Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 110
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Diabetes ; 68(5): 1073-1083, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30936141

RESUMO

Nonalcoholic fatty liver disease (NAFLD) is a risk factor for type 2 diabetes (T2D). We aimed to identify the peripheral blood DNA methylation signature of hepatic fat. We conducted epigenome-wide association studies of hepatic fat in 3,400 European ancestry (EA) participants and in 401 Hispanic ancestry and 724 African ancestry participants from four population-based cohort studies. Hepatic fat was measured using computed tomography or ultrasound imaging and DNA methylation was assessed at >400,000 cytosine-guanine dinucleotides (CpGs) in whole blood or CD14+ monocytes using a commercial array. We identified 22 CpGs associated with hepatic fat in EA participants at a false discovery rate <0.05 (corresponding P = 6.9 × 10-6) with replication at Bonferroni-corrected P < 8.6 × 10-4 Mendelian randomization analyses supported the association of hypomethylation of cg08309687 (LINC00649) with NAFLD (P = 2.5 × 10-4). Hypomethylation of the same CpG was also associated with risk for new-onset T2D (P = 0.005). Our study demonstrates that a peripheral blood-derived DNA methylation signature is robustly associated with hepatic fat accumulation. The hepatic fat-associated CpGs may represent attractive biomarkers for T2D. Future studies are warranted to explore mechanisms and to examine DNA methylation signatures of NAFLD across racial/ethnic groups.

2.
Nat Genet ; 51(4): 636-648, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30926973

RESUMO

The concentrations of high- and low-density-lipoprotein cholesterol and triglycerides are influenced by smoking, but it is unknown whether genetic associations with lipids may be modified by smoking. We conducted a multi-ancestry genome-wide gene-smoking interaction study in 133,805 individuals with follow-up in an additional 253,467 individuals. Combined meta-analyses identified 13 new loci associated with lipids, some of which were detected only because association differed by smoking status. Additionally, we demonstrate the importance of including diverse populations, particularly in studies of interactions with lifestyle factors, where genomic and lifestyle differences by ancestry may contribute to novel findings.


Assuntos
Lipídeos/sangue , Lipídeos/genética , Fumar/sangue , Fumar/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Estudo de Associação Genômica Ampla/métodos , Genótipo , Humanos , Estilo de Vida , Desequilíbrio de Ligação/genética , Masculino , Pessoa de Meia-Idade , Adulto Jovem
3.
Diabetes Care ; 42(5): 946-953, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30796111

RESUMO

OBJECTIVE: South Asians have a higher prevalence of type 2 diabetes compared with other race/ethnic groups. Body composition is associated with the risk for type 2 diabetes. Differences in body composition between South Asians and other race/ethnic groups are one hypothesized mechanism to explain the disproportionate prevalence of type 2 diabetes in this population. RESEARCH DESIGN AND METHODS: This study used data from the Mediators of Atherosclerosis in South Asians Living in America (MASALA) and the Multi-Ethnic Study of Atherosclerosis (MESA) cohorts to determine whether body composition mediated the elevated prevalence of impaired fasting glucose and type 2 diabetes in South Asians. Participants (n = 2,615) with complete body composition data were included. Ordinal logistic regression models were calculated to determine the odds for glycemic impairment in South Asians compared with the MESA cohort. RESULTS: In multivariate models, South Asians had a significantly higher prevalence of glycemic impairment and type 2 diabetes compared with all four race/ethnic groups included in the MESA (P < 0.001 for all). In unadjusted and multivariate adjusted models, South Asians had higher odds for impaired fasting glucose and type 2 diabetes compared with all other race/ethnic groups (P < 0.001 for all). The addition of body composition measures did not significantly mitigate this relationship. CONCLUSIONS: We did not identify strong evidence that accounting for body composition explains differences in the risk for type 2 diabetes. Future prospective studies of the MESA and MASALA cohorts are needed to understand how adipose tissue impacts the risk for type 2 diabetes and how to best assess this risk.

