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1.
Cell Rep ; 42(11): 113371, 2023 11 28.
Artigo em Inglês | MEDLINE | ID: mdl-37938972

RESUMO

Senescent cells are a major contributor to age-dependent cardiovascular tissue dysfunction, but knowledge of their in vivo cell markers and tissue context is lacking. To reveal tissue-relevant senescence biology, we integrate the transcriptomes of 10 experimental senescence cell models with a 224 multi-tissue gene co-expression network based on RNA-seq data of seven tissues biopsies from ∼600 coronary artery disease (CAD) patients. We identify 56 senescence-associated modules, many enriched in CAD GWAS genes and correlated with cardiometabolic traits-which supports universality of senescence gene programs across tissues and in CAD. Cross-tissue network analyses reveal 86 candidate senescence-associated secretory phenotype (SASP) factors, including COL6A3. Experimental knockdown of COL6A3 induces transcriptional changes that overlap the majority of the experimental senescence models, with cell-cycle arrest linked to modulation of DREAM complex-targeted genes. We provide a transcriptomic resource for cellular senescence and identify candidate biomarkers, SASP factors, and potential drivers of senescence in human tissues.


Assuntos
Senescência Celular , Transcriptoma , Humanos , Transcriptoma/genética , Senescência Celular/genética , Fenótipo , Biomarcadores , Colágeno , Colágeno Tipo VI/genética
2.
Nat Cardiovasc Res ; 1(1): 85-100, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36276926

RESUMO

Coronary atherosclerosis results from the delicate interplay of genetic and exogenous risk factors, principally taking place in metabolic organs and the arterial wall. Here we show that 224 gene-regulatory coexpression networks (GRNs) identified by integrating genetic and clinical data from patients with (n = 600) and without (n = 250) coronary artery disease (CAD) with RNA-seq data from seven disease-relevant tissues in the Stockholm-Tartu Atherosclerosis Reverse Network Engineering Task (STARNET) study largely capture this delicate interplay, explaining >54% of CAD heritability. Within 89 cross-tissue GRNs associated with clinical severity of CAD, 374 endocrine factors facilitated inter-organ interactions, primarily along an axis from adipose tissue to the liver (n = 152). This axis was independently replicated in genetically diverse mouse strains and by injection of recombinant forms of adipose endocrine factors (EPDR1, FCN2, FSTL3 and LBP) that markedly altered blood lipid and glucose levels in mice. Altogether, the STARNET database and the associated GRN browser (http://starnet.mssm.edu) provide a multiorgan framework for exploration of the molecular interplay between cardiometabolic disorders and CAD.

3.
PLoS Genet ; 18(6): e1010261, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35714152

RESUMO

Genome wide association studies (GWAS) have identified thousands of single nucleotide polymorphisms (SNPs) associated with the risk of common disorders. However, since the large majority of these risk SNPs reside outside gene-coding regions, GWAS generally provide no information about causal mechanisms regarding the specific gene(s) that are affected or the tissue(s) in which these candidate gene(s) exert their effect. The 'gold standard' method for understanding causal genes and their mechanisms of action are laborious basic science studies often involving sophisticated knockin or knockout mouse lines, however, these types of studies are impractical as a high-throughput means to understand the many risk variants that cause complex diseases like coronary artery disease (CAD). As a solution, we developed a streamlined, data-driven informatics pipeline to gain mechanistic insights on complex genetic loci. The pipeline begins by understanding the SNPs in a given locus in terms of their relative location and linkage disequilibrium relationships, and then identifies nearby expression quantitative trait loci (eQTLs) to determine their relative independence and the likely tissues that mediate their disease-causal effects. The pipeline then seeks to understand associations with other disease-relevant genes, disease sub-phenotypes, potential causality (Mendelian randomization), and the regulatory and functional involvement of these genes in gene regulatory co-expression networks (GRNs). Here, we applied this pipeline to understand a cluster of SNPs associated with CAD within and immediately adjacent to the gene encoding HDAC9. Our pipeline demonstrated, and validated, that this locus is causal for CAD by modulation of TWIST1 expression levels in the arterial wall, and by also governing a GRN related to metabolic function in skeletal muscle. Our results reconciled numerous prior studies, and also provided clear evidence that this locus does not govern HDAC9 expression, structure or function. This pipeline should be considered as a powerful and efficient way to understand GWAS risk loci in a manner that better reflects the highly complex nature of genetic risk associated with common disorders.


