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1.
Mod Pathol ; : 100540, 2024 Jun 18.
Article in English | MEDLINE | ID: mdl-38901674

ABSTRACT

Nephrogenic adenoma is a benign, reactive lesion seen predominantly in the urinary bladder and often associated with an antecedent inflammation, instrumentation, or operative history. Its histopathological diversity can create diagnostic dilemmas and pathologists utilize morphological evaluation along with available immunohistochemical markers to navigate these challenges. Immunohistochemical assays currently do not designate or specify nephrogenic adenoma's potential putative cell of origin. Leveraging single-cell RNA sequencing technology, we nominated a principal cell collecting duct marker, L1 cell adhesion molecule (L1CAM), as a potential biomarker for nephrogenic adenoma. Immunohistochemical characterization revealed L1CAM to be positive in all 35 (100%) patient samples of nephrogenic adenoma; negative expression was seen in the benign urothelium, benign prostatic glands, urothelial carcinoma in situ, prostatic adenocarcinoma, majority of high-grade urothelial carcinoma, and metastatic urothelial carcinoma. In the study, we also utilized single-cell RNA sequencing to nominate a novel compendium of biomarkers specific for proximal tubule, loop of Henle, and distal tubule (including principal and intercalated cells) which can be used to perform nephronal mapping utilizing RNA in situ hybridization and immunohistochemistry technology. Employing this technique on nephrogenic adenoma we found enrichment of both principal cell marker L1CAM and, the proximal tubule types-A and -B cells markers, PDZKI1P1 and PIGR respectively. The cell type markers for the intercalated cell of distal tubules (LINC01187 and FOXI1), and the loop of Henle (UMOD and IRX5), were found to be uniformly absent in nephrogenic adenoma. Overall, our findings show that based on cell type-specific implications of L1CAM expression, the shared expression pattern of L1CAM between distal tubule principal cell (P) cells and nephrogenic adenoma. L1CAM expression will be of potential value in assisting surgical pathologists towards a diagnosis of nephrogenic adenoma in challenging patient samples.

2.
Am J Surg ; 230: 39-42, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38052669

ABSTRACT

BACKGROUND: Studies have shown that patients with abdominal pain and biliary dyskinesia (low ejection fraction <35 â€‹%) have significant improvement of symptoms following laparoscopic cholecystectomy, but there is lack of evidence that demonstrates whether patients with biliary symptoms and a normal ejection fraction (>35 â€‹%) will have similar results. METHODS: Retrospective, single center study of patients with biliary pain and negative workup, including HIDA with EF>35 â€‹%, who were treated with laparoscopic cholecystectomy from 2017 to 2022. RESULTS: There were 117 total patients. The mean age was 45.49 â€‹± â€‹15.5 years and 101 (86 â€‹%) were female. 101 (86 â€‹%) of patients underwent a right upper quadrant ultrasound, 91 had normal findings, 9 difficult to visualize anatomy and 1 had adenomyomatosis. All patients had a normal HIDA scan and ejection fraction 104 (89 â€‹%) of patients followed up in clinic within 30 days of surgical intervention. 87 (84 â€‹%) reported resolution of pre-operative symptomatology after surgical intervention. There was no statistically significant correlation between pain with CCK administration during HIDA (p â€‹= â€‹0.803) scan or ejection fraction (p â€‹= â€‹0.0977) with resolution of symptoms. CONCLUSIONS: Laparoscopic cholecystectomy appears to be a beneficial intervention for patients with abdominal pain and normokinetic biliary disease. Offering surgical intervention early on can potentially save patients from exhaustive diagnostic investigations and possibly misdiagnosis.


Subject(s)
Biliary Dyskinesia , Cholecystectomy, Laparoscopic , Gallbladder Diseases , Humans , Female , Adult , Middle Aged , Male , Cholecystectomy, Laparoscopic/adverse effects , Cholecystectomy, Laparoscopic/methods , Retrospective Studies , Imino Acids , Biliary Dyskinesia/diagnosis , Biliary Dyskinesia/surgery , Gallbladder Diseases/surgery , Abdominal Pain/etiology , Treatment Outcome
3.
Environ Int ; 183: 108339, 2024 Jan.
Article in English | MEDLINE | ID: mdl-38043319

