon 5 of ZEB1 (c.672delA) that cosegregated with the affected disease status. Conclusion: The detailed clinical features of PPCD associated with a novel ZEB1 mutation are supportive of the previously proposed range of phenotype parameters. Further phenotype-genotype correlations may provide insights into the clinical variability and pathological processes affecting the corneal endothelium, Descemet's membrane, retinal photoreceptor function and extraocular tissues of some patients. © 2009 Acta Ophthalmol. Source

Fussner E.,Genetics and Genome Biology Program | Ahmed K.,Genetics and Genome Biology Program | Dehghani H.,Ferdowsi University of Mashhad | Strauss M.,Max Planck Institute | Bazett-Jones D.P.,Genetics and Genome Biology Program
Cold Spring Harbor Symposia on Quantitative Biology

Extensive alterations in chromatin structure at the nucleosome level are linked to developmental potential. We hypothesize that such alterations in chromatin structure reflect and, to some extent, depend on the large-scale reorganization of the nuclear landscape. We have used electron spectroscopic imaging (ESI) to visualize chromatin organization at the mesoscale level of resolution in both pluripotent and differentiated cell types. Pluripotent cells are characterized by a highly dispersed mesh of 10-nm chromatin fibers that fill the nuclear volume. In contrast, differentiated cells display a propensity to form compact chromatin domains that lead to large regions of the nucleus devoid of DNA. Surprisingly, ESI combined with tomography methods reveals that the compact chromatin domains consist of 10-nm rather than 30-nm chromatin fibers. We propose that the transition between compact silent chromatin and open transcriptionally poised or active chromatin is based on the modulation of the packing density of 10-nm fibers rather than a transition between 10- and 30-nm fiber types. © 2010 Cold Spring Harbor Laboratory Press. Source

Ahmed K.,Genetics and Genome Biology Program | Dehghani H.,Ferdowsi University of Mashhad | Rugg-Gunn P.,Hubrecht Institute for Developmental Biology and Stem Cell Research | Fussner E.,Genetics and Genome Biology Program | And 2 more authors.

An open chromatin architecture devoid of compact chromatin is thought to be associated with pluripotency in embryonic stem cells. Establishing this distinct epigenetic state may also be required for somatic cell reprogramming. However, there has been little direct examination of global structural domains of chromatin during the founding and loss of pluripotency that occurs in preimplantation mouse development. Here, we used electron spectroscopic imaging to examine large-scale chromatin structural changes during the transition from one-cell to early postimplantation stage embryos. In one-cell embryos chromatin was extensively dispersed with no noticeable accumulation at the nuclear envelope. Major changes were observed from one-cell to two-cell stage embryos, where chromatin became confined to discrete blocks of compaction and with an increased concentration at the nuclear envelope. In eight-cell embryos and pluripotent epiblast cells, chromatin was primarily distributed as an extended meshwork of uncompacted fibres and was indistinguishable from chromatin organization in embryonic stem cells. In contrast, lineage-committed trophectoderm and primitive endoderm cells, and the stem cell lines derived from these tissues, displayed higher levels of chromatin compaction, suggesting an association between developmental potential and chromatin organisation. We examined this association in vivo and found that deletion of Oct4, a factor required for pluripotency, caused the formation of large blocks of compact chromatin in putative epiblast cells. Together, these studies show that an open chromatin architecture is established in the embryonic lineages during development and is sufficient to distinguish pluripotent cells from tissue-restricted progenitor cells. © 2010 Ahmed et al. Source

Rzeczkowska P.A.,Burton | Rzeczkowska P.A.,University of Toronto | Hou H.,Genetics and Genome Biology Program | Wilson M.D.,Genetics and Genome Biology Program | And 2 more authors.

All reproductively competent adults have gone through puberty. While key genes and signaling pathways that lead to the onset of sexual maturation are known, the molecular mechanisms that determine when an individual enters puberty are only beginning to be understood. Both genetic and environmental factors determine the timing of puberty. New advances in understanding how environmentally sensitive, yet highly heritable developmental processes are regulated have come from the field of epigenetics. Of note, studies investigating the epigenetic control of the onset of puberty suggest that epigenetic repression of key inhibitory loci may play a fundamental role in the initiation of puberty. Current technologies that not only read out the DNA sequence, but also determine how the DNA is modified in response to the environment, promise new insight into how puberty is regulated, including the identification and understanding of gene regulatory networks that control the biological pathways affecting pubertal timing. Here we review the findings to date and discuss how epigenetic investigation can further our understanding of this fundamental aspect of human development. © 2014 S. Karger AG, Basel. Source

Discover hidden collaborations