Assuntos
Doença da Artéria Coronariana , Estudo de Associação Genômica Ampla , Proteína 1 Relacionada a Twist/metabolismo , Animais , Doença da Artéria Coronariana/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla/métodos , Histona Desacetilases/metabolismo , Desequilíbrio de Ligação , Camundongos , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas/genética , Proteínas Repressoras/metabolismo
5.
Basic Res Cardiol ; 117(1): 6, 2022 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-35175464

RESUMO

The majority of risk loci identified by genome-wide association studies (GWAS) are in non-coding regions, hampering their functional interpretation. Instead, transcriptome-wide association studies (TWAS) identify gene-trait associations, which can be used to prioritize candidate genes in disease-relevant tissue(s). Here, we aimed to systematically identify susceptibility genes for coronary artery disease (CAD) by TWAS. We trained prediction models of nine CAD-relevant tissues using EpiXcan based on two genetics-of-gene-expression panels, the Stockholm-Tartu Atherosclerosis Reverse Network Engineering Task (STARNET) and the Genotype-Tissue Expression (GTEx). Based on these prediction models, we imputed gene expression of respective tissues from individual-level genotype data on 37,997 CAD cases and 42,854 controls for the subsequent gene-trait association analysis. Transcriptome-wide significant association (i.e. P < 3.85e-6) was observed for 114 genes. Of these, 96 resided within previously identified GWAS risk loci and 18 were novel. Stepwise analyses were performed to study their plausibility, biological function, and pathogenicity in CAD, including analyses for colocalization, damaging mutations, pathway enrichment, phenome-wide associations with human data and expression-traits correlations using mouse data. Finally, CRISPR/Cas9-based gene knockdown of two newly identified TWAS genes, RGS19 and KPTN, in a human hepatocyte cell line resulted in reduced secretion of APOB100 and lipids in the cell culture medium. Our CAD TWAS work (i) prioritized candidate causal genes at known GWAS loci, (ii) identified 18 novel genes to be associated with CAD, and iii) suggested potential tissues and pathways of action for these TWAS CAD genes.


Assuntos
Doença da Artéria Coronariana , Estudo de Associação Genômica Ampla , Animais , Doença da Artéria Coronariana/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla/métodos , Camundongos , Polimorfismo de Nucleotídeo Único , Transcriptoma
6.
Circ Genom Precis Med ; 15(1): e003365, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34961328

RESUMO

BACKGROUND: Hundreds of candidate genes have been associated with coronary artery disease (CAD) through genome-wide association studies. However, a systematic way to understand the causal mechanism(s) of these genes, and a means to prioritize them for further study, has been lacking. This represents a major roadblock for developing novel disease- and gene-specific therapies for patients with CAD. Recently, powerful integrative genomics analyses pipelines have emerged to identify and prioritize candidate causal genes by integrating tissue/cell-specific gene expression data with genome-wide association study data sets. METHODS: We aimed to develop a comprehensive integrative genomics analyses pipeline for CAD and to provide a prioritized list of causal CAD genes. To this end, we leveraged several complimentary informatics approaches to integrate summary statistics from CAD genome-wide association studies (from UK Biobank and CARDIoGRAMplusC4D) with transcriptomic and expression quantitative trait loci data from 9 cardiometabolic tissue/cell types in the STARNET study (Stockholm-Tartu Atherosclerosis Reverse Network Engineering Task). RESULTS: We identified 162 unique candidate causal CAD genes, which exerted their effect from between one and up to 7 disease-relevant tissues/cell types, including the arterial wall, blood, liver, skeletal muscle, adipose, foam cells, and macrophages. When their causal effect was ranked, the top candidate causal CAD genes were CDKN2B (associated with the 9p21.3 risk locus) and PHACTR1; both exerting their causal effect in the arterial wall. A majority of candidate causal genes were represented in cross-tissue gene regulatory co-expression networks that are involved with CAD, with 22/162 being key drivers in those networks. CONCLUSIONS: We identified and prioritized candidate causal CAD genes, also localizing their tissue(s) of causal effect. These results should serve as a resource and facilitate targeted studies to identify the functional impact of top causal CAD genes.