ABSTRACT

Cardiometabolic disorders (CMD) are a growing public health problem across the world. Among the known cardiometabolic risk factors are compounds that induce endocrine and metabolic dysfunctions, such as endocrine disrupting chemicals (EDCs). To date, how EDCs influence molecular programs and cardiometabolic risks has yet to be fully elucidated, especially considering the complexity contributed by species-, chemical-, and dose-specific effects. Moreover, different experimental and analytical methodologies employed by different studies pose challenges when comparing findings across studies. To explore the molecular mechanisms of EDCs in a systematic manner, we established a data-driven computational approach to meta-analyze 30 human, mouse, and rat liver transcriptomic datasets for 4 EDCs, namely bisphenol A (BPA), bis(2-ethylhexyl) phthalate (DEHP), tributyltin (TBT), and perfluorooctanoic acid (PFOA). Our computational pipeline uniformly re-analyzed pre-processed quality-controlled microarray data and raw RNAseq data, derived differentially expressed genes (DEGs) and biological pathways, modeled gene regulatory networks and regulators, and determined CMD associations based on gene overlap analysis. Our approach revealed that DEHP and PFOA shared stable transcriptomic signatures that are enriched for genes associated with CMDs, suggesting similar mechanisms of action such as perturbations of peroxisome proliferator-activated receptor gamma (PPARγ) signaling and liver gene network regulators VNN1 and ACOT2. In contrast, TBT exhibited highly divergent gene signatures, pathways, network regulators, and disease associations from the other EDCs. In addition, we found that the rat, mouse, and human BPA studies showed highly variable transcriptomic patterns, providing molecular support for the variability in BPA responses. Our work offers insights into the commonality and differences in the molecular mechanisms of various EDCs and establishes a streamlined data-driven workflow to compare molecular mechanisms of environmental substances to elucidate the underlying connections between chemical exposure and disease risks.


Subject(s)
Cardiovascular Diseases , Diethylhexyl Phthalate , Endocrine Disruptors , Phenols , Humans , Mice , Rats , Animals , Transcriptome , Gene Regulatory Networks , Endocrine Disruptors/metabolism , Gene Expression Profiling , Liver/metabolism , Benzhydryl Compounds
4.
Surgery ; 175(3): 671-676, 2024 Mar.
Article in English | MEDLINE | ID: mdl-37891061

ABSTRACT

BACKGROUND: Same-day discharge after mastectomy has potential patient- and hospital-level benefits; however, few data are available regarding factors affecting the likelihood of same-day discharge in order to address barriers. We sought to evaluate factors contributing to same-day discharge, focusing on the timing of mastectomy during the operative day. METHODS: We conducted a single-institution retrospective review of patients who underwent mastectomies for malignancy over a 3-y time frame. Clinicopathologic variables were collected along with a binary variable for mastectomy start time (morning versus afternoon). Our primary endpoint was rate of same-day discharge. A multivariable logistic regression model was constructed from significant univariate variables to determine independent predictors of same-day discharge. A secondary endpoint was a cost-utility analysis for morning versus afternoon start time, using hospital cost data. RESULTS: There were 451 patients included in the analysis. Factors associated with same-day discharge rate included the American Society of Anesthesiologists score, use of a preoperative regional anesthesia block, type of mastectomy performed, individual surgeon variation, and a morning start for the mastectomy. On multivariable analysis, morning start was a strong independent predictor of same-day discharge (odd ratio = 2.83; 95% CI, 1.75-4.60). The cost-utility analysis favored a morning start, with average cost savings of $550 per patient. CONCLUSION: Despite patient- and surgeon-specific variations, simple scheduling policies can improve same-day discharge rates after mastectomy, leading to improved hospital bed use and cost reduction.


Subject(s)
Breast Neoplasms , Mastectomy , Humans , Female , Breast Neoplasms/surgery , Cost Savings , Ambulatory Surgical Procedures , Patient Discharge , Retrospective Studies
5.
Elife ; 122023 Dec 07.
Article in English | MEDLINE | ID: mdl-38060277

ABSTRACT

Mouse models have been used extensively to study human coronary artery disease (CAD) or atherosclerosis and to test therapeutic targets. However, whether mouse and human share similar genetic factors and pathogenic mechanisms of atherosclerosis has not been thoroughly investigated in a data-driven manner. We conducted a cross-species comparison study to better understand atherosclerosis pathogenesis between species by leveraging multiomics data. Specifically, we compared genetically driven and thus CAD-causal gene networks and pathways, by using human GWAS of CAD from the CARDIoGRAMplusC4D consortium and mouse GWAS of atherosclerosis from the Hybrid Mouse Diversity Panel (HMDP) followed by integration with functional multiomics human (STARNET and GTEx) and mouse (HMDP) databases. We found that mouse and human shared >75% of CAD causal pathways. Based on network topology, we then predicted key regulatory genes for both the shared pathways and species-specific pathways, which were further validated through the use of single cell data and the latest CAD GWAS. In sum, our results should serve as a much-needed guidance for which human CAD-causal pathways can or cannot be further evaluated for novel CAD therapies using mouse models.