4.
Psychosom Med ; 80(3): 242-251, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29280852

RESUMO

OBJECTIVE: Shared genetic background may explain phenotypic associations between depression and Type 2 diabetes (T2D). We aimed to study, on a genome-wide level, if genetic correlation and pleiotropic loci exist between depressive symptoms and T2D or glycemic traits. METHODS: We estimated single-nucleotide polymorphism (SNP)-based heritability and analyzed genetic correlation between depressive symptoms and T2D and glycemic traits with the linkage disequilibrium score regression by combining summary statistics of previously conducted meta-analyses for depressive symptoms by CHARGE consortium (N = 51,258), T2D by DIAGRAM consortium (N = 34,840 patients and 114,981 controls), fasting glucose, fasting insulin, and homeostatic model assessment of ß-cell function and insulin resistance by MAGIC consortium (N = 58,074). Finally, we investigated pleiotropic loci using a bivariate genome-wide association study approach with summary statistics from genome-wide association study meta-analyses and reported loci with genome-wide significant bivariate association p value (p < 5 × 10). Biological annotation and function of significant pleiotropic SNPs were assessed in several databases. RESULTS: The SNP-based heritability ranged from 0.04 to 0.10 in each individual trait. In the linkage disequilibrium score regression analyses, depressive symptoms showed no significant genetic correlation with T2D or glycemic traits (p > 0.37). However, we identified pleiotropic genetic variations for depressive symptoms and T2D (in the IGF2BP2, CDKAL1, CDKN2B-AS, and PLEKHA1 genes), and fasting glucose (in the MADD, CDKN2B-AS, PEX16, and MTNR1B genes). CONCLUSIONS: We found no significant overall genetic correlations between depressive symptoms, T2D, or glycemic traits suggesting major differences in underlying biology of these traits. However, several potential pleiotropic loci were identified between depressive symptoms, T2D, and fasting glucose, suggesting that previously established phenotypic associations may be partly explained by genetic variation in these specific loci.

5.
Nat Commun ; 8(1): 393, 2017 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-28855511

RESUMO

Little is known regarding the epigenetic basis of atherosclerosis. Here we present the CD14+ blood monocyte transcriptome and epigenome signatures associated with human atherosclerosis. The transcriptome signature includes transcription coactivator, ARID5B, which is known to form a chromatin derepressor complex with a histone H3K9Me2-specific demethylase and promote adipogenesis and smooth muscle development. ARID5B CpG (cg25953130) methylation is inversely associated with both ARID5B expression and atherosclerosis, consistent with this CpG residing in an ARID5B enhancer region, based on chromatin capture and histone marks data. Mediation analysis supports assumptions that ARID5B expression mediates effects of cg25953130 methylation and several cardiovascular disease risk factors on atherosclerotic burden. In lipopolysaccharide-stimulated human THP1 monocytes, ARID5B knockdown reduced expression of genes involved in atherosclerosis-related inflammatory and lipid metabolism pathways, and inhibited cell migration and phagocytosis. These data suggest that ARID5B expression, possibly regulated by an epigenetically controlled enhancer, promotes atherosclerosis by dysregulating immunometabolism towards a chronic inflammatory phenotype.The molecular mechanisms mediating the impact of environmental factors in atherosclerosis are unclear. Here, the authors examine CD14+ blood monocyte's transcriptome and epigenome signatures to find differential methylation and expression of ARID5B to be associated with human atherosclerosis.


Assuntos
Aterosclerose/genética , Proteínas de Ligação a DNA/genética , Monócitos/metabolismo , Fatores de Transcrição/genética , Transcriptoma , Idoso , Aterosclerose/metabolismo , Metilação de DNA , Proteínas de Ligação a DNA/metabolismo , Epigênese Genética , Feminino , Histonas/genética , Histonas/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Monócitos/química , Fatores de Transcrição/metabolismo
6.
Hypertension ; 70(4): 743-750, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28784648

RESUMO

Hypertension represents a major cardiovascular risk factor. The pathophysiology of increased blood pressure (BP) is not yet completely understood. Transcriptome profiling offers possibilities to uncover genetics effects on BP. Based on 2 populations including 2549 individuals, a meta-analyses of monocytic transcriptome-wide profiles were performed to identify transcripts associated with BP. Replication was performed in 2 independent studies of whole-blood transcriptome data including 1990 individuals. For identified candidate genes, a direct link between long-term changes in BP and gene expression over time and by treatment with BP-lowering therapy was assessed. The predictive value of protein levels encoded by candidate genes for subsequent cardiovascular disease was investigated. Eight transcripts (CRIP1, MYADM, TIPARP, TSC22D3, CEBPA, F12, LMNA, and TPPP3) were identified jointly accounting for up to 13% (95% confidence interval, 8.7-16.2) of BP variability. Changes in CRIP1, MYADM, TIPARP, LMNA, TSC22D3, CEBPA, and TPPP3 expression associated with BP changes-among these, CRIP1 gene expression was additionally correlated to measures of cardiac hypertrophy. Assessment of circulating CRIP1 (cystein-rich protein 1) levels as biomarkers showed a strong association with increased risk for incident stroke (hazard ratio, 1.06; 95% confidence interval, 1.03-1.09; P=5.0×10-5). Our comprehensive analysis of global gene expression highlights 8 novel transcripts significantly associated with BP, providing a link between gene expression and BP. Translational approaches further established evidence for the potential use of CRIP1 as emerging disease-related biomarker.


