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1.
J Exp Med ; 217(2)2020 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-31757866

RESUMO

Systemic sclerosis (SSc; scleroderma) is a multisystem fibrotic disease. The mammalian cleavage factor I 25-kD subunit (CFIm25; encoded by NUDT21) is a key regulator of alternative polyadenylation, and its depletion causes predominantly 3'UTR shortening through loss of stimulation of distal polyadenylation sites. A shortened 3'UTR will often lack microRNA target sites, resulting in increased mRNA translation due to evasion of microRNA-mediated repression. Herein, we report that CFlm25 is downregulated in SSc skin, primary dermal fibroblasts, and two murine models of dermal fibrosis. Knockdown of CFIm25 in normal skin fibroblasts is sufficient to promote the 3'UTR shortening of key TGFß-regulated fibrotic genes and enhance their protein expression. Moreover, several of these fibrotic transcripts show 3'UTR shortening in SSc skin. Finally, mice with CFIm25 deletion in fibroblasts show exaggerated skin fibrosis upon bleomycin treatment, and CFIm25 restoration attenuates bleomycin-induced skin fibrosis. Overall, our data link this novel RNA-processing mechanism to dermal fibrosis and SSc pathogenesis.


Assuntos
Fator de Especificidade de Clivagem e Poliadenilação/metabolismo , Regulação para Baixo/genética , Poliadenilação/genética , Escleroderma Sistêmico/metabolismo , Regiões 3' não Traduzidas/genética , Animais , Bleomicina/farmacologia , Células Cultivadas , Fator de Especificidade de Clivagem e Poliadenilação/genética , Modelos Animais de Doenças , Feminino , Fibroblastos/metabolismo , Fibrose , Técnicas de Silenciamento de Genes , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Escleroderma Sistêmico/induzido quimicamente , Escleroderma Sistêmico/patologia , Pele/patologia , Transfecção
2.
J Clin Invest ; 129(5): 1984-1999, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30830875

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a chronic and deadly disease with a poor prognosis and few treatment options. Pathological remodeling of the extracellular matrix (ECM) by myofibroblasts is a key factor that drives disease pathogenesis, although the underlying mechanisms remain unknown. Alternative polyadenylation (APA) has recently been shown to play a major role in cellular responses to stress by driving the expression of fibrotic factors and ECMs through altering microRNA sensitivity, but a connection to IPF has not been established. Here, we demonstrate that CFIm25, a global regulator of APA, is down-regulated in the lungs of patients with IPF and mice with pulmonary fibrosis, with its expression selectively reduced in alpha-smooth muscle actin (α-SMA) positive fibroblasts. Following the knockdown of CFIm25 in normal human lung fibroblasts, we identified 808 genes with shortened 3'UTRs, including those involved in the transforming growth factor-ß signaling pathway, the Wnt signaling pathway, and cancer pathways. The expression of key pro-fibrotic factors can be suppressed by CFIm25 overexpression in IPF fibroblasts. Finally, we demonstrate that deletion of CFIm25 in fibroblasts or myofibroblast precursors using either the Col1a1 or the Foxd1 promoter enhances pulmonary fibrosis after bleomycin exposure in mice. Taken together, our results identified CFIm25 down-regulation as a novel mechanism to elevate pro-fibrotic gene expression in pulmonary fibrosis.


Assuntos
Fator de Especificidade de Clivagem e Poliadenilação/metabolismo , Poliadenilação , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/fisiopatologia , Regiões 3' não Traduzidas , Actinas/metabolismo , Adulto , Idoso , Animais , Bleomicina/farmacologia , Progressão da Doença , Regulação para Baixo , Matriz Extracelular/metabolismo , Feminino , Fibroblastos/metabolismo , Humanos , Pulmão/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Músculo Liso/metabolismo , Miofibroblastos/metabolismo , RNA Interferente Pequeno/metabolismo , Transdução de Sinais , Fator de Crescimento Transformador beta/metabolismo
3.
Biochem Biophys Res Commun ; 503(2): 856-862, 2018 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-29928883