Subject(s)
Atherosclerosis , Coronary Artery Disease , Humans , Mice , Animals , Coronary Artery Disease/genetics , Atherosclerosis/genetics , Gene Regulatory Networks , Genome-Wide Association Study/methods , Polymorphism, Single Nucleotide , Genetic Predisposition to Disease
6.
bioRxiv ; 2023 Sep 20.
Article in English | MEDLINE | ID: mdl-37333408

ABSTRACT

Mouse models have been used extensively to study human coronary artery disease (CAD) or atherosclerosis and to test therapeutic targets. However, whether mouse and human share similar genetic factors and pathogenic mechanisms of atherosclerosis has not been thoroughly investigated in a data-driven manner. We conducted a cross-species comparison study to better understand atherosclerosis pathogenesis between species by leveraging multiomics data. Specifically, we compared genetically driven and thus CAD-causal gene networks and pathways, by using human GWAS of CAD from the CARDIoGRAMplusC4D consortium and mouse GWAS of atherosclerosis from the Hybrid Mouse Diversity Panel (HMDP) followed by integration with functional multiomics human (STARNET and GTEx) and mouse (HMDP) databases. We found that mouse and human shared >75% of CAD causal pathways. Based on network topology, we then predicted key regulatory genes for both the shared pathways and species-specific pathways, which were further validated through the use of single cell data and the latest CAD GWAS. In sum, our results should serve as a much-needed guidance for which human CAD-causal pathways can or cannot be further evaluated for novel CAD therapies using mouse models.

7.
BMJ Case Rep ; 15(11)2022 Nov 15.
Article in English | MEDLINE | ID: mdl-36379636

ABSTRACT

Histoplasmosis is a systemic infection caused by the fungus, Histoplasma capsulatum Infection of H. capsulatum frequently occurs by inhaling the spores of the fungus, which is found in bat and bird droppings, or soil enriched with their excrement. If not detected and treated, histoplasmosis can develop late, severe complications such as mediastinal fibrosis, or even develop into a disseminated infection. However, histoplasmosis infections are often asymptomatic, making its detection more difficult. Further, only 6% of histoplasmosis cases will present with erythema nodosum, with most cases associated with female patients. This case presents a woman in her 50s with a pertinent history of fibromyalgia and hypothyroidism secondary to Hashimoto's who initially sought medical care for painful nodules on her legs and was eventually diagnosed with histoplasmosis. This report clearly demonstrates the importance of maintaining a broad differential when working up inflammatory manifestations, such as erythema nodosum.


Subject(s)
Erythema Nodosum , Histoplasmosis , Humans , Female , Histoplasmosis/complications , Histoplasmosis/diagnosis , Histoplasmosis/drug therapy , Histoplasma , Erythema Nodosum/etiology , Erythema Nodosum/complications
8.
Front Integr Neurosci ; 12: 52, 2018.
Article in English | MEDLINE | ID: mdl-30405367

ABSTRACT

The incidence of oral cancer in the United States is increasing, especially in young people and women. Patients with oral cancer report severe functional pain. Using a patient cohort accrued through the New York University Oral Cancer Center and immune-competent mouse models, we identify a sex difference in the prevalence and severity of oral cancer pain. A neutrophil-mediated endogenous analgesic mechanism is present in male mice with oral cancer. Local naloxone treatment potentiates cancer mediator-induced orofacial nociceptive behavior in male mice only. Tongues from male mice with oral cancer have significantly more infiltrating neutrophils compared to female mice with oral cancer. Neutrophils isolated from the cancer-induced inflammatory microenvironment express beta-endorphin and met-enkephalin. Furthermore, neutrophil depletion results in nociceptive behavior in male mice. These data suggest a role for sex-specific, immune cell-mediated endogenous analgesia in the treatment of oral cancer pain.

