Distinct and Synergistic Contributions of Epithelial Stress and Adaptive Immunity to Functions of Intraepithelial Killer Cells and Active Celiac Disease.

Background & Aims: The mechanisms of tissue destruction during progression of celiac disease are poorly defined. It is not clear how tissue stress and adaptive immunity contribute to the activation of intraepithelial cytotoxic T cells and the development of villous atrophy. We analyzed epithelial cells and intraepithelial cytotoxic T cells in family members of patients with celiac disease, who were without any signs of adaptive antigluten immunity, and in potential celiac disease patients, who have antibodies against tissue transglutaminase 2 in the absence of villous atrophy.

Platinum sensitivity-related germline polymorphism discovered via a cell-based approach and analysis of its association with outcome in ovarian cancer patients.

Purpose: Cell-based approaches were used to identify genetic markers predictive of patients' risk for poor response prior to chemotherapy.

Experimental Design: We conducted genome-wide association studies (GWAS) to identify single-nucleotide polymorphisms (SNP) associated with cellular sensitivity to carboplatin through their effects on mRNA expression using International HapMap lymphoblastoid cell lines (LCL) and replicated them in additional LCLs. SNPs passing both stages of the cell-based study were tested for association with progression-free survival (PFS) in patients.

PACdb: a database for cell-based pharmacogenomics.

We have developed Pharmacogenomics And Cell database (PACdb), a results database that makes available relationships between single nucleotide polymorphisms, gene expression, and cellular sensitivity to various drugs in cell-based models to help determine genetic variants associated with drug response. The current version also supports summary analysis on differentially expressed genes between the HapMap samples of European and African ancestry, as well as queries for summary information of correlations between gene expression and pharmacological phenotypes. At present, data generated on the following anticancer agents are included: carboplatin, cisplatin, etoposide, daunorubicin, and cytarabine (Ara-C).

SCAN: SNP and copy number annotation.

Motivation: Genome-wide association studies (GWAS) generate relationships between hundreds of thousands of single nucleotide polymorphisms (SNPs) and complex phenotypes. The contribution of the traditionally overlooked copy number variations (CNVs) to complex traits is also being actively studied. To facilitate the interpretation of the data and the designing of follow-up experimental validations, we have developed a database that enables the sensible prioritization of these variants by combining several approaches, involving not only publicly available physical and functional annotations but also multilocus linkage disequilibrium (LD) annotations as well as annotations of expression quantitative trait loci (eQTLs).

Common variants at five new loci associated with early-onset inflammatory bowel disease.

The inflammatory bowel diseases (IBD) Crohn's disease and ulcerative colitis are common causes of morbidity in children and young adults in the western world. Here we report the results of a genome-wide association study in early-onset IBD involving 3,426 affected individuals and 11,963 genetically matched controls recruited through international collaborations in Europe and North America, thereby extending the results from a previous study of 1,011 individuals with early-onset IBD. We have identified five new regions associated with early-onset IBD susceptibility, including 16p11 near the cytokine gene IL27 (rs8049439, P = 2.

{beta}3-integrin expression on tumor cells inhibits tumor progression, reduces metastasis, and is associated with a favorable prognosis in patients with ovarian cancer.

The role of the vitronectin receptor (alpha(v)beta(3)-integrin) as a tumor promoter seems well established, and, consequently, therapies that block this integrin are currently in clinical testing. We undertook the current study to determine whether alpha(v)beta(3)-integrin is an appropriate target in ovarian cancer treatment. Expression of beta(3)-integrin in SKOV3ip1 ovarian cancer cells led to the overexpression of alpha(v)beta(3)-integrin on the cell surface and increased adhesion.

Frequency of failure to inform patients of clinically significant outpatient test results.

Background: Failing to inform a patient of an abnormal outpatient test result can be a serious error, but little is known about the frequency of such errors or the processes for managing results that may reduce errors.

Methods: We conducted a retrospective medical record review of 5434 randomly selected patients aged 50 to 69 years in 19 community-based and 4 academic medical center primary care practices. Primary care practice physicians were surveyed about their processes for managing test results, and individual physicians were notified of apparent failures to inform and asked whether they had informed the patient.

Using cases and parents to study multiplicative gene-by-environment interaction.

With case-parent triads, one can estimate genotype relative risks by measuring the apparent overtransmission of susceptibility genotypes from parents to affected offspring. Results obtained using such designs, properly analyzed, resist both bias due to population structure and bias due to self-selection. Most diseases are not purely genetic, and environmental cofactors can also be important.