RESUMO

BACKGROUND: Non-small cell lung cancer (NSCLC) is a life-threatening disease that has a poor prognosis and low survival rate. Cleavage factor Im 25 (CFIm25) is a RNA-binding protein that if down-regulated causes 3'UTR shortening and thus promotes the transcript stability of target genes. It is not clear whether CFIm25 and alternative polyadenylation (APA) play a role during cancer development. The purpose of this study is to explore the role of CFIm25 in lung cancer cell proliferation. METHODS: CFIm25 was knocked down in A549 cells. Western blots were carried out to determine the protein expression of CFIm25, insulin growth factor 1 receptor (IGF1R), CyclinD1 (CCND1) and TP53. Real-time qRT PCR was performed to determine the total transcript levels of CFIm25 targets and the normalized fold changes in their distal PAS (dPAS) usage. Immunofluorescence was carried out to check the expression of CFIm25, IGF1R and CCND1. Cell proliferation over time was determined using the WST-1 reagent. RESULTS: The transcript levels of CCND1 and GSK3ß were significantly increased and the dPAS usage of several oncogenes (IGF1R, CCND1 and GSK3ß) were decreased after CFIm25 knockdown. The protein level of IGF1R was increased, and we detected increased percentage of CCND1 positive cells and cell proliferation over time in CFIm25 knockdown cells. In addition, the mRNA and APA analysis of IGF1R using patient RNA-seq data from the Cancer Genome Atlas indicated that IGF1R is shortened in both lung adenocarcinoma and lung squamous cell carcinoma compared to normal controls. CONCLUSIONS: Our findings suggest that CFIm25 plays an important role in lung cancer cell proliferation through regulating the APA of oncogenes, including IGF1R, and promoting their protein expression.


Assuntos
Proliferação de Células/genética , Fator de Especificidade de Clivagem e Poliadenilação/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/genética , Poliadenilação/genética , Fatores de Poliadenilação e Clivagem de mRNA/genética , Regiões 3' não Traduzidas/genética , Células A549 , Processamento Alternativo , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Fator de Especificidade de Clivagem e Poliadenilação/metabolismo , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Modelos Genéticos , Interferência de RNA , Receptor IGF Tipo 1 , Receptores de Somatomedina/genética , Receptores de Somatomedina/metabolismo , Fatores de Poliadenilação e Clivagem de mRNA/metabolismo
4.
PLoS One ; 11(2): e0148765, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26849558

RESUMO

INTRODUCTION: Health benefits of low-to-moderate alcohol consumption may operate through an improved lipid profile. A Mendelian randomization (MR) approach was used to examine whether alcohol consumption causally affects lipid levels. METHODS: This analysis involved 10,893 European Americans (EA) from the Atherosclerosis Risk in Communities (ARIC) study. Common and rare variants in alcohol dehydrogenase and acetaldehyde dehydrogenase genes were evaluated for MR assumptions. Five variants, residing in the ADH1B, ADH1C, and ADH4 genes, were selected as genetic instruments and were combined into an unweighted genetic score. Triglycerides (TG), total cholesterol, high-density lipoprotein cholesterol (HDL-c) and its subfractions (HDL2-c and HDL3-c), low-density lipoprotein cholesterol (LDL-c), small dense LDL-c (sdLDL-c), apolipoprotein B (apoB), and lipoprotein (a) (Lp(a)) levels were analyzed. RESULTS: Alcohol consumption significantly increased HDL2-c and reduced TG, total cholesterol, LDL-c, sdLDL-c, and apoB levels. For each of these lipids a non-linear trend was observed. Compared to the first quartile of alcohol consumption, the third quartile had a 12.3% lower level of TG (p < 0.001), a 7.71 mg/dL lower level of total cholesterol (p = 0.007), a 10.3% higher level of HDL2-c (p = 0.007), a 6.87 mg/dL lower level of LDL-c (p = 0.012), a 7.4% lower level of sdLDL-c (p = 0.037), and a 3.5% lower level of apoB (p = 0.058, poverall = 0.022). CONCLUSIONS: This study supports the causal role of regular low-to-moderate alcohol consumption in increasing HDL2-c, reducing TG, total cholesterol, and LDL-c, and provides evidence for the novel finding that low-to-moderate consumption of alcohol reduces apoB and sdLDL-c levels among EA. However, given the nonlinearity of the effect of alcohol consumption, even within the range of low-to-moderate drinking, increased consumption does not always result in a larger benefit.


Assuntos
Álcool Desidrogenase/genética , Consumo de Bebidas Alcoólicas , Aterosclerose , Lipídeos/sangue , Consumo de Bebidas Alcoólicas/sangue , Consumo de Bebidas Alcoólicas/genética , Aterosclerose/sangue , Aterosclerose/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
5.
Am J Respir Cell Mol Biol ; 54(4): 574-83, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26414702

