StraplineThe National Center for Biotechnology Information has created the dbGaP public repository for individual-level phenotype, exposure, genotype, and sequence data, and the associations between them. dbGaP assigns stable, unique identifiers to studies and subsets of information from those studies, including documents, individual phenotypic variables, tables of trait data, sets of genotype data, computed phenotype-genotype associations and groups of study subjects who have given similar consents for use of their data. IntroductionThe technical advances and declining costs for high-throughput genotyping afford investigators fresh opportunities to do increasingly complex analyses of genetic associations with phenotypic and disease characteristics. The leading candidates for such genome wide association studies (GWAS) are existing large-scale cohort and clinical studies that collected rich sets of phenotype data. To support investigator access to data from these initiatives at the National Institutes of Health (NIH) and elsewhere, the National Center for Biotechnology Information (NCBI) has created a database of Genotypes and Phenotypes (dbGaP) with stable identifiers that make it possible for published studies to discuss or cite the primary data in a specific and uniform way. dbGaP provides unprecedented access to the large-scale genetic and phenotypic datasets required for GWAS designs, including public access to study documents linked to summary data on specific phenotype variables, statistical overviews of the genetic information, position of published associations on the genome, and authorized access to individual-level data.The purposes of this description of dbGaP are three-fold: (1) to describe dbGaP's functionality for users and submitters; (2) to describe dbGaP's design and operational processes for database methodologists to emulate or improve upon; and (3) to reassure the lay and scientific public that individual-level phenotype and genotype data are securely and responsibly managed. dbGaP accommodates studies of varying design. It contains four basic types of data: (1) Study documentation, including study descriptions, protocol documents, and data collection instruments, such as questionnaires; (2) Phenotypic data for each variable assessed, at both an individual level and in summary form; (3) Genetic data, including study subjects' individual genotypes, pedigree information, fine mapping results, and resequencing traces; and (4) Statistical results, including association and linkage analyses, when available.Address editorial correspondence to: Stephen Sherry, PhD, National Center for Biotechnology Information, 8600 Rockville Pike, MSC 3804, Bethesda, MD 20894-3804, phone: 301-435-7799, fax: 301-480-5789, e-mail: sherry@ncbi.nlm To protect the confidentiality of study subjects, dbGaP accepts only de-identified data and requires investigators to go through an authorization process in order to access individual-level phenotype and genotype datasets. Summary phenotype and genotype data, as well as stu...

Inhibitors of histone deacetylases (HDACs) induce growth arrest, differentiation, and apoptosis of colon cancer cell lines in vitro and have demonstrated anti-cancer efficacy in clinical trials. Whereas a role for HDAC1 and -2 in mediating components of the HDAC inhibitor response has been reported, the role of HDAC3 is unknown. Here we demonstrate increased protein expression of HDAC3 in human colon tumors and in duodenal adenomas from Apc1638 N/؉ mice. HDAC3 was also maximally expressed in proliferating crypt cells in normal intestine. Silencing of HDAC3 expression in colon cancer cell lines resulted in growth inhibition, a decrease in cell survival, and increased apoptosis. Similar effects were observed for HDAC2 and, to a lesser extent, for HDAC1. HDAC3 silencing also selectively induced expression of alkaline phosphatase, a marker of colon cell maturation. Concurrent with its effect on cell growth, overexpression of HDAC3 and other Class I HDACs inhibited basal and butyrate-induced p21 transcription in a Sp1/Sp3-dependent manner, whereas silencing of HDAC3 stimulated p21 promoter activity and expression. However, the magnitude of the effects elicited by silencing of individual Class I HDACs was significantly less than that induced by HDAC inhibitors. These findings identify HDAC3 as a gene deregulated in human colon cancer and as a novel regulator of colon cell maturation and p21 expression. These findings also demonstrate that multiple Class I HDACs are involved in repressing p21 and suggest that the growthinhibitory and apoptotic effects induced by HDAC inhibitors are probably mediated through the inhibition of multiple HDACs.Acetylation of DNA-bound core histones and sequence-specific transcription factors is a fundamental mechanism of transcriptional regulation. Histone acetylation is typically associated with increased transcription (1) and is regulated by two opposing classes of enzymes: histone acetyltransferases, which add acetyl groups to specific amino acids of the histone protein, and histone deacetylases (HDACs), 2 which catalyze their removal. A second mechanism by which HDACs may regulate gene transcription is by regulating acetylation of DNA sequence-specific transcription factors. Examples include p53, E2F, and Sp3, where deacetylation has been linked to reduced DNA binding or transcriptional activity (2-4). Through these mechanisms, HDACs are emerging as critical regulators of cell growth, differentiation, and apoptotic programs. We and others have demonstrated that inhibitors of HDACs, such as sodium butyrate, trichostatin A (TSA), suberoylanilide hydroxamic acid (SAHA), and valproic acid, induce cell cycle arrest, differentiation, and apoptosis in colon cancer cell lines in vitro (5-10). These observations suggest a physiological role for transcriptional repression mediated by HDACs in maintaining cell proliferation and survival and inhibiting differentiation. Correspondingly, the deregulation of HDAC-mediated transcriptional repression has been linked to tumorigenesis. The up-regulated e...

The Database of Genotypes and Phenotypes (dbGap, http://www.ncbi.nlm.nih.gov/gap) is a National Institutes of Health-sponsored repository charged to archive, curate and distribute information produced by studies investigating the interaction of genotype and phenotype. Information in dbGaP is organized as a hierarchical structure and includes the accessioned objects, phenotypes (as variables and datasets), various molecular assay data (SNP and Expression Array data, Sequence and Epigenomic marks), analyses and documents. Publicly accessible metadata about submitted studies, summary level data, and documents related to studies can be accessed freely on the dbGaP website. Individual-level data are accessible via Controlled Access application to scientists across the globe.