Assuntos
Proteínas de Transporte/genética , Hipertensão , Proteínas com Domínio LIM/genética , Acidente Vascular Cerebral , Adulto , Pressão Sanguínea/genética , Determinação da Pressão Arterial/métodos , Determinação da Pressão Arterial/estatística & dados numéricos , Proteínas Estimuladoras de Ligação a CCAAT/genética , Feminino , Expressão Gênica , Perfilação da Expressão Gênica , Estudo de Associação Genômica Ampla , Humanos , Hipertensão/diagnóstico , Hipertensão/genética , Masculino , Proteínas Proteolipídicas Associadas a Linfócitos e Mielina/genética , Poli(ADP-Ribose) Polimerases/genética , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/prevenção & controle , Fatores de Transcrição/genética
8.
Sci Rep ; 7: 45040, 2017 04 28.
Artigo em Inglês | MEDLINE | ID: mdl-28452372

RESUMO

HapMap imputed genome-wide association studies (GWAS) have revealed >50 loci at which common variants with minor allele frequency >5% are associated with kidney function. GWAS using more complete reference sets for imputation, such as those from The 1000 Genomes project, promise to identify novel loci that have been missed by previous efforts. To investigate the value of such a more complete variant catalog, we conducted a GWAS meta-analysis of kidney function based on the estimated glomerular filtration rate (eGFR) in 110,517 European ancestry participants using 1000 Genomes imputed data. We identified 10 novel loci with p-value < 5 × 10-8 previously missed by HapMap-based GWAS. Six of these loci (HOXD8, ARL15, PIK3R1, EYA4, ASTN2, and EPB41L3) are tagged by common SNPs unique to the 1000 Genomes reference panel. Using pathway analysis, we identified 39 significant (FDR < 0.05) genes and 127 significantly (FDR < 0.05) enriched gene sets, which were missed by our previous analyses. Among those, the 10 identified novel genes are part of pathways of kidney development, carbohydrate metabolism, cardiac septum development and glucose metabolism. These results highlight the utility of re-imputing from denser reference panels, until whole-genome sequencing becomes feasible in large samples.


Assuntos
Biologia Computacional/métodos , Loci Gênicos , Rim/fisiologia , Frequência do Gene , Genoma Humano , Estudo de Associação Genômica Ampla , Técnicas de Genotipagem , Humanos , Polimorfismo de Nucleotídeo Único
9.
Obesity (Silver Spring) ; 25(6): 1115-1121, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28452401

RESUMO

OBJECTIVE: To determine whether greater pericardial fat volume would be associated with increased risk of incident atrial fibrillation (AF). METHODS: In the Multi-Ethnic Study of Atherosclerosis and Jackson Heart Study, pericardial fat volume was quantified by computed tomography. Incident AF was identified from discharge diagnosis codes, study electrocardiograms, and Medicare claims. RESULTS: Among 7,991 participants, 40% were African American, 32% white, 18% Hispanic, and 10% Chinese American; mean age was 62 years; 55% were women. During an average of 10.0 years of follow-up in the Multi-Ethnic Study of Atherosclerosis and 4.5 years in the Jackson Heart Study, 756 incident AF cases were identified. After adjustment for age, sex, study, race/ethnicity, height, glucose status, systolic blood pressure, treated hypertension, and BMI, greater pericardial fat volume was associated with higher AF risk in Hispanics (hazard ratio 1.24 per SD, 95% confidence interval 1.05-1.46) but not overall (hazard ratio 1.06, 95% confidence interval 0.97-1.15). In mediation analysis, pericardial fat volume partially mediated the association of BMI with incident AF in Hispanics. CONCLUSIONS: After adjustment for BMI, greater pericardial fat volume was associated with incident AF in Hispanics but not overall. Additional research is needed on the mechanisms by which pericardial fat volume is related to increased AF risk and possible differences by race/ethnicity.


Assuntos
Gordura Abdominal/metabolismo , Tecido Adiposo/fisiopatologia , Aterosclerose/etnologia , Fibrilação Atrial/etnologia , Doenças Cardiovasculares/etnologia , Pericárdio/anormalidades , Idoso , Idoso de 80 Anos ou mais , Aterosclerose/terapia , Fibrilação Atrial/terapia , Doenças Cardiovasculares/complicações , Grupos Étnicos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
10.
Metabolism ; 70: 98-106, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28403949

RESUMO

BACKGROUND: Low levels of the soluble receptor for advanced glycation endproducts (sRAGE) have been implicated in a number of chronic diseases. Previous studies indicate that sRAGE levels are ~30% lower in Blacks compared to Whites. However, the reasons for these differences are unclear. PURPOSE: We aimed to identify predictors of circulating sRAGE biomarkers among Black and White adults at high cardiac risk. METHODS: Serum levels of total sRAGE, endogenous secretory RAGE (esRAGE), carboxymethyl-lysine (CML, a major RAGE ligand), and their ratios were measured in 99 Blacks and 454 Whites. RESULTS: Blacks had a more adverse cardiovascular risk profile, as well as lower median levels of total sRAGE (972 vs. 1564pg/ml) and esRAGE (474 vs. 710pg/ml) compared to Whites (p<0.0001). In addition, the proportion of esRAGE was higher in Blacks (47% vs. 44%, p=0.02), as were the CML/total sRAGE (0.89 vs. 0.56ng/pg) and CML/esRAGE (1.72 vs. 1.20ng/pg) ratios (p<0.0001). Racial differences persisted after adjustment for key covariates including age, gender, tobacco use, comorbidities, BMI, blood pressure, glucose, insulin, triglycerides, C-reactive protein, and renal function (p<0.05). Race alone accounted for nearly half of the variability in total sRAGE levels (10.6%; model explained 23.9%). In stratified analyses, gender and heart rate were independently associated with total sRAGE and esRAGE in Whites, while CML and C-reactive protein were associated with total sRAGE in Blacks. CONCLUSIONS: We identified several independent predictors of sRAGE biomarkers. Notably, Black race was associated with an adverse AGE/RAGE profile, including lower sRAGE and higher CML/sRAGE ratios.