RESUMO

Group III pulmonary hypertension (PH) is a highly prevalent and deadly lung disorder with limited treatment options other than transplantation. Group III PH affects patients with ongoing chronic lung injury, such as idiopathic pulmonary fibrosis (IPF). Between 30 and 40% of patients with IPF are diagnosed with PH. The diagnosis of PH has devastating consequences to these patients, leading to increased morbidity and mortality, yet the molecular mechanisms involved in the development of PH in patients with chronic lung disease remain elusive. Our hypothesis was that the hypoxic-adenosinergic system is enhanced in patients with group III PH compared with patients with IPF with no PH. Explanted lung tissue was analyzed for markers of the hypoxic-adenosine axis, including expression levels of hypoxia-inducible factor (HIF)-1A, adenosine A2B receptor, CD73, and equilibrative nucleotide transporter-1. In addition, we assessed whether altered mitochondrial metabolism was present in these samples. Increased expression of HIF-1A was observed in tissues from patients with group III PH. These changes were consistent with increased evidence of adenosine accumulation in group III PH. A novel observation of our study was of evidence suggesting altered mitochondrial metabolism in lung tissue from group III PH leading to increased succinate levels that are able to further stabilize HIF-1A. Our data demonstrate that the hypoxic-adenosine axis is up-regulated in group III PH and that subsequent succinate accumulation may play a part in the development of group III PH.


Assuntos
Adenosina/metabolismo , Hipertensão Pulmonar/metabolismo , Hipóxia/metabolismo , Idoso , Feminino , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Masculino , Fibrose Pulmonar/metabolismo , Remodelação Vascular
6.
FASEB J ; 30(2): 874-83, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26527068

RESUMO

Idiopathic pulmonary fibrosis is a devastating lung disease with limited treatment options. The signaling molecule adenosine is produced in response to injury and serves a protective role in early stages of injury and is detrimental during chronic stages of disease such as seen in lung conditions such as pulmonary fibrosis. Understanding the association of extracellular adenosine levels and the progression of pulmonary fibrosis is critical for designing adenosine based approaches to treat pulmonary fibrosis. The goal of this study was to use various models of experimental lung fibrosis to understand when adenosine levels are elevated during pulmonary fibrosis and whether these elevations were associated with disease progression and severity. To accomplish this, extracellular adenosine levels, defined as adenosine levels found in bronchioalveolar lavage fluid, were determined in mouse models of resolvable and progressive pulmonary fibrosis. We found that relative bronchioalveolar lavage fluid adenosine levels are progressively elevated in association with pulmonary fibrosis and that adenosine levels diminish in association with the resolution of lung fibrosis. In addition, treatment of these models with dipyridamole, an inhibitor of nucleoside transporters that potentiates extracellular adenosine levels, demonstrated that the resolution of lung fibrosis is blocked by the failure of adenosine levels to subside. Furthermore, exacerbating adenosine levels led to worse fibrosis in a progressive fibrosis model. Increased adenosine levels were associated with elevation of IL-6 and IL-17, which are important inflammatory cytokines in pulmonary fibrosis. These results demonstrate that extracellular adenosine levels are closely associated with the progression of experimental pulmonary fibrosis and that this signaling pathway may mediate fibrosis by regulating IL-6 and IL-17 production.


Assuntos
Adenosina/metabolismo , Fibrose Pulmonar Idiopática/metabolismo , Interleucina-17/metabolismo , Interleucina-6/metabolismo , Proteínas de Transporte de Nucleosídeos/metabolismo , Animais , Líquido da Lavagem Broncoalveolar , Modelos Animais de Doenças , Feminino , Fibrose Pulmonar Idiopática/patologia , Camundongos
7.
FASEB J ; 29(1): 50-60, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25318478

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a lethal, fibroproliferative disease. Pulmonary hypertension (PH) can develop secondary to IPF and increase mortality. Alternatively, activated macrophages (AAMs) contribute to the pathogenesis of both IPF and PH. Here we hypothesized that adenosine signaling through the ADORA2B on AAMs impacts the progression of these disorders and that conditional deletion of ADORA2B on myeloid cells would have a beneficial effect in a model of these diseases. Conditional knockout mice lacking ADORA2B on myeloid cells (Adora2B(f/f)-LysM(Cre)) were exposed to the fibrotic agent bleomycin (BLM; 0.035 U/g body weight, i.p.). At 14, 17, 21, 25, or 33 d after exposure, SpO2, bronchoalveolar lavage fluid (BALF), and histologic analyses were performed. On day 33, lung function and cardiovascular analyses were determined. Markers for AAM and mediators of fibrosis and PH were assessed. Adora2B(f/f)-LysM(Cre) mice presented with attenuated fibrosis, improved lung function, and no evidence of PH compared with control mice exposed to BLM. These findings were accompanied by reduced expression of CD206 and arginase-1, markers for AAMs. A 10-fold reduction in IL-6 and a 5-fold decrease in hyaluronan, both linked to lung fibrosis and PH, were also observed. These data suggest that activation of the ADORA2B on macrophages plays an active role in the pathogenesis of lung fibrosis and PH.