9.
Proc Natl Acad Sci U S A ; 114(45): E9655-E9664, 2017 11 07.
Article in English | MEDLINE | ID: mdl-29078374

ABSTRACT

Chronic obstructive pulmonary disease (COPD) has been linked to particulate matter (PM) exposure. Using transcriptomic analysis, we demonstrate that diesel exhaust particles, one of the major sources of particulate emission, down-regulated genes located in mitochondrial complexes I and V and induced experimental COPD in a mouse model. 1-Nitropyrene was identified as a major toxic component of PM-induced COPD. In the panel study, COPD patients were found to be more susceptible to PM than individuals with normal lung function due to an increased inflammatory response. Mechanistically, exposure to PM in human bronchial epithelial cells led to a decline in CCAAT/enhancer-binding protein alpha (C/EBPα), which triggered aberrant expression of NADH dehydrogenase genes and ultimately led to enhanced autophagy. ATG7-deficient mice, which have lower autophagy rates, were protected from PM-induced experimental COPD. Using metabolomics analysis, we further established that treatment with taurine and 3-methyladenine completely restored mitochondrial gene expression levels, thereby ameliorating the PM-induced emphysema. Our studies suggest a potential therapeutic intervention for the C/EBPα/mitochondria/autophagy axis in PM-induced COPD.


Subject(s)
Mitochondria/drug effects , Mitochondria/metabolism , NADH Dehydrogenase/metabolism , Particulate Matter/pharmacology , Pulmonary Emphysema/chemically induced , Pulmonary Emphysema/drug therapy , Taurine/therapeutic use , Adenine/analogs & derivatives , Adenine/pharmacology , Aged , Animals , Autophagy/drug effects , CCAAT-Enhancer-Binding Proteins/metabolism , Cell Line , Epithelial Cells/drug effects , Epithelial Cells/metabolism , Female , Genes, Mitochondrial/drug effects , Humans , Lung/drug effects , Lung/metabolism , Male , Mice , Mice, Inbred C57BL , Middle Aged , Pulmonary Disease, Chronic Obstructive/drug therapy , Pulmonary Disease, Chronic Obstructive/metabolism , Pulmonary Emphysema/metabolism
10.
Proc Natl Acad Sci U S A ; 108(45): 18560-5, 2011 Nov 08.
Article in English | MEDLINE | ID: mdl-22042857

ABSTRACT

The circadian clock generates daily rhythms in mammalian liver processes, such as glucose and lipid homeostasis, xenobiotic metabolism, and regeneration. The mechanisms governing these rhythms are not well understood, particularly the distinct contributions of the cell-autonomous clock and central pacemaker to rhythmic liver physiology. Through microarray expression profiling in Met murine hepatocytes (MMH)-D3, we identified over 1,000 transcripts that exhibit circadian oscillations, demonstrating that the cell-autonomous clock can drive many rhythms, and that MMH-D3 is a valid circadian model system. The genes represented by these circadian transcripts displayed both cophasic and antiphasic organization within a protein-protein interaction network, suggesting the existence of competition for binding sites or partners by genes of disparate transcriptional phases. Multiple pathways displayed enrichment in MMH-D3 circadian transcripts, including the polyamine synthesis module of the glutathione metabolic pathway. The polyamine synthesis module, which is highly associated with cell proliferation and whose products are required for initiation of liver regeneration, includes enzymes whose transcripts exhibit circadian oscillations, such as ornithine decarboxylase and spermidine synthase. Metabolic profiling revealed that the enzymatic product of spermidine synthase, spermidine, cycles as well. Thus, the cell-autonomous hepatocyte clock can drive a significant amount of transcriptional rhythms and orchestrate physiologically relevant modules such as polyamine synthesis.


Subject(s)
Biogenic Polyamines/biosynthesis , Circadian Rhythm , Hepatocytes/cytology , Transcription, Genetic , Animals , Mice
11.
N Engl J Med ; 365(8): 709-17, 2011 Aug 25.
Article in English | MEDLINE | ID: mdl-21793740