Assuntos
Aterosclerose , Doença da Artéria Coronariana , Aterosclerose/genética , Doença da Artéria Coronariana/genética , Doença da Artéria Coronariana/metabolismo , Redes Reguladoras de Genes , Estudo de Associação Genômica Ampla/métodos , Genômica/métodos , Humanos , Locos de Características Quantitativas
7.
J Hum Genet ; 66(6): 625-636, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33469137

RESUMO

The stress hormone cortisol modulates fuel metabolism, cardiovascular homoeostasis, mood, inflammation and cognition. The CORtisol NETwork (CORNET) consortium previously identified a single locus associated with morning plasma cortisol. Identifying additional genetic variants that explain more of the variance in cortisol could provide new insights into cortisol biology and provide statistical power to test the causative role of cortisol in common diseases. The CORNET consortium extended its genome-wide association meta-analysis for morning plasma cortisol from 12,597 to 25,314 subjects and from ~2.2 M to ~7 M SNPs, in 17 population-based cohorts of European ancestries. We confirmed the genetic association with SERPINA6/SERPINA1. This locus contains genes encoding corticosteroid binding globulin (CBG) and α1-antitrypsin. Expression quantitative trait loci (eQTL) analyses undertaken in the STARNET cohort of 600 individuals showed that specific genetic variants within the SERPINA6/SERPINA1 locus influence expression of SERPINA6 rather than SERPINA1 in the liver. Moreover, trans-eQTL analysis demonstrated effects on adipose tissue gene expression, suggesting that variations in CBG levels have an effect on delivery of cortisol to peripheral tissues. Two-sample Mendelian randomisation analyses provided evidence that each genetically-determined standard deviation (SD) increase in morning plasma cortisol was associated with increased odds of chronic ischaemic heart disease (0.32, 95% CI 0.06-0.59) and myocardial infarction (0.21, 95% CI 0.00-0.43) in UK Biobank and similarly in CARDIoGRAMplusC4D. These findings reveal a causative pathway for CBG in determining cortisol action in peripheral tissues and thereby contributing to the aetiology of cardiovascular disease.


Assuntos
Doenças Cardiovasculares/genética , Infarto do Miocárdio/genética , Transcortina/genética , alfa 1-Antitripsina/genética , Corticosteroides/sangue , Adulto , Bancos de Espécimes Biológicos , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/patologia , Feminino , Regulação da Expressão Gênica , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Fígado/metabolismo , Fígado/patologia , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Infarto do Miocárdio/sangue , Infarto do Miocárdio/patologia , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas/genética , Reino Unido
8.
Nat Commun ; 12(1): 547, 2021 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-33483510

RESUMO

Elevated plasma cholesterol and type 2 diabetes (T2D) are associated with coronary artery disease (CAD). Individuals treated with cholesterol-lowering statins have increased T2D risk, while individuals with hypercholesterolemia have reduced T2D risk. We explore the relationship between lipid and glucose control by constructing network models from the STARNET study with sequencing data from seven cardiometabolic tissues obtained from CAD patients during coronary artery by-pass grafting surgery. By integrating gene expression, genotype, metabolomic, and clinical data, we identify a glucose and lipid determining (GLD) regulatory network showing inverse relationships with lipid and glucose traits. Master regulators of the GLD network also impact lipid and glucose levels in inverse directions. Experimental inhibition of one of the GLD network master regulators, lanosterol synthase (LSS), in mice confirms the inverse relationships to glucose and lipid levels as predicted by our model and provides mechanistic insights.