Assuntos
Hipertensão Pulmonar/etiologia , Fibrose Pulmonar Idiopática/etiologia , Receptor A2B de Adenosina/deficiência , Animais , Bleomicina/toxicidade , Modelos Animais de Doenças , Humanos , Hipertensão Pulmonar/patologia , Hipertensão Pulmonar/fisiopatologia , Fibrose Pulmonar Idiopática/patologia , Fibrose Pulmonar Idiopática/fisiopatologia , Ativação de Macrófagos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células Mieloides/fisiologia , Receptor A2B de Adenosina/genética , Receptor A2B de Adenosina/fisiologia
8.
Am J Respir Crit Care Med ; 190(12): 1402-12, 2014 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-25358054

RESUMO

RATIONALE: Idiopathic pulmonary fibrosis (IPF) is a deadly lung disease with few therapeutic options. Apoptosis of alveolar epithelial cells, followed by abnormal tissue repair characterized by hyperplastic epithelial cell formation, is a pathogenic process that contributes to the progression of pulmonary fibrosis. However, the signaling pathways responsible for increased proliferation of epithelial cells remain poorly understood. OBJECTIVES: To investigate the role of deoxycytidine kinase (DCK), an important enzyme for the salvage of deoxynucleotides, in the progression of pulmonary fibrosis. METHODS: DCK expression was examined in the lungs of patients with IPF and mice exposed to bleomycin. The regulation of DCK expression by hypoxia was studied in vitro and the importance of DCK in experimental pulmonary fibrosis was examined using a DCK inhibitor and alveolar epithelial cell-specific knockout mice. MEASUREMENTS AND MAIN RESULTS: DCK was elevated in hyperplastic alveolar epithelial cells of patients with IPF and in mice exposed to bleomycin. Increased DCK was localized to cells associated with hypoxia, and hypoxia directly induced DCK in alveolar epithelial cells in vitro. Hypoxia-induced DCK expression was abolished by silencing hypoxia-inducible factor 1α and treatment of bleomycin-exposed mice with a DCK inhibitor attenuated pulmonary fibrosis in association with decreased epithelial cell proliferation. Furthermore, DCK expression, and proliferation of epithelial cells and pulmonary fibrosis was attenuated in mice with conditional deletion of hypoxia-inducible factor 1α in the alveolar epithelium. CONCLUSIONS: Our findings suggest that the induction of DCK after hypoxia plays a role in the progression of pulmonary fibrosis by contributing to alveolar epithelial cell proliferation.


Assuntos
Desoxicitidina Quinase/fisiologia , Hipóxia/complicações , Fibrose Pulmonar Idiopática/etiologia , Animais , Linhagem Celular , Proliferação de Células/fisiologia , Humanos , Hipóxia/enzimologia , Hipóxia/fisiopatologia , Fibrose Pulmonar Idiopática/enzimologia , Fibrose Pulmonar Idiopática/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Alvéolos Pulmonares/enzimologia , Alvéolos Pulmonares/fisiopatologia , Reação em Cadeia da Polimerase em Tempo Real , Mucosa Respiratória/enzimologia
9.
J Clin Psychopharmacol ; 33(2): 206-10, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23422394

RESUMO

Genetic association studies thus far have used detailed diagnoses of alcoholism to identify loci associated with risk. This proof-of-concept analysis examined whether population data of lifetime heaviest alcohol consumption may be used to identify genetic loci that modulate risk. We conducted a genetic association study in European Americans between variants in approximately 2100 genes and alcohol consumption as part of the Candidate gene Association Resource project. We defined cases as individuals with a history of drinking 5 or more drinks per day almost every day of the week and controls as current light drinkers (1-5 drinks per week). We cross-validated identified single nucleotide polymorphisms in a meta-analysis of 2 cohorts of unrelated individuals--Atherosclerosis Risk in Communities (ARIC) and Cardiovascular Health Study (CHS)--and in a separate cohort of related individuals--Framingham Heart Study (FHS). The most significant variant in the meta-analysis of ARIC and CHS was rs6933598 in methylenetetrahydrofolate dehydrogenase (P = 7.46 × 10(-05)) with a P value in FHS of 0.042. The top variants in FHS were rs12249562 in cubulin (P = 3.03 × 10(-05)) and rs9839267 near cholecystokinin (P = 3.05 × 10(-05)) with a P value of 0.019 for rs9839267 in CHS. We have here shown feasibility in evaluating lifetime incidence of heavy alcohol drinking from population-based studies for the purpose of conducting genetic association analyses.