ABSTRACT

BACKGROUND: A large outbreak of diarrhea and the hemolytic-uremic syndrome caused by an unusual serotype of Shiga-toxin-producing Escherichia coli (O104:H4) began in Germany in May 2011. As of July 22, a large number of cases of diarrhea caused by Shiga-toxin-producing E. coli have been reported--3167 without the hemolytic-uremic syndrome (16 deaths) and 908 with the hemolytic-uremic syndrome (34 deaths)--indicating that this strain is notably more virulent than most of the Shiga-toxin-producing E. coli strains. Preliminary genetic characterization of the outbreak strain suggested that, unlike most of these strains, it should be classified within the enteroaggregative pathotype of E. coli. METHODS: We used third-generation, single-molecule, real-time DNA sequencing to determine the complete genome sequence of the German outbreak strain, as well as the genome sequences of seven diarrhea-associated enteroaggregative E. coli serotype O104:H4 strains from Africa and four enteroaggregative E. coli reference strains belonging to other serotypes. Genomewide comparisons were performed with the use of these enteroaggregative E. coli genomes, as well as those of 40 previously sequenced E. coli isolates. RESULTS: The enteroaggregative E. coli O104:H4 strains are closely related and form a distinct clade among E. coli and enteroaggregative E. coli strains. However, the genome of the German outbreak strain can be distinguished from those of other O104:H4 strains because it contains a prophage encoding Shiga toxin 2 and a distinct set of additional virulence and antibiotic-resistance factors. CONCLUSIONS: Our findings suggest that horizontal genetic exchange allowed for the emergence of the highly virulent Shiga-toxin-producing enteroaggregative E. coli O104:H4 strain that caused the German outbreak. More broadly, these findings highlight the way in which the plasticity of bacterial genomes facilitates the emergence of new pathogens.


Subject(s)
Disease Outbreaks , Escherichia coli Infections/microbiology , Genome, Bacterial , Hemolytic-Uremic Syndrome/microbiology , Shiga-Toxigenic Escherichia coli/genetics , Bacterial Typing Techniques , Base Sequence , Diarrhea/epidemiology , Diarrhea/microbiology , Escherichia coli Infections/epidemiology , Feces/microbiology , Female , Germany/epidemiology , Hemolytic-Uremic Syndrome/epidemiology , Humans , Middle Aged , Phylogeny , Polymerase Chain Reaction , Sequence Analysis, DNA , Shiga-Toxigenic Escherichia coli/classification , Shiga-Toxigenic Escherichia coli/isolation & purification
12.
Genome Res ; 21(7): 1008-16, 2011 Jul.
Article in English | MEDLINE | ID: mdl-21602305

ABSTRACT

To map the genetics of gene expression in metabolically relevant tissues and investigate the diversity of expression SNPs (eSNPs) in multiple tissues from the same individual, we collected four tissues from approximately 1000 patients undergoing Roux-en-Y gastric bypass (RYGB) and clinical traits associated with their weight loss and co-morbidities. We then performed high-throughput genotyping and gene expression profiling and carried out a genome-wide association analyses for more than 100,000 gene expression traits representing four metabolically relevant tissues: liver, omental adipose, subcutaneous adipose, and stomach. We successfully identified 24,531 eSNPs corresponding to about 10,000 distinct genes. This represents the greatest number of eSNPs identified to our knowledge by any study to date and the first study to identify eSNPs from stomach tissue. We then demonstrate how these eSNPs provide a high-quality disease map for each tissue in morbidly obese patients to not only inform genetic associations identified in this cohort, but in previously published genome-wide association studies as well. These data can aid in elucidating the key networks associated with morbid obesity, response to RYGB, and disease as a whole.


Subject(s)
Gastric Mucosa/metabolism , Liver/metabolism , Obesity, Morbid/epidemiology , Obesity, Morbid/genetics , Adiposity/genetics , Adult , Cohort Studies , Comorbidity , Databases, Genetic , Female , Gastric Bypass , Gene Expression Profiling , Genome-Wide Association Study/methods , Genotype , Humans , Male , Middle Aged , Obesity, Morbid/surgery , Polymorphism, Single Nucleotide , Weight Loss
13.
J Clin Invest ; 120(7): 2414-22, 2010 Jul.
Article in English | MEDLINE | ID: mdl-20577049

ABSTRACT

Atherosclerosis represents the most significant risk factor for coronary artery disease (CAD), the leading cause of death in developed countries. To better understand the pathogenesis of atherosclerosis, we applied a likeli-hood-based model selection method to infer gene-disease causality relationships for the aortic lesion trait in a segregating mouse population demonstrating a spectrum of susceptibility to developing atherosclerotic lesions. We identified 292 genes that tested causal for aortic lesions from liver and adipose tissues of these mice, and we experimentally validated one of these candidate causal genes, complement component 3a receptor 1 (C3ar1), using a knockout mouse model. We also found that genes identified by this method overlapped with genes progressively regulated in the aortic arches of 2 mouse models of atherosclerosis during atherosclerotic lesion development. By comparing our gene set with findings from public human genome-wide association studies (GWAS) of CAD and related traits, we found that 5 genes identified by our study overlapped with published studies in humans in which they were identified as risk factors for multiple atherosclerosis-related pathologies, including myocardial infarction, serum uric acid levels, mean platelet volume, aortic root size, and heart failure. Candidate causal genes were also found to be enriched with CAD risk polymorphisms identified by the Wellcome Trust Case Control Consortium (WTCCC). Our findings therefore validate the ability of causality testing procedures to provide insights into the mechanisms underlying atherosclerosis development.