Assuntos
Glicemia/metabolismo , Doença da Artéria Coronariana/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Glucose/metabolismo , Metabolismo dos Lipídeos , Modelos Biológicos , Animais , Colesterol/sangue , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/genética , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/genética , Feminino , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Hipercolesterolemia/sangue , Hipercolesterolemia/genética , Hipercolesterolemia/metabolismo , Camundongos Endogâmicos C57BL , Polimorfismo de Nucleotídeo Único
9.
Eur J Heart Fail ; 23(3): 445-453, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33135840

RESUMO

AIMS: To examine the current status of care and needs of adult congenital heart disease (ACHD) services in the Central and South Eastern European (CESEE) region. METHODS AND RESULTS: We obtained data regarding the national ACHD status for 19 CESEE countries from their ACHD representative based on an extensive survey for 2017 and/or 2018. Thirteen countries reported at least one tertiary ACHD centre with a median year of centre establishment in 2007 (interquartile range 2002-2013). ACHD centres reported a median of 2114 patients under active follow-up with an annual cardiac catheter and surgical intervention volume of 49 and 40, respectively. The majority (90%) of catheter or surgical interventions were funded by government reimbursement schemes. However, all 19 countries had financial caps on a hospital level, leading to patient waiting lists and restrictions in the number of procedures that can be performed. The median number of ACHD specialists per country was 3. The majority of centres (75%) did not have ACHD specialist nurses. The six countries with no dedicated ACHD centres had lower Gross Domestic Product per capita compared to the remainder (P = 0.005). CONCLUSION: The majority of countries in CESEE now have established ACHD services with adequate infrastructure and a patient workload comparable to the rest of Europe, but important gaps still exist. ACHD care is challenged or compromised by limited financial resources, insufficient staffing levels, and reimbursement caps on essential procedures compared to Western Europe. Active advocacy and increased resources are required to address the inequalities of care across the continent.


Assuntos
Cardiologia , Cardiopatias Congênitas , Insuficiência Cardíaca , Adulto , Consenso , Europa (Continente) , Humanos
10.
Atherosclerosis ; 311: 20-29, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32919281

RESUMO

BACKGROUND AND AIMS: Coronary artery disease (CAD) arises from the interaction of genetic and environmental factors. Although genome-wide association studies (GWAS) have identified multiple risk loci and single nucleotide polymorphisms (SNPs) associated with risk of CAD, they are predominantly located in non-coding or intergenic regions and their mechanisms of effect are largely unknown. Accordingly, our objective was to develop a data-driven informatics pipeline to understand complex CAD risk loci, and to apply this to a poorly understood cluster of SNPs in the vicinity of ZEB2. METHODS: We developed a unique informatics pipeline leveraging a multi-tissue CAD genetics-of-gene-expression dataset, GWAS datasets, and other resources. The pipeline first dissected SNP locations and their linkage disequilibrium relationships, and progressed through analyses of tissue-specific expression quantitative trait loci, and then gene-gene, gene-phenotype, SNP-phenotype relationships. The pipeline concluded by exploring CAD-relevant gene regulatory networks (GRNs). RESULTS: We identified three independent CAD risk SNPs in close proximity to the ZEB2 coding region (rs6740731, rs17678683 and rs2252641/rs1830321). Our pipeline determined that these SNPs likely act in concert via the atherosclerotic arterial wall and adipose tissues, by governing metabolic and lipid functions. In addition, ZEB2 is the top key driver of a liver-specific GRN that is related to lipid levels, metabolic and anthropometric measures, and CAD severity. CONCLUSIONS: Using a novel informatics pipeline, we disclosed the multi-faceted mechanisms of action of the ZEB2-associated CAD risk SNPs. This pipeline can serve as a roadmap to dissect complex SNP-gene-tissue-phenotype relationships and to reveal targets for tissue- and gene-specific therapeutic interventions.