Expression and alternative splicing of folate pathway genes in HapMap lymphoblastoid cell lines.

Aim: Folate is vital for cell growth and development through its important role in one-carbon metabolism - an essential process in the synthesis of amino acids and nucleic acids. Folate pathway genes have been considered as therapeutic targets of drugs for the treatment of cancer and other diseases. Racial and ethnic disparities of folate metabolism and outcome of antifolate therapies have been reported.

Ulcerative colitis-risk loci on chromosomes 1p36 and 12q15 found by genome-wide association study.

Ulcerative colitis is a chronic inflammatory disease of the colon that presents as diarrhea and gastrointestinal bleeding. We performed a genome-wide association study using DNA samples from 1,052 individuals with ulcerative colitis and preexisting data from 2,571 controls, all of European ancestry. In an analysis that controlled for gender and population structure, ulcerative colitis loci attaining genome-wide significance and subsequent replication in two independent populations were identified on chromosomes 1p36 (rs6426833, combined P = 5.

Population-specific genetic variants important in susceptibility to cytarabine arabinoside cytotoxicity.

Cytarabine arabinoside (ara-C) is an antimetabolite used to treat hematologic malignancies. Resistance is a common reason for treatment failure with adverse side effects contributing to morbidity and mortality. Identification of genetic factors important in susceptibility to ara-C cytotoxicity may allow for individualization of treatment.

Identification of genomic regions contributing to etoposide-induced cytotoxicity.

Etoposide is routinely used in combination-based chemotherapy for testicular cancer and small-cell lung cancer; however, myelosuppression, therapy-related leukemia and neurotoxicity limit its utility. To determine the genetic contribution to cellular sensitivity to etoposide, we evaluated cell growth inhibition in Centre d' Etude du Polymorphisme Humain lymphoblastoid cell lines from 24 multi-generational pedigrees (321 samples) following treatment with 0.02-2.

Dynamic contrast-enhanced magnetic resonance imaging pharmacodynamic biomarker study of sorafenib in metastatic renal carcinoma.

Purpose: Sorafenib is an antiangiogenic agent with activity in renal cancer. We conducted a randomized trial to investigate dynamic contrast magnetic resonance imaging (DCE-MRI) as a pharmacodynamic biomarker.

Patients And Methods: Patients were randomly assigned to placebo or 200 or 400 mg twice per day of sorafenib.

Genetic variants associated with carboplatin-induced cytotoxicity in cell lines derived from Africans.

To gain a better understanding of the genetic variants associated with carboplatin-induced cytotoxicity in individuals of African descent, we present a step-wise approach integrating genotypes, gene expression, and sensitivity of HapMap cell lines to carboplatin. Cell lines derived from 30 trios of African descent (YRI) were used to develop a preclinical model to identify genetic variants and gene expression that contribute to carboplatin-induced cytotoxicity. Cytotoxicity was determined as cell growth inhibition at increasing concentrations of carboplatin for 72 h.

Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease.

Several risk factors for Crohn's disease have been identified in recent genome-wide association studies. To advance gene discovery further, we combined data from three studies on Crohn's disease (a total of 3,230 cases and 4,829 controls) and carried out replication in 3,664 independent cases with a mixture of population-based and family-based controls. The results strongly confirm 11 previously reported loci and provide genome-wide significant evidence for 21 additional loci, including the regions containing STAT3, JAK2, ICOSLG, CDKAL1 and ITLN1.

Identification of genetic variants and gene expression relationships associated with pharmacogenes in humans.

Objectives: The very important pharmacogenes (VIPs) were selected by Pharmacogenetic Research Network (National Institutes of Health-PGRN) owing to their significant effects on drug treatment both at the pharmacokinetic and pharmacodynamic levels. Our objective was to identify single nucleotide polymorphisms (SNPs) that potentially affected the expression of these genes or potential SNP-gene interactions involved to improve our understanding of genetic effects on drug therapy.

Basic Methods: Gene expression was evaluated in 176 International HapMap lymphoblastoid cell lines derived from CEU (CEPH, Utah residents with ancestry from northern and western Europe; n=87) and YRI (Yoruba in Ibadan, Nigeria; n=89) using Affymetrix GeneChip Human Exon 1.

Genetic variants contributing to daunorubicin-induced cytotoxicity.

Identifying heritable genetic variants responsible for chemotherapeutic toxicities has been challenging due in part to its multigenic nature. To date, there is a paucity of data on genetic variants associated with patients experiencing severe myelosuppression or cardiac toxicity following treatment with daunorubicin. We present a genome-wide model using International HapMap cell lines that integrate genotype and gene expression to identify genetic variants that contribute to daunorubicin-induced cytotoxicity.