Subject(s)
Atherosclerosis/genetics , Coronary Artery Disease/genetics , Coronary Disease/genetics , Myocardial Infarction/genetics , Adipose Tissue , Animals , Aorta , Genes , Genome-Wide Association Study , Humans , Liver , Mice , Mice, Knockout , Phenotype , Polymorphism, Genetic , Risk Factors
14.
Genetics ; 185(3): 1059-68, 2010 Jul.
Article in English | MEDLINE | ID: mdl-20439777

ABSTRACT

By treating the transcript abundance as a quantitative trait, gene expression can be mapped to local or distant genomic regions relative to the gene encoding the transcript. Local expression quantitative trait loci (eQTL) generally act in cis (that is, control the expression of only the contiguous structural gene), whereas distal eQTL act in trans. Distal eQTL are more difficult to identify with certainty due to the fact that significant thresholds are very high since all regions of the genome must be tested, and confounding factors such as batch effects can produce false positives. Here, we compare findings from two large genetic crosses between mouse strains C3H/HeJ and C57BL/6J to evaluate the reliability of distal eQTL detection, including "hotspots" influencing the expression of multiple genes in trans. We found that >63% of local eQTL and >18% of distal eQTL were replicable at a threshold of LOD > 4.3 between crosses and 76% of local and >24% of distal eQTL at a threshold of LOD > 6. Additionally, at LOD > 4.3 four tissues studied (adipose, brain, liver, and muscle) exhibited >50% preservation of local eQTL and >17% preservation of distal eQTL. We observed replicated distal eQTL hotspots between the crosses on chromosomes 9 and 17. Finally, >69% of local eQTL and >10% of distal eQTL were preserved in most tissues between sexes. We conclude that most local eQTL are highly replicable between mouse crosses, tissues, and sex as compared to distal eQTL, which exhibited modest replicability.


Subject(s)
DNA Replication , Gene Expression Profiling , Genome , Quantitative Trait Loci , Adipose Tissue/metabolism , Animals , Brain/metabolism , Chromosome Mapping , Female , Liver/metabolism , Mice , Mice, Inbred C3H , Mice, Inbred C57BL , Muscles/metabolism , Organ Specificity , Phenotype , Sex Factors , Tissue Distribution
15.
Circ Cardiovasc Genet ; 2(6): 573-82, 2009 Dec.
Article in English | MEDLINE | ID: mdl-20031637

ABSTRACT

BACKGROUND: Disruption of the elastic lamina, as an early indicator of aneurysm formation, and vascular calcification frequently occur together in atherosclerotic lesions of humans. METHODS AND RESULTS: We now report evidence of shared genetic basis for disruption of the elastic lamina (medial disruption) and medial calcification in an F(2) mouse intercross between C57BL/6J and C3H/HeJ on a hyperlipidemic apolipoprotein E (ApoE(-/-)) null BACKGROUND: gene, known to mediate myocardial calcification. Using transgenic complementation, we show that Abcc6 also contributes to aortic medial calcification. CONCLUSIONS: Our data indicate that calcification, though possibly contributory, does not always lead to medial disruption and that in addition to aneurysm formation, medial disruption may be the precursor to calcification.


Subject(s)
Atherosclerosis/genetics , Atherosclerosis/pathology , Calcinosis , ATP-Binding Cassette Transporters/genetics , ATP-Binding Cassette Transporters/metabolism , Animals , Aorta/pathology , Apolipoproteins E/genetics , Apolipoproteins E/metabolism , Atherosclerosis/metabolism , Disease Models, Animal , Female , Humans , Male , Mice , Mice, Inbred C3H , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Multidrug Resistance-Associated Proteins , Quantitative Trait Loci
16.
Hum Mol Genet ; 18(21): 4118-29, 2009 Nov 01.
Article in English | MEDLINE | ID: mdl-19648292