Assuntos
Doença da Artéria Coronariana , Estudo de Associação Genômica Ampla , Doença da Artéria Coronariana/genética , Redes Reguladoras de Genes , Predisposição Genética para Doença , Humanos , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Homeobox 2 de Ligação a E-box com Dedos de Zinco/genética
12.
BMC Med Genomics ; 12(Suppl 6): 108, 2019 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-31345219

RESUMO

BACKGROUND: Genetic loss-of-function variants (LoFs) associated with disease traits are increasingly recognized as critical evidence for the selection of therapeutic targets. We integrated the analysis of genetic and clinical data from 10,511 individuals in the Mount Sinai BioMe Biobank to identify genes with loss-of-function variants (LoFs) significantly associated with cardiovascular disease (CVD) traits, and used RNA-sequence data of seven metabolic and vascular tissues isolated from 600 CVD patients in the Stockholm-Tartu Atherosclerosis Reverse Network Engineering Task (STARNET) study for validation. We also carried out in vitro functional studies of several candidate genes, and in vivo studies of one gene. RESULTS: We identified LoFs in 433 genes significantly associated with at least one of 10 major CVD traits. Next, we used RNA-sequence data from the STARNET study to validate 115 of the 433 LoF harboring-genes in that their expression levels were concordantly associated with corresponding CVD traits. Together with the documented hepatic lipid-lowering gene, APOC3, the expression levels of six additional liver LoF-genes were positively associated with levels of plasma lipids in STARNET. Candidate LoF-genes were subjected to gene silencing in HepG2 cells with marked overall effects on cellular LDLR, levels of triglycerides and on secreted APOB100 and PCSK9. In addition, we identified novel LoFs in DGAT2 associated with lower plasma cholesterol and glucose levels in BioMe that were also confirmed in STARNET, and showed a selective DGAT2-inhibitor in C57BL/6 mice not only significantly lowered fasting glucose levels but also affected body weight. CONCLUSION: In sum, by integrating genetic and electronic medical record data, and leveraging one of the world's largest human RNA-sequence datasets (STARNET), we identified known and novel CVD-trait related genes that may serve as targets for CVD therapeutics and as such merit further investigation.


Assuntos
Doenças Cardiovasculares/genética , Genômica , Mutação , Doenças Cardiovasculares/sangue , Colesterol/sangue , Genótipo , Humanos , Triglicerídeos/sangue
13.
Nat Genet ; 51(4): 592-599, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30926968

RESUMO

Transcriptome-wide association studies (TWAS) integrate genome-wide association studies (GWAS) and gene expression datasets to identify gene-trait associations. In this Perspective, we explore properties of TWAS as a potential approach to prioritize causal genes at GWAS loci, by using simulations and case studies of literature-curated candidate causal genes for schizophrenia, low-density-lipoprotein cholesterol and Crohn's disease. We explore risk loci where TWAS accurately prioritizes the likely causal gene as well as loci where TWAS prioritizes multiple genes, some likely to be non-causal, owing to sharing of expression quantitative trait loci (eQTL). TWAS is especially prone to spurious prioritization with expression data from non-trait-related tissues or cell types, owing to substantial cross-cell-type variation in expression levels and eQTL strengths. Nonetheless, TWAS prioritizes candidate causal genes more accurately than simple baselines. We suggest best practices for causal-gene prioritization with TWAS and discuss future opportunities for improvement. Our results showcase the strengths and limitations of using eQTL datasets to determine causal genes at GWAS loci.