Assuntos
Consumo de Bebidas Alcoólicas/genética , Alcoolismo/genética , População Branca/genética , Idoso , Consumo de Bebidas Alcoólicas/epidemiologia , Alcoolismo/diagnóstico , Estudos de Casos e Controles , Estudos de Viabilidade , Estudos de Associação Genética/métodos , Loci Gênicos , Predisposição Genética para Doença , Variação Genética , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único , Risco
10.
J Gen Virol ; 94(Pt 3): 534-542, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23152368

RESUMO

Human chronic hepatitis C virus (HCV) infections pose a significant public health threat, necessitating the development of novel treatments and vaccines. HCV infections range from spontaneous resolution to end-stage liver disease. Approximately 10-30% of HCV infections undergo spontaneous resolution independent of treatment by yet-to-be-defined mechanisms. These individuals test positive for anti-HCV antibodies in the absence of detectable viral serum RNA. To identify genes associated with HCV clearance, this study compared gene expression profiles between current drug users chronically infected with HCV and drug users who cleared their HCV infection. This analysis identified 91 differentially regulated (up- or downregulated by twofold or more) genes potentially associated with HCV clearance. The majority of genes identified were associated with immune function, with the remaining genes categorized either as cancer related or 'other'. Identification of factors and pathways that may influence virus clearance will be essential to the development of novel treatment strategies.


Assuntos
Regulação da Expressão Gênica/imunologia , Hepacivirus/fisiologia , Hepatite C/virologia , Adulto , Anticorpos Antivirais/sangue , Antivirais/uso terapêutico , Estudos de Casos e Controles , Feminino , Hepatite B/prevenção & controle , Vacinas contra Hepatite B/imunologia , Hepatite C/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade
11.
PLoS One ; 7(12): e50198, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23236364

RESUMO

Meta-analyses of European populations has successfully identified genetic variants in over 100 loci associated with lipid levels, but our knowledge in other ethnicities remains limited. To address this, we performed dense genotyping of ∼2,000 candidate genes in 7,657 African Americans, 1,315 Hispanics and 841 East Asians, using the IBC array, a custom ∼50,000 SNP genotyping array. Meta-analyses confirmed 16 lipid loci previously established in European populations at genome-wide significance level, and found multiple independent association signals within these lipid loci. Initial discovery and in silico follow-up in 7,000 additional African American samples, confirmed two novel loci: rs5030359 within ICAM1 is associated with total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) (p = 8.8×10(-7) and p = 1.5×10(-6) respectively) and a nonsense mutation rs3211938 within CD36 is associated with high-density lipoprotein cholesterol (HDL-C) levels (p = 13.5×10(-12)). The rs3211938-G allele, which is nearly absent in European and Asian populations, has been previously found to be associated with CD36 deficiency and shows a signature of selection in Africans and African Americans. Finally, we have evaluated the effect of SNPs established in European populations on lipid levels in multi-ethnic populations and show that most known lipid association signals span across ethnicities. However, differences between populations, especially differences in allele frequency, can be leveraged to identify novel signals, as shown by the discovery of ICAM1 and CD36 in the current report.


Assuntos
Povo Asiático/genética , População Negra/genética , Colesterol/genética , Hispânico ou Latino/genética , Lipoproteínas HDL/genética , Lipoproteínas LDL/genética , Triglicerídeos/genética , Alelos , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único
12.
Am J Hum Genet ; 91(5): 823-38, 2012 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-23063622

RESUMO

Genome-wide association studies (GWASs) have identified many SNPs underlying variations in plasma-lipid levels. We explore whether additional loci associated with plasma-lipid phenotypes, such as high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), and triglycerides (TGs), can be identified by a dense gene-centric approach. Our meta-analysis of 32 studies in 66,240 individuals of European ancestry was based on the custom ∼50,000 SNP genotyping array (the ITMAT-Broad-CARe array) covering ∼2,000 candidate genes. SNP-lipid associations were replicated either in a cohort comprising an additional 24,736 samples or within the Global Lipid Genetic Consortium. We identified four, six, ten, and four unreported SNPs in established lipid genes for HDL-C, LDL-C, TC, and TGs, respectively. We also identified several lipid-related SNPs in previously unreported genes: DGAT2, HCAR2, GPIHBP1, PPARG, and FTO for HDL-C; SOCS3, APOH, SPTY2D1, BRCA2, and VLDLR for LDL-C; SOCS3, UGT1A1, BRCA2, UBE3B, FCGR2A, CHUK, and INSIG2 for TC; and SERPINF2, C4B, GCK, GATA4, INSR, and LPAL2 for TGs. The proportion of explained phenotypic variance in the subset of studies providing individual-level data was 9.9% for HDL-C, 9.5% for LDL-C, 10.3% for TC, and 8.0% for TGs. This large meta-analysis of lipid phenotypes with the use of a dense gene-centric approach identified multiple SNPs not previously described in established lipid genes and several previously unknown loci. The explained phenotypic variance from this approach was comparable to that from a meta-analysis of GWAS data, suggesting that a focused genotyping approach can further increase the understanding of heritability of plasma lipids.