Assuntos
Receptor para Produtos Finais de Glicação Avançada/sangue , Grupo com Ancestrais do Continente Africano , Idoso , Idoso de 80 Anos ou mais , Proteína C-Reativa/análise , Grupos de Populações Continentais , Grupo com Ancestrais do Continente Europeu , Feminino , Frequência Cardíaca , Humanos , Lisina/análogos & derivados , Lisina/sangue , Masculino , Pessoa de Meia-Idade , Fatores Sexuais
11.
JACC Cardiovasc Imaging ; 10(9): 1016-1027, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28330662

RESUMO

OBJECTIVES: The study sought to determine the associations between local (pericardial) fat and incident cardiovascular disease (CVD) events and cardiac remodeling independent of markers of overall adiposity. BACKGROUND: The impact of pericardial fat-a local fat depot encasing the heart-on myocardial function and long-term CV prognosis independent of systemic consequences of adiposity or hepatic fat is an area of active debate. METHODS: We studied 4,234 participants enrolled in the MESA (Multi-Ethnic Study of Atherosclerosis) study with concomitant cardiac magnetic resonance imaging and computed tomography (CT) measurements for pericardial fat volume and hepatic attenuation (a measure of liver fat). Poisson and Cox regression were used to estimate the annualized risk of incident hard atherosclerotic CVD (ASCVD), all-cause death, heart failure, all-cause CVD, hard coronary heart disease, and stroke as a function of pericardial and hepatic fat. Generalized additive models were used to assess the association between cardiac magnetic resonance indices of left ventricular (LV) structure and function and pericardial fat. Models were adjusted for relevant clinical, demographic, and cardiometabolic covariates. RESULTS: MESA study participants with higher pericardial and hepatic fat were more likely to be older, were more frequently men, and had a higher prevalence of cardiometabolic risk factors (including dysglycemia, dyslipidemia, hypertension), as well as adiposity-associated inflammation. Over a median 12.2-year follow-up (interquartile range: 11.6 to 12.8 years), pericardial fat was associated with a higher rate of incident hard ASCVD (standardized hazard ratio: 1.22; 95% confidence interval: 1.10 to 1.35; p = 0.0001). Hepatic fat by CT was not significantly associated with hard ASCVD (standardized hazard ratio: 0.96; 95% confidence interval: 0.86 to 1.08; p = 0.52). Higher pericardial fat was associated with greater indexed LV mass (37.8 g/m2.7 vs. 33.9 g/m2.7, highest quartile vs. lowest quartile; p < 0.01), LV mass-to-volume ratio (1.2 vs. 1.1, highest quartile vs. lowest quartile; p < 0.01). In adjusted models, a higher pericardial fat volume was associated with greater LV mass (p < 0.0001) and concentricity (p < 0.0001). CONCLUSIONS: Pericardial fat is associated with poorer CVD prognosis and LV remodeling, independent of insulin resistance, inflammation, and CT measures of hepatic fat.


Assuntos
Tecido Adiposo/diagnóstico por imagem , Adiposidade , Doenças Cardiovasculares/diagnóstico por imagem , Fígado Gorduroso/diagnóstico por imagem , Fígado/diagnóstico por imagem , Pericárdio/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Tecido Adiposo/fisiopatologia , Adiposidade/etnologia , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Doenças Cardiovasculares/etnologia , Doenças Cardiovasculares/mortalidade , Doenças Cardiovasculares/fisiopatologia , Distribuição de Qui-Quadrado , Comorbidade , Fígado Gorduroso/etnologia , Fígado Gorduroso/mortalidade , Fígado Gorduroso/fisiopatologia , Humanos , Incidência , Modelos Lineares , Fígado/fisiopatologia , Estudos Longitudinais , Imagem por Ressonância Magnética , Pessoa de Meia-Idade , Pericárdio/fisiopatologia , Valor Preditivo dos Testes , Prognóstico , Modelos de Riscos Proporcionais , Estudos Prospectivos , Fatores de Risco , Fatores Sexuais , Fatores de Tempo , Estados Unidos/epidemiologia , Função Ventricular Esquerda , Remodelação Ventricular
12.
Nat Genet ; 49(1): 125-130, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27918534