ABSTRACT

Copy number variants (CNVs) are genomic segments which are duplicated or deleted among different individuals. CNVs have been implicated in both Mendelian and complex traits, including immune and behavioral disorders, but the study of the mechanisms by which CNVs influence gene expression and clinical phenotypes in humans is complicated by the limited access to tissues and by population heterogeneity. We now report studies of the effect of 19 CNVs on gene expression and metabolic traits in a mouse intercross between strains C57BL/6J and C3H/HeJ. We found that 83% of genes predicted to occur within CNVs were differentially expressed. The expression of most CNV genes was correlated with copy number, but we also observed evidence that gene expression was altered in genes flanking CNVs, suggesting that CNVs may contain regulatory elements for these genes. Several CNVs mapped to hotspots, genomic regions influencing expression of tens or hundreds of genes. Several metabolic traits including cholesterol, triglycerides, glucose and body weight mapped to three CNVs in the genome, in mouse chromosomes 1, 4 and 17. Predicted CNV genes, such as Itlna, Defcr-1, Trim12 and Trim34 were highly correlated with these traits. Our results suggest that CNVs have a significant impact on gene expression and that CNVs may be playing a role in the mechanisms underlying metabolic traits in mice.


Subject(s)
Basal Metabolism/genetics , Gene Dosage/genetics , Gene Expression Profiling , Oligonucleotide Array Sequence Analysis/methods , Adipose Tissue/metabolism , Animals , Brain/metabolism , Chromosome Mapping , Chromosomes, Mammalian/genetics , Comparative Genomic Hybridization , Crosses, Genetic , Female , Genetic Variation , Liver/metabolism , Male , Mice , Mice, Inbred C3H , Mice, Inbred C57BL , Mice, Inbred Strains , Muscles/metabolism , Quantitative Trait Loci/genetics
17.
Nat Genet ; 41(4): 415-23, 2009 Apr.
Article in English | MEDLINE | ID: mdl-19270708

ABSTRACT

A principal task in dissecting the genetics of complex traits is to identify causal genes for disease phenotypes. We previously developed a method to infer causal relationships among genes through the integration of DNA variation, gene transcription and phenotypic information. Here we have validated our method through the characterization of transgenic and knockout mouse models of genes predicted to be causal for abdominal obesity. Perturbation of eight out of the nine genes, with Gas7, Me1 and Gpx3 being newly confirmed, resulted in significant changes in obesity-related traits. Liver expression signatures revealed alterations in common metabolic pathways and networks contributing to abdominal obesity and overlapped with a macrophage-enriched metabolic network module that is highly associated with metabolic traits in mice and humans. Integration of gene expression in the design and analysis of traditional F(2) intercross studies allows high-confidence prediction of causal genes and identification of pathways and networks involved.


Subject(s)
Carrier Proteins/genetics , Glutathione Peroxidase/genetics , Glycoproteins/genetics , Nerve Tissue Proteins/genetics , Obesity/genetics , Abdomen/anatomy & histology , Adipose Tissue/anatomy & histology , Animals , Disease Models, Animal , Female , Gene Expression Profiling , Genetic Variation , Humans , Liver/physiology , Male , Mice , Mice, Knockout , Mice, Transgenic , Muscle, Skeletal/anatomy & histology , Phenotype , Reproducibility of Results , Transcription, Genetic , Vesicular Transport Proteins
18.
Arterioscler Thromb Vasc Biol ; 29(3): 348-55, 2009 Mar.
Article in English | MEDLINE | ID: mdl-19122174

ABSTRACT

OBJECTIVE: We sought to determine the genetic factors contributing to atherosclerotic plaque size and cellular composition in the innominate artery, a murine model of advanced atherosclerosis. METHODS AND RESULTS: We examined genetic contributions to innominate atherosclerotic plaque size and cellular composition in an intercross between C57BL/6J.Apoe(-/-), a strain susceptible to aortic lesions, and C3H/HeJ.Apoe(-/-), a strain resistant to aortic lesions. Surprisingly, total innominate lesion size was similar in the two strains. Genetic analyses identified one novel locus on Chromosome 2 for innominate artery lesion size, a significant locus for fibrous cap thickness on Chromosome 15, and several suggestive loci for cellular composition, all distinct from loci influencing aortic lesions. The Chromosome 2 locus contains a candidate, CD44. We show that CD44 is expressed in the innominate artery and differs strikingly in expression between the parental strains. CONCLUSION: Multiple aspects of innominate lesion composition are genetically determined, but in a manner largely independent of the genetic contributions to aortic lesions.