Assuntos
Estudo de Associação Genômica Ampla , Lipídeos/genética , Locos de Características Quantitativas , HDL-Colesterol/sangue , HDL-Colesterol/genética , LDL-Colesterol/sangue , LDL-Colesterol/genética , Feminino , Genótipo , Humanos , Lipídeos/sangue , Masculino , Fenótipo , Polimorfismo de Nucleotídeo Único , Fatores Sexuais , Triglicerídeos/sangue , Triglicerídeos/genética , População Branca
13.
PLoS One ; 7(5): e36473, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22629316

RESUMO

BACKGROUND: Whereas it is well established that plasma lipid levels have substantial heritability within populations, it remains unclear how many of the genetic determinants reported in previous studies (largely performed in European American cohorts) are relevant in different ethnicities. METHODOLOGY/PRINCIPAL FINDINGS: We tested a set of ∼50,000 polymorphisms from ∼2,000 candidate genes and genetic loci from genome-wide association studies (GWAS) for association with low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) in 25,000 European Americans and 9,000 African Americans in the National Heart, Lung, and Blood Institute (NHLBI) Candidate Gene Association Resource (CARe). We replicated associations for a number of genes in one or both ethnicities and identified a novel lipid-associated variant in a locus harboring ICAM1. We compared the architecture of genetic loci associated with lipids in both African Americans and European Americans and found that the same genes were relevant across ethnic groups but the specific associated variants at each gene often differed. CONCLUSIONS/SIGNIFICANCE: We identify or provide further evidence for a number of genetic determinants of plasma lipid levels through population association studies. In many loci the determinants appear to differ substantially between African Americans and European Americans.


Assuntos
Negro ou Afro-Americano/genética , HDL-Colesterol/genética , LDL-Colesterol/genética , Polimorfismo de Nucleotídeo Único , Triglicerídeos/genética , População Branca/genética , Estudos de Associação Genética , Loci Gênicos , Humanos
14.
Circ Cardiovasc Genet ; 5(1): 73-80, 2012 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-22057756

RESUMO

BACKGROUND: Multiple genetic loci have been associated with blood lipid levels. We tested the hypothesis that persons with an unfavorable lipid gene profile would experience a greater increase in lipid levels and a higher incidence of abnormal lipid levels relative to those with more-favorable lipid gene profiles. METHODS AND RESULTS: A total of 9328 individuals of European descent (aged 45-64 years) in the ARIC (Atherosclerosis Risk in Communities) study were followed for 9 years. Separate gene scores were created for each lipid phenotype on the basis of 95 loci identified in a published genome-wide association study of >100 000 people of European-descent. Adjusted linear and survival models were used to estimate associations with lipid levels and incidence of lipid-lowering medication or abnormal lipid levels. Age and sex interactions were also explored. The cross-sectional difference (mg/dL) per 1 SD was -1.89 for high-density lipoprotein cholesterol (HDL-C), 9.5 for low-density lipoprotein cholesterol (LDL-C), and 22.8 for triglycerides (P<5×10(-34) for all). Longitudinally, overall triglyceride levels rose over time, and each 1-SD greater triglyceride gene score was associated with an average increase in triglyceride levels of 0.3 mg/dL (P=0.003) over 3 years. The HDL-C, LDL-C, and total cholesterol gene scores were not related to change. All lipid gene scores were positively related to incidence of abnormal lipid levels over follow-up (hazard ratios per SD range, 1.15-1.36). CONCLUSIONS: Associations of genetic variants with lipid levels over time are complex. The triglyceride gene score was positively related to change in triglycerides levels, but similar longitudinal results were not observed for LDL-C or HDL-C levels. Unfavorable gene scores were nevertheless related to higher incidence of abnormal levels.


Assuntos
Aterosclerose/genética , Lipídeos/sangue , Lipídeos/genética , População Branca/genética , Adulto , Idoso , HDL-Colesterol/sangue , HDL-Colesterol/genética , LDL-Colesterol/sangue , LDL-Colesterol/genética , Estudos Transversais , Feminino , Seguimentos , Loci Gênicos , Genótipo , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Triglicerídeos/sangue , Triglicerídeos/genética
15.
Ann Epidemiol ; 21(11): 815-23, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21982484

RESUMO

PURPOSE: To investigate the potential interaction between folate intake and the paraoxonase 1 (PON1) Q192R polymorphism with the risk of incident coronary heart disease (CHD) and ischemic stroke in the Atherosclerosis Risk in Communities study, a population-based prospective cohort of cardiovascular disease in 15,792 white and African-American subject. METHODS: Race-stratified Cox proportional hazards models were performed to examine the interaction between folate intake and the PON1 Q192R polymorphism. RESULTS: A significant inverse association between folate intake and risk of incident CHD among white subjects was found (hazard rate ratio, 1.30; 95% confidence interval, 1.09-1.56; P = .004; folate intake ≤155 µg vs ≥279 µg, reference group). An interaction effect was observed between the dominant genetic model and folate intake with regards to incident ischemic stroke in white subjects (hazard rate ratio, 0.68; 95% confidence interval, 0.91-0.99; and 1.24 from 1st-4th quartile, respectively; P-trend = .05). CONCLUSIONS: There was an interaction between folate intake and PON1 Q192 polymorphism with regard to the risk of ischemic stroke in white subjects. Future studies should investigate the interaction between additional polymorphisms within the PON1 gene and genetic variants in other folate metabolizing genes with folate intake on the risk of incident CHD and stroke.