RESUMO

Variation in body fat distribution contributes to the metabolic sequelae of obesity. The genetic determinants of body fat distribution are poorly understood. The goal of this study was to gain new insights into the underlying genetics of body fat distribution by conducting sample-size-weighted fixed-effects genome-wide association meta-analyses in up to 9,594 women and 8,738 men of European, African, Hispanic and Chinese ancestry, with and without sex stratification, for six traits associated with ectopic fat (hereinafter referred to as ectopic-fat traits). In total, we identified seven new loci associated with ectopic-fat traits (ATXN1, UBE2E2, EBF1, RREB1, GSDMB, GRAMD3 and ENSA; P < 5 × 10-8; false discovery rate < 1%). Functional analysis of these genes showed that loss of function of either Atxn1 or Ube2e2 in primary mouse adipose progenitor cells impaired adipocyte differentiation, suggesting physiological roles for ATXN1 and UBE2E2 in adipogenesis. Future studies are necessary to further explore the mechanisms by which these genes affect adipocyte biology and how their perturbations contribute to systemic metabolic disease.


Assuntos
Adipócitos/citologia , Distribuição da Gordura Corporal , Diferenciação Celular , Loci Gênicos/genética , Marcadores Genéticos/genética , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único/genética , Adipócitos/metabolismo , Animais , Estudos de Coortes , Grupos Étnicos/genética , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/genética , Fenótipo
13.
Sci Rep ; 6: 35371, 2016 11 08.
Artigo em Inglês | MEDLINE | ID: mdl-27824142

RESUMO

Atrial fibrillation (AF) is a heritable disease that affects more than thirty million individuals worldwide. Extensive efforts have been devoted to the study of genetic determinants of AF. The objective of our study is to examine the effect of gene-gene interaction on AF susceptibility. We performed a large-scale association analysis of gene-gene interactions with AF in 8,173 AF cases, and 65,237 AF-free referents collected from 15 studies for discovery. We examined putative interactions between genome-wide SNPs and 17 known AF-related SNPs. The top interactions were then tested for association in an independent cohort for replication, which included more than 2,363 AF cases and 114,746 AF-free referents. One interaction, between rs7164883 at the HCN4 locus and rs4980345 at the SLC28A1 locus, was found to be significantly associated with AF in the discovery cohorts (interaction OR = 1.44, 95% CI: 1.27-1.65, P = 4.3 × 10-8). Eight additional gene-gene interactions were also marginally significant (P < 5 × 10-7). However, none of the top interactions were replicated. In summary, we did not find significant interactions that were associated with AF susceptibility. Future increases in sample size and denser genotyping might facilitate the identification of gene-gene interactions associated with AF.


Assuntos
Fibrilação Atrial/genética , Estudos de Associação Genética , Idoso , Estudos de Coortes , Epistasia Genética , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/genética , Masculino , Proteínas de Membrana Transportadoras/genética , Pessoa de Meia-Idade , Análise Multivariada , Proteínas Musculares/genética , Análise de Sequência com Séries de Oligonucleotídeos , Polimorfismo de Nucleotídeo Único , Canais de Potássio/genética
14.
J Am Heart Assoc ; 5(11)2016 11 17.
Artigo em Inglês | MEDLINE | ID: mdl-27856485

RESUMO

BACKGROUND: South Asians have a low body mass index and high prevalence of cardiovascular disease (CVD) relative to other racial/ethnic groups. Radiographically detected ectopic fat distribution is better associated with CVD than body mass index. We assessed whether differences in ectopic fat depots explained differences in the prevalence/severity of coronary artery calcium (CAC), a predictor of incident CVD events, among South Asians compared with other racial/ethnic groups. METHODS AND RESULTS: We examined the associations of radiographically detected visceral, intermuscular, intrahepatic, and pericardial fat with CAC among adults without baseline CVD. We compared 803 South Asians in the Mediators of Atherosclerosis in South Asians Living in America to 4 racial/ethnic groups in the Multi-Ethnic Study of Atherosclerosis: 2622 whites, 1893 blacks, 1496 Latinos, and 803 Chinese Americans. We adjusted for body mass index and known CVD risk factors. South Asians had the highest intrahepatic fat and lowest pericardial fat volume (PFV). There was a positive graded association between ectopic fat and higher CAC scores in all the groups with the strongest associations observed with PFV. PFV was independently associated with CAC severity in South Asians (P=0.01) and blacks (P=0.05) and borderline in whites (P=0.06). PFV partially explained the higher CAC burden in South Asians compared with blacks, but not the other racial/ethnic groups. CONCLUSIONS: Differences in PFV explain a small fraction of the higher CAC burden in South Asians. Our findings suggest that ectopic fat depots may not explain the elevated CAC risk in South Asians.