Subject(s)
Atherosclerosis/genetics , Brachiocephalic Trunk/pathology , Chromosomes, Mammalian , Hyperlipidemias/genetics , Animals , Apolipoproteins E/deficiency , Apolipoproteins E/genetics , Atherosclerosis/pathology , Disease Models, Animal , Female , Gene Expression Profiling/methods , Genetic Linkage , Genetic Predisposition to Disease , Hyaluronan Receptors/genetics , Hyperlipidemias/complications , Hyperlipidemias/pathology , Lipids/blood , Lod Score , Male , Mice , Mice, Inbred C3H , Mice, Inbred C57BL , Mice, Knockout , Quantitative Trait Loci , Sex Factors , Species Specificity
19.
Endocrinology ; 150(3): 1235-49, 2009 Mar.
Article in English | MEDLINE | ID: mdl-18974276

ABSTRACT

We previously used high-density expression arrays to interrogate a genetic cross between strains C3H/HeJ and C57BL/6J and observed thousands of differences in gene expression between sexes. We now report analyses of the molecular basis of these sex differences and of the effects of sex on gene expression networks. We analyzed liver gene expression of hormone-treated gonadectomized mice as well as XX male and XY female mice. Differences in gene expression resulted in large part from acute effects of gonadal hormones acting in adulthood, and the effects of sex chromosomes, apart from hormones, were modest. We also determined whether there are sex differences in the organization of gene expression networks in adipose, liver, skeletal muscle, and brain tissue. Although coexpression networks of highly correlated genes were largely conserved between sexes, some exhibited striking sex dependence. We observed strong body fat and lipid correlations with sex-specific modules in adipose and liver as well as a sexually dimorphic network enriched for genes affected by gonadal hormones. Finally, our analyses identified chromosomal loci regulating sexually dimorphic networks. This study indicates that gonadal hormones play a strong role in sex differences in gene expression. In addition, it results in the identification of sex-specific gene coexpression networks related to genetic and metabolic traits.


Subject(s)
Gene Regulatory Networks , Gonadal Hormones/physiology , Sex Characteristics , Animals , Apolipoproteins E/genetics , Crosses, Genetic , Dihydrotestosterone/pharmacology , Estradiol/pharmacology , Female , Gene Expression Regulation/drug effects , Gene Regulatory Networks/drug effects , Gene Regulatory Networks/physiology , Gonadal Hormones/pharmacology , Liver/drug effects , Liver/metabolism , Male , Mice , Mice, Inbred C3H , Mice, Inbred C57BL , Mice, Knockout
20.
PLoS One ; 3(10): e3583, 2008.
Article in English | MEDLINE | ID: mdl-18974833

ABSTRACT

A wealth of genetic associations for cardiovascular and metabolic phenotypes in humans has been accumulating over the last decade, in particular a large number of loci derived from recent genome wide association studies (GWAS). True complex disease-associated loci often exert modest effects, so their delineation currently requires integration of diverse phenotypic data from large studies to ensure robust meta-analyses. We have designed a gene-centric 50 K single nucleotide polymorphism (SNP) array to assess potentially relevant loci across a range of cardiovascular, metabolic and inflammatory syndromes. The array utilizes a "cosmopolitan" tagging approach to capture the genetic diversity across approximately 2,000 loci in populations represented in the HapMap and SeattleSNPs projects. The array content is informed by GWAS of vascular and inflammatory disease, expression quantitative trait loci implicated in atherosclerosis, pathway based approaches and comprehensive literature searching. The custom flexibility of the array platform facilitated interrogation of loci at differing stringencies, according to a gene prioritization strategy that allows saturation of high priority loci with a greater density of markers than the existing GWAS tools, particularly in African HapMap samples. We also demonstrate that the IBC array can be used to complement GWAS, increasing coverage in high priority CVD-related loci across all major HapMap populations. DNA from over 200,000 extensively phenotyped individuals will be genotyped with this array with a significant portion of the generated data being released into the academic domain facilitating in silico replication attempts, analyses of rare variants and cross-cohort meta-analyses in diverse populations. These datasets will also facilitate more robust secondary analyses, such as explorations with alternative genetic models, epistasis and gene-environment interactions.


Subject(s)
Cardiovascular Diseases/genetics , Genome-Wide Association Study/methods , Oligonucleotide Array Sequence Analysis/methods , Polymorphism, Single Nucleotide , Cardiovascular Diseases/ethnology , Concept Formation , Gene Frequency , Genome-Wide Association Study/instrumentation , Genotype , Humans , Population Groups/genetics , Quality Control , Research Design
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