Assuntos
Arildialquilfosfatase/genética , Aterosclerose/epidemiologia , Doença das Coronárias/epidemiologia , Ácido Fólico/administração & dosagem , Acidente Vascular Cerebral/epidemiologia , Adulto , Negro ou Afro-Americano , Aterosclerose/etnologia , Aterosclerose/genética , Estudos de Coortes , Doença das Coronárias/etnologia , Doença das Coronárias/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Acidente Vascular Cerebral/etnologia , Acidente Vascular Cerebral/genética , Estados Unidos/epidemiologia , População Branca
16.
J Am Coll Cardiol ; 55(15): 1600-7, 2010 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-20378078

RESUMO

OBJECTIVES: We evaluated whether carotid intima-media thickness (CIMT) and the presence or absence of plaque improved coronary heart disease (CHD) risk prediction when added to traditional risk factors (TRF). BACKGROUND: Traditional CHD risk prediction schemes need further improvement as the majority of the CHD events occur in the "low" and "intermediate" risk groups. On an ultrasound scan, CIMT and presence of plaque are associated with CHD, and therefore could potentially help improve CHD risk prediction. METHODS: Risk prediction models (overall, and in men and women) considered included TRF only, TRF plus CIMT, TRF plus plaque, and TRF plus CIMT plus plaque. Model predictivity was determined by calculating the area under the receiver-operating characteristic curve (AUC) adjusted for optimism. Cox proportional hazards models were used to estimate 10-year CHD risk for each model, and the number of subjects reclassified was determined. Observed events were compared with expected events, and the net reclassification index was calculated. RESULTS: Of 13,145 eligible subjects (5,682 men, 7,463 women), approximately 23% were reclassified by adding CIMT plus plaque information. Overall, the CIMT plus TRF plus plaque model provided the most improvement in AUC, which increased from 0.742 (TRF only) to 0.755 (95% confidence interval for the difference in adjusted AUC: 0.008 to 0.017) in the overall sample. Similarly, the CIMT plus TRF plus plaque model had the best net reclassification index of 9.9% in the overall population. Sex-specific analyses are presented in the manuscript. CONCLUSIONS: Adding plaque and CIMT to TRF improves CHD risk prediction in the ARIC (Atherosclerosis Risk In Communities) study.


Assuntos
Aterosclerose/complicações , Artéria Carótida Primitiva/diagnóstico por imagem , Artéria Carótida Interna/diagnóstico por imagem , Doença da Artéria Coronariana/epidemiologia , Medição de Risco , Túnica Íntima/diagnóstico por imagem , Aterosclerose/diagnóstico , Aterosclerose/epidemiologia , Intervalos de Confiança , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/etiologia , Feminino , Seguimentos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Curva ROC , Características de Residência , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Ultrassonografia , Estados Unidos/epidemiologia
18.
Cancer Epidemiol Biomarkers Prev ; 19(2): 558-65, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20142250

RESUMO

There is a known inverse association between type 2 diabetes (T2D) and prostate cancer (PrCa) that is poorly understood. Genetic studies of the T2D-PrCa association may provide insight into the underlying mechanisms of this association. We evaluated associations in the Atherosclerosis Risk in Communities study between PrCa and nine T2D single nucleotide polymorphisms from genome-wide association studies of T2D (in CDKAL1, CDKN2A/B, FTO, HHEX, IGF2BP2, KCNJ11, PPARG, SLC30A8, and TCF7L2) and four T2D single nucleotide polymorphisms from pre-genome-wide association studies (in ADRB2, CAPN10, SLC2A2, and UCP2). From 1987 to 2000, there were 397 incident PrCa cases among 6,642 men ages 45 to 64 years at baseline. We used race-adjusted Cox proportional hazards models to estimate associations between PrCa and increasing number of T2D risk-raising alleles. PrCa was positively associated with the CAPN10 rs3792267 G allele [hazard ratio (HR) 1.20; 95% confidence interval (CI), 1.00-1.44] and inversely associated with the SLC2A2 rs5400 Thr110 allele (HR, 0.85; 95% CI, 0.72, 1.00), the UCP2 rs660339 Val55 allele (HR, 0.84; 95% CI, 0.73, 0.97) and the IGF2BP2 rs4402960 T allele (HR, 0.79; 95% CI, 0.61-1.02; blacks only). The TCF7L2 rs7903146 T allele was inversely associated with PrCa using a dominant genetic model (HR, 0.79; 95% CI, 0.65-0.97). Further knowledge of T2D gene-PrCa mechanisms may improve understanding of PrCa etiology.