Assuntos
Tecido Adiposo/diagnóstico por imagem , Coristoma/etnologia , Doença da Artéria Coronariana/etnologia , Grupos Étnicos/estatística & dados numéricos , Calcificação Vascular/etnologia , Adulto , Afro-Americanos , Idoso , Idoso de 80 Anos ou mais , Americanos Asiáticos , Bangladesh/etnologia , Coristoma/diagnóstico por imagem , Doença da Artéria Coronariana/diagnóstico por imagem , Estudos Transversais , Grupo com Ancestrais do Continente Europeu , Feminino , Cardiopatias/diagnóstico por imagem , Cardiopatias/etnologia , Hispano-Americanos , Humanos , Índia/etnologia , Gordura Intra-Abdominal/diagnóstico por imagem , Fígado/diagnóstico por imagem , Hepatopatias/diagnóstico por imagem , Hepatopatias/etnologia , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/diagnóstico por imagem , Doenças Musculares/diagnóstico por imagem , Doenças Musculares/etnologia , Nepal/etnologia , Paquistão/etnologia , Pericárdio/diagnóstico por imagem , Sri Lanka/etnologia , Tomografia Computadorizada por Raios X , Estados Unidos , Calcificação Vascular/diagnóstico por imagem
15.
Circ Cardiovasc Genet ; 9(5): 436-447, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27651444

RESUMO

BACKGROUND: DNA methylation leaves a long-term signature of smoking exposure and is one potential mechanism by which tobacco exposure predisposes to adverse health outcomes, such as cancers, osteoporosis, lung, and cardiovascular disorders. METHODS AND RESULTS: To comprehensively determine the association between cigarette smoking and DNA methylation, we conducted a meta-analysis of genome-wide DNA methylation assessed using the Illumina BeadChip 450K array on 15 907 blood-derived DNA samples from participants in 16 cohorts (including 2433 current, 6518 former, and 6956 never smokers). Comparing current versus never smokers, 2623 cytosine-phosphate-guanine sites (CpGs), annotated to 1405 genes, were statistically significantly differentially methylated at Bonferroni threshold of P<1×10-7 (18 760 CpGs at false discovery rate <0.05). Genes annotated to these CpGs were enriched for associations with several smoking-related traits in genome-wide studies including pulmonary function, cancers, inflammatory diseases, and heart disease. Comparing former versus never smokers, 185 of the CpGs that differed between current and never smokers were significant P<1×10-7 (2623 CpGs at false discovery rate <0.05), indicating a pattern of persistent altered methylation, with attenuation, after smoking cessation. Transcriptomic integration identified effects on gene expression at many differentially methylated CpGs. CONCLUSIONS: Cigarette smoking has a broad impact on genome-wide methylation that, at many loci, persists many years after smoking cessation. Many of the differentially methylated genes were novel genes with respect to biological effects of smoking and might represent therapeutic targets for prevention or treatment of tobacco-related diseases. Methylation at these sites could also serve as sensitive and stable biomarkers of lifetime exposure to tobacco smoke.


Assuntos
Metilação de DNA , Epigênese Genética , Fumar/efeitos adversos , Fumar/genética , Transcriptoma , Idoso , Estudos de Casos e Controles , Ilhas de CpG , Feminino , Perfilação da Expressão Gênica/métodos , Marcadores Genéticos , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Leucócitos/química , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Fenótipo , Fumar/etnologia , Abandono do Hábito de Fumar , Prevenção do Hábito de Fumar , Fatores de Tempo
16.
PLoS One ; 11(6): e0157654, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27311062

RESUMO

BACKGROUND: Pericardial fat has been implicated in the pathogenesis of obesity-related cardiovascular disease. Proposed mechanisms may be relevant in right heart failure, but relationships between pericardial fat and right ventricular (RV) morphology have not been explored. METHODS: The Multi-Ethnic Study of Atherosclerosis is a prospective cohort that enrolled participants without clinical cardiovascular disease. Pericardial fat was measured using computed tomography and RV parameters using cardiac MRI. Linear regression estimated associations of pericardial fat with RV mass, RV end diastolic volume (RV-EDV), RV end systolic volume (RV-ESV), RV stroke volume (RV-SV), and RV ejection fraction (RV-EF). Limited models adjusted for age, gender, race, height, and study site with and without weight. Fully adjusted models also accounted for socioeconomic parameters and health behaviors. Adjustment for left ventricular morphology, metabolic syndrome, and systemic inflammation was also performed. RESULTS: The study sample included 3988 participants with complete assessment of RV morphology, pericardial fat and all covariates. Greater pericardial fat volume was associated with reduced RV mass (-0.3g per 40 cm3 increase in pericardial fat, p<0.001), smaller RV-EDV (-3.7ml per 40 cm3 increase in pericardial fat, p<0.001), smaller RV-ESV (-1.0ml per 40cm3 increase in pericardial fat, p<0.001), and smaller RV-SV (-2.7mL per 40 cm3 increase in pericardial fat, p<0.001) in participants after adjustment for weight. Associations were unchanged when accounting for health behaviors, markers of systemic inflammation, and the metabolic syndrome. CONCLUSIONS: Greater pericardial fat was associated with reduced RV mass, smaller RV-EDV, smaller RV-ESV, and smaller RV-SV in participants after adjustment for weight. Relationships between pericardial fat and RV morphology could be relevant to diseases of right heart failure.