Assuntos
Predisposição Genética para Doença/genética , Transcriptoma/genética , Doença de Crohn/genética , Variação Genética/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Lipoproteínas LDL/genética , Locos de Características Quantitativas/genética , Esquizofrenia/genética
14.
PeerJ ; 6: e4466, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29527417

RESUMO

RNA editing modifies transcripts and may alter their regulation or function. In humans, the most common modification is adenosine to inosine (A-to-I). We examined the global characteristics of RNA editing in 4,301 human tissue samples. More than 1.6 million A-to-I edits were identified in 62% of all protein-coding transcripts. mRNA recoding was extremely rare; only 11 novel recoding sites were uncovered. Thirty single nucleotide polymorphisms from genome-wide association studies were associated with RNA editing; one that influences type 2 diabetes (rs2028299) was associated with editing in ARPIN. Twenty-five genes, including LRP11 and PLIN5, had editing sites that were associated with plasma lipid levels. Our findings provide new insights into the genetic regulation of RNA editing and establish a rich catalogue for further exploration of this process.

15.
Nat Genet ; 49(9): 1385-1391, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28714975

RESUMO

Genome-wide association studies (GWAS) in coronary artery disease (CAD) had identified 66 loci at 'genome-wide significance' (P < 5 × 10-8) at the time of this analysis, but a much larger number of putative loci at a false discovery rate (FDR) of 5% (refs. 1,2,3,4). Here we leverage an interim release of UK Biobank (UKBB) data to evaluate the validity of the FDR approach. We tested a CAD phenotype inclusive of angina (SOFT; ncases = 10,801) as well as a stricter definition without angina (HARD; ncases = 6,482) and selected cases with the former phenotype to conduct a meta-analysis using the two most recent CAD GWAS. This approach identified 13 new loci at genome-wide significance, 12 of which were on our previous list of loci meeting the 5% FDR threshold, thus providing strong support that the remaining loci identified by FDR represent genuine signals. The 304 independent variants associated at 5% FDR in this study explain 21.2% of CAD heritability and identify 243 loci that implicate pathways in blood vessel morphogenesis as well as lipid metabolism, nitric oxide signaling and inflammation.


Assuntos
Doença da Artéria Coronariana/genética , Loci Gênicos/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Estudos de Associação Genética/métodos , Estudos de Associação Genética/normas , Estudos de Associação Genética/estatística & dados numéricos , Estudo de Associação Genômica Ampla/normas , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Genótipo , Sistemas de Informação em Saúde/normas , Sistemas de Informação em Saúde/estatística & dados numéricos , Humanos , Metanálise como Assunto , Fenótipo , Polimorfismo de Nucleotídeo Único , Reprodutibilidade dos Testes , Fatores de Risco , Reino Unido
16.
Science ; 353(6301): 827-30, 2016 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-27540175

RESUMO

Genome-wide association studies (GWAS) have identified hundreds of cardiometabolic disease (CMD) risk loci. However, they contribute little to genetic variance, and most downstream gene-regulatory mechanisms are unknown. We genotyped and RNA-sequenced vascular and metabolic tissues from 600 coronary artery disease patients in the Stockholm-Tartu Atherosclerosis Reverse Networks Engineering Task study (STARNET). Gene expression traits associated with CMD risk single-nucleotide polymorphism (SNPs) identified by GWAS were more extensively found in STARNET than in tissue- and disease-unspecific gene-tissue expression studies, indicating sharing of downstream cis-/trans-gene regulation across tissues and CMDs. In contrast, the regulatory effects of other GWAS risk SNPs were tissue-specific; abdominal fat emerged as an important gene-regulatory site for blood lipids, such as for the low-density lipoprotein cholesterol and coronary artery disease risk gene PCSK9 STARNET provides insights into gene-regulatory mechanisms for CMD risk loci, facilitating their translation into opportunities for diagnosis, therapy, and prevention.