Loss of E-cadherin promotes ovarian cancer metastasis via alpha 5-integrin, which is a therapeutic target.

E-cadherin loss is frequently associated with ovarian cancer metastasis. Given that adhesion to the abdominal peritoneum is the first step in ovarian cancer dissemination, we reasoned that down-regulation of E-cadherin would affect expression of cell matrix adhesion receptors. We show here that inhibition of E-cadherin in ovarian cancer cells causes up-regulation of alpha(5)-integrin protein expression and transcription.

Transmission disequilibrium testing of the chromosome 15q11-q13 region in autism.

Evidence implicates the serotonin transporter gene (SLC6A4) and the 15q11-q13 genes as candidates for autism as well as restricted repetitive behavior (RRB). We conducted dense transmission disequilibrium mapping of the 15q11-q13 region with 93 single nucleotide polymorphisms (SNPs) in 86 strictly defined autism trios and tested association between SNPs and autism using the transmission disequilibrium test (TDT). As exploratory analyses, parent-of-origin effects were examined using likelihood-ratio tests (LRTs) and genotype-phenotype associations for specific RRB using the Family-Based Association Test (FBAT).

Evaluation of genetic variation contributing to differences in gene expression between populations.

Gene expression is a complex quantitative trait partially regulated by genetic variation in DNA sequence. Population differences in gene expression could contribute to some of the observed differences in susceptibility to common diseases and response to drug treatments. We characterized gene expression in the full set of HapMap lymphoblastoid cell lines derived from individuals of European and African ancestry for 9156 transcript clusters (gene-level) evaluated with the Affymetrix GeneChip Human Exon 1.

Identification of genetic variants contributing to cisplatin-induced cytotoxicity by use of a genomewide approach.

Cisplatin, a platinating agent commonly used to treat several cancers, is associated with nephrotoxicity, neurotoxicity, and ototoxicity, which has hindered its utility. To gain a better understanding of the genetic variants associated with cisplatin-induced toxicity, we present a stepwise approach integrating genotypes, gene expression, and sensitivity of HapMap cell lines to cisplatin. Cell lines derived from 30 trios of European descent (CEU) and 30 trios of African descent (YRI) were used to develop a preclinical model to identify genetic variants and gene expression that contribute to cisplatin-induced cytotoxicity in two different populations.

Let-7 expression defines two differentiation stages of cancer.

The early phases of carcinogenesis resemble embryonic development, often involving the reexpression of embryonic mesenchymal genes. The NCI60 panel of human tumor cell lines can genetically be subdivided into two superclusters (SCs) that correspond to CD95 Type I and II cells. SC1 cells are characterized by a mesenchymal and SC2 cells by an epithelial gene signature, suggesting that SC1 cells represent less differentiated, advanced stages of cancer.

A genome-wide approach to identify genetic variants that contribute to etoposide-induced cytotoxicity.

Large interindividual variance has been observed in sensitivity to drugs. To comprehensively decipher the genetic contribution to these variations in drug susceptibility, we present a genome-wide model using human lymphoblastoid cell lines from the International HapMap consortium, of which extensive genotypic information is available, to identify genetic variants that contribute to chemotherapeutic agent-induced cytotoxicity. Our model integrated genotype, gene expression, and sensitivity of HapMap cell lines to drugs.

Genetic polymorphisms in transforming growth factor beta-1 (TGFB1) and childhood asthma and atopy.

Transforming growth factor beta-1 (TGFB1) may influence asthma by modulating allergic airway inflammation and airway remodeling. The role of single nucleotide polymorphisms (SNPs) of TGFB1 in asthma remains inconclusive. We examined TGFB1 SNPs in relation to asthma risk and degree of atopy among 546 case-parent triads, consisting of asthmatics aged 4-17 years and their parents in Mexico City.

c-Met overexpression is a prognostic factor in ovarian cancer and an effective target for inhibition of peritoneal dissemination and invasion.

The hepatocyte growth factor receptor c-Met is a receptor tyrosine kinase that plays an important role in tumor growth by activating mitogenic signaling pathways. The goal of this study was to evaluate the role of c-Met in the biology of ovarian cancer and to determine its potential as a therapeutic target. c-Met protein expression was detected by immunohistochemistry in 138 advanced-stage ovarian cancers using a tissue microarray annotated with disease-specific patient follow-up.