Assuntos
Tecido Adiposo/diagnóstico por imagem , Ventrículos do Coração/diagnóstico por imagem , Obesidade/diagnóstico por imagem , Pericárdio/diagnóstico por imagem , Função Ventricular Direita , Tecido Adiposo/patologia , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Aterosclerose , Biomarcadores/sangue , Índice de Massa Corporal , Proteína C-Reativa/metabolismo , Grupos de Populações Continentais , Diástole/fisiologia , Feminino , Comportamentos Relacionados com a Saúde/etnologia , Ventrículos do Coração/patologia , Humanos , Interleucina-6/sangue , Imagem por Ressonância Magnética , Masculino , Síndrome Metabólica/diagnóstico , Síndrome Metabólica/etnologia , Síndrome Metabólica/fisiopatologia , Pessoa de Meia-Idade , Obesidade/etnologia , Obesidade/patologia , Pericárdio/patologia , Estudos Prospectivos , Fatores Sexuais , Volume Sistólico/fisiologia , Sístole/fisiologia , Tomografia Computadorizada por Raios X
17.
Genet Epidemiol ; 40(5): 404-15, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27230302

RESUMO

Studying gene-environment (G × E) interactions is important, as they extend our knowledge of the genetic architecture of complex traits and may help to identify novel variants not detected via analysis of main effects alone. The main statistical framework for studying G × E interactions uses a single regression model that includes both the genetic main and G × E interaction effects (the "joint" framework). The alternative "stratified" framework combines results from genetic main-effect analyses carried out separately within the exposed and unexposed groups. Although there have been several investigations using theory and simulation, an empirical comparison of the two frameworks is lacking. Here, we compare the two frameworks using results from genome-wide association studies of systolic blood pressure for 3.2 million low frequency and 6.5 million common variants across 20 cohorts of European ancestry, comprising 79,731 individuals. Our cohorts have sample sizes ranging from 456 to 22,983 and include both family-based and population-based samples. In cohort-specific analyses, the two frameworks provided similar inference for population-based cohorts. The agreement was reduced for family-based cohorts. In meta-analyses, agreement between the two frameworks was less than that observed in cohort-specific analyses, despite the increased sample size. In meta-analyses, agreement depended on (1) the minor allele frequency, (2) inclusion of family-based cohorts in meta-analysis, and (3) filtering scheme. The stratified framework appears to approximate the joint framework well only for common variants in population-based cohorts. We conclude that the joint framework is the preferred approach and should be used to control false positives when dealing with low-frequency variants and/or family-based cohorts.


Assuntos
Pressão Sanguínea/genética , Interação Gene-Ambiente , Fumar , Estudos de Coortes , Bases de Dados Factuais , Família , Frequência do Gene , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Fenótipo
18.
PLoS One ; 11(3): e0144997, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26950853

RESUMO

BACKGROUND: Data are limited on genome-wide association studies (GWAS) for incident coronary heart disease (CHD). Moreover, it is not known whether genetic variants identified to date also associate with risk of CHD in a prospective setting. METHODS: We performed a two-stage GWAS analysis of incident myocardial infarction (MI) and CHD in a total of 64,297 individuals (including 3898 MI cases, 5465 CHD cases). SNPs that passed an arbitrary threshold of 5×10-6 in Stage I were taken to Stage II for further discovery. Furthermore, in an analysis of prognosis, we studied whether known SNPs from former GWAS were associated with total mortality in individuals who experienced MI during follow-up. RESULTS: In Stage I 15 loci passed the threshold of 5×10-6; 8 loci for MI and 8 loci for CHD, for which one locus overlapped and none were reported in previous GWAS meta-analyses. We took 60 SNPs representing these 15 loci to Stage II of discovery. Four SNPs near QKI showed nominally significant association with MI (p-value<8.8×10-3) and three exceeded the genome-wide significance threshold when Stage I and Stage II results were combined (top SNP rs6941513: p = 6.2×10-9). Despite excellent power, the 9p21 locus SNP (rs1333049) was only modestly associated with MI (HR = 1.09, p-value = 0.02) and marginally with CHD (HR = 1.06, p-value = 0.08). Among an inception cohort of those who experienced MI during follow-up, the risk allele of rs1333049 was associated with a decreased risk of subsequent mortality (HR = 0.90, p-value = 3.2×10-3). CONCLUSIONS: QKI represents a novel locus that may serve as a predictor of incident CHD in prospective studies. The association of the 9p21 locus both with increased risk of first myocardial infarction and longer survival after MI highlights the importance of study design in investigating genetic determinants of complex disorders.