Assuntos
Diabetes Mellitus Tipo 2/genética , Predisposição Genética para Doença , Neoplasias da Próstata/genética , Aterosclerose/genética , Calpaína/genética , Estudos de Coortes , Estudo de Associação Genômica Ampla , Transportador de Glucose Tipo 2/genética , Humanos , Canais Iônicos/genética , Masculino , Pessoa de Meia-Idade , Proteínas Mitocondriais/genética , Polimorfismo de Nucleotídeo Único , Modelos de Riscos Proporcionais , Proteínas de Ligação a RNA/genética , Fatores de Transcrição TCF/genética , Proteína 2 Semelhante ao Fator 7 de Transcrição , Proteína Desacopladora 2
19.
Atherosclerosis ; 210(1): 188-93, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20064641

RESUMO

OBJECTIVE: Genetic variation in matrix metalloproteinase (MMP) promoter regions alter the transcriptional activity of MMPs and has been consistently associated with CHD, presumably through plaque degradation and remodeling. We examined the association of MMP promoter variation with multiple plaque characteristics measured by gadolinium-enhanced MRI among 1700 participants in the Atherosclerosis Risk in Communities (ARIC) Carotid MRI Study. METHODS: For the analyses presented here, 1700 participants of the biracial ARIC Carotid MRI Study ( approximately 1000 participants with thick carotid artery walls and approximately 700 randomly sampled participants) were evaluated for associations of MMP genetic variation with multiple plaque characteristics, including carotid artery wall thickness, lipid core and fibrous cap measures. MRI studies were performed on a 1.5T scanner equipped with a bilateral 4-element phased array carotid coil. RESULTS: Fifty-one percent of the participants were female, 77% white, 23% African American, and the mean age was 70 years. MMP2 C-1306T variant genotypes (CT+TT) were significantly associated with higher cap thickness measures, but not with wall thickness or lipid core measures. Individuals with the CC genotype had approximately 0.1mm thinner cap thickness compared to those carrying a T allele (P=0.02). CONCLUSION: Genetic variation within the MMP2 promoter region was associated with cap thickness and therefore may influence the role of MMP2 in plaque vulnerability.


Assuntos
Aterosclerose/genética , Aterosclerose/patologia , Artérias Carótidas/patologia , Metaloproteinase 2 da Matriz/genética , Regiões Promotoras Genéticas/genética , Idoso , Feminino , Variação Genética , Genótipo , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Transcrição Gênica
20.
Hypertens Res ; 33(2): 165-9, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19960019

RESUMO

Endothelial nitric oxide synthase breaks down nitric oxide and has a key role in blood pressure regulation. Earlier studies have shown associations between single nucleotide polymorphisms (SNPs) in the NOS3 gene and hypertension. Studies also suggest that such associations may vary by dietary fat intake. We investigated associations between the NOS3 Glu298Asp SNP (rs1799983) and hypertension, as well as the interaction between NOS3 genotypes and dietary fat intake using data from baseline examination in white and African American participants in the Atherosclerosis Risk in Community (ARIC) study. Dietary fat intake was measured by a Food Frequency Questionnaire during the baseline examination in 15 792 individuals aged 45-64 years in ARIC study participants. Race-stratified unconditional logistic regression was performed to investigate the association between prevalent hypertension and NOS3 Glu298Asp genotypes. There was no significant interaction between dietary fat intake and NOS3 Glu298Asp genotype with regards to hypertension status in either African Americans or whites (P for interaction=0.3 and 0.4, respectively). We found a significant relationship between NOS3 Glu298Asp and triglycerides in African Americans. We did not find an association between the NOS3 Glu298Asp polymorphism and hypertension, and dietary fat intake did not interact with NOS3 genotypes to influence hypertension. We recommend further exploration of the relationship between NOS3 Glu298Asp and triglycerides in African Americans.


Assuntos
Negro ou Afro-Americano/genética , Gorduras na Dieta/administração & dosagem , Hipertensão/genética , Óxido Nítrico Sintase Tipo III/genética , Polimorfismo de Nucleotídeo Único , População Branca/genética , Aterosclerose/etiologia , Ingestão de Energia , Genótipo , Humanos , Hipertensão/etnologia , Pessoa de Meia-Idade
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