Assuntos
Doença da Artéria Coronariana/genética , Regulação da Expressão Gênica , Gordura Abdominal/metabolismo , Doença de Alzheimer/genética , LDL-Colesterol/sangue , LDL-Colesterol/genética , Doença da Artéria Coronariana/epidemiologia , Feminino , Redes Reguladoras de Genes , Estudo de Associação Genômica Ampla , Humanos , Fígado/metabolismo , Masculino , Músculo Esquelético/metabolismo , Especificidade de Órgãos/genética , Polimorfismo de Nucleotídeo Único , Pró-Proteína Convertase 9 , Pró-Proteína Convertases/genética , Locos de Características Quantitativas , Risco , Serina Endopeptidases/genética
17.
Cell Syst ; 2(3): 196-208, 2016 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-27135365

RESUMO

Inferring molecular networks can reveal how genetic perturbations interact with environmental factors to cause common complex diseases. We analyzed genetic and gene expression data from seven tissues relevant to coronary artery disease (CAD) and identified regulatory gene networks (RGNs) and their key drivers. By integrating data from genome-wide association studies, we identified 30 CAD-causal RGNs interconnected in vascular and metabolic tissues, and we validated them with corresponding data from the Hybrid Mouse Diversity Panel. As proof of concept, by targeting the key drivers AIP, DRAP1, POLR2I, and PQBP1 in a cross-species-validated, arterial-wall RGN involving RNA-processing genes, we re-identified this RGN in THP-1 foam cells and independent data from CAD macrophages and carotid lesions. This characterization of the molecular landscape in CAD will help better define the regulation of CAD candidate genes identified by genome-wide association studies and is a first step toward achieving the goals of precision medicine.


Assuntos
Redes Reguladoras de Genes , Animais , Proteínas de Transporte , Doença da Artéria Coronariana , Proteínas de Ligação a DNA , Estudo de Associação Genômica Ampla , Humanos , Camundongos , Proteínas Nucleares , Proteínas Repressoras
18.
Circ Cardiovasc Genet ; 8(2): 305-15, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25578447

RESUMO

BACKGROUND: Despite recent discoveries of new genetic risk factors, the majority of risk for coronary artery disease (CAD) remains elusive. As the most proximal sensor of DNA variation, RNA abundance can help identify subpopulations of genetic variants active in and across tissues mediating CAD risk through gene expression. METHODS AND RESULTS: By generating new genomic data on DNA and RNA samples from the Stockholm Atherosclerosis Gene Expression (STAGE) study, 8156 cis-acting expression quantitative trait loci (eQTLs) for 6450 genes across 7 CAD-relevant tissues were detected. The inherited risk enrichments of tissue-defined sets of these eQTLs were assessed using 2 independent genome-wide association data sets. eQTLs acting across increasing numbers of tissues were found increasingly enriched for CAD risk and resided at regulatory hot spots. The risk enrichment of 42 eQTLs acting across 5 to 6 tissues was particularly high (≤7.3-fold) and confirmed in the combined genome-wide association data from Coronary Artery Disease Genome Wide Replication And Meta-Analysis Consortium. Sixteen of the 42 eQTLs associated with 19 master regulatory genes and 29 downstream gene sets (n>30) were further risk enriched comparable to that of the 153 genome-wide association risk single-nucleotide polymorphisms established for CAD (8.4-fold versus 10-fold). Three gene sets, governed by the master regulators FLYWCH1, PSORSIC3, and G3BP1, segregated the STAGE patients according to extent of CAD, and small interfering RNA targeting of these master regulators affected cholesterol-ester accumulation in foam cells of the THP1 monocytic cell line. CONCLUSIONS: eQTLs acting across multiple tissues are significant carriers of inherited risk for CAD. FLYWCH1, PSORSIC3, and G3BP1 are novel master regulatory genes in CAD that may be suitable targets.


Assuntos
Doença da Artéria Coronariana/genética , Doença da Artéria Coronariana/metabolismo , Bases de Dados Genéticas , Regulação da Expressão Gênica , Proteínas Musculares , Locos de Características Quantitativas , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Proteínas Musculares/biossíntese , Proteínas Musculares/genética , Especificidade de Órgãos/genética
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