Assuntos
Doença da Artéria Coronariana/genética , Estudo de Associação Genômica Ampla , Infarto do Miocárdio/genética , Idoso , Estudos de Coortes , Comportamento Cooperativo , Doença da Artéria Coronariana/epidemiologia , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/epidemiologia , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos
19.
Am J Clin Nutr ; 103(2): 567-78, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26791180

RESUMO

BACKGROUND: DNA methylation is influenced by diet and single nucleotide polymorphisms (SNPs), and methylation modulates gene expression. OBJECTIVE: We aimed to explore whether the gene-by-diet interactions on blood lipids act through DNA methylation. DESIGN: We selected 7 SNPs on the basis of predicted relations in fatty acids, methylation, and lipids. We conducted a meta-analysis and a methylation and mediation analysis with the use of data from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium and the ENCODE (Encyclopedia of DNA Elements) consortium. RESULTS: On the basis of the meta-analysis of 7 cohorts in the CHARGE consortium, higher plasma HDL cholesterol was associated with fewer C alleles at ATP-binding cassette subfamily A member 1 (ABCA1) rs2246293 (ß = -0.6 mg/dL, P = 0.015) and higher circulating eicosapentaenoic acid (EPA) (ß = 3.87 mg/dL, P = 5.62 × 10(21)). The difference in HDL cholesterol associated with higher circulating EPA was dependent on genotypes at rs2246293, and it was greater for each additional C allele (ß = 1.69 mg/dL, P = 0.006). In the GOLDN (Genetics of Lipid Lowering Drugs and Diet Network) study, higher ABCA1 promoter cg14019050 methylation was associated with more C alleles at rs2246293 (ß = 8.84%, P = 3.51 × 10(18)) and lower circulating EPA (ß = -1.46%, P = 0.009), and the mean difference in methylation of cg14019050 that was associated with higher EPA was smaller with each additional C allele of rs2246293 (ß = -2.83%, P = 0.007). Higher ABCA1 cg14019050 methylation was correlated with lower ABCA1 expression (r = -0.61, P = 0.009) in the ENCODE consortium and lower plasma HDL cholesterol in the GOLDN study (r = -0.12, P = 0.0002). An additional mediation analysis was meta-analyzed across the GOLDN study, Cardiovascular Health Study, and the Multi-Ethnic Study of Atherosclerosis. Compared with the model without the adjustment of cg14019050 methylation, the model with such adjustment provided smaller estimates of the mean plasma HDL cholesterol concentration in association with both the rs2246293 C allele and EPA and a smaller difference by rs2246293 genotypes in the EPA-associated HDL cholesterol. However, the differences between 2 nested models were NS (P > 0.05). CONCLUSION: We obtained little evidence that the gene-by-fatty acid interactions on blood lipids act through DNA methylation.


Assuntos
Transportador 1 de Cassete de Ligação de ATP/genética , HDL-Colesterol/sangue , Metilação de DNA , Ácido Eicosapentaenoico/sangue , Epigênese Genética , Regulação da Expressão Gênica , Polimorfismo de Nucleotídeo Único , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Apolipoproteínas E/sangue , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Estudos de Coortes , Dieta/efeitos adversos , Ácido Eicosapentaenoico/análise , Ácidos Graxos/análise , Ácidos Graxos/sangue , Humanos , Lipídeos/sangue , Lipídeos/química , Regiões Promotoras Genéticas , Triglicerídeos/sangue , Triglicerídeos/química
20.
PLoS One ; 10(10): e0139559, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26448048

RESUMO

BACKGROUND: Few studies have investigated the relationship of anthropometric measurements with computed tomography (CT) body fat composition, and even fewer determined if these relationships differ by sex and race. METHODS: CT scans from 1,851 participants in the population based Multi-Ethnic Study of Atherosclerosis were assessed for visceral and subcutaneous fat areas by semi-automated segmentation of body compartments. Regression models were used to investigate relationships for anthropometry with visceral and subcutaneous fat separately by sex and race/ethnicity. RESULTS: Participants were 50% female, 41% Caucasian, 13% Asian, 21% African American, and 25% Hispanic. For visceral fat, the positive relationship with weight (p = 0.028), waist circumference (p<0.001), waist to hip ratio (p<0.001), and waist to height ratio (p = 0.05) differed by sex, with a steeper slope for men. That is, across the range of these anthropometric measures the rise in visceral fat is faster for men than for women. Additionally, there were differences by race/ethnicity in the relationship with height (p<0.001), weight (p<0.001), waist circumference (p<0.001), hip circumference (p = 0.006), and waist to hip ratio (p = 0.001) with the Hispanic group having shallower slopes. For subcutaneous fat, interaction by sex was found for all anthropometric indices at p<0.05, but not for race/ethnicity. CONCLUSION: The relationship between anthropometry and underlying adiposity differs by sex and race/ethnicity. When anthropometry is used as a proxy for visceral fat in research, sex-specific models should be used.


Assuntos
Tecido Adiposo/diagnóstico por imagem , Aterosclerose/etnologia , Adiposidade , Idoso , Idoso de 80 Anos ou mais , Antropometria , Aterosclerose/patologia , Composição Corporal , Índice de Massa Corporal , Grupos Étnicos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores Sexuais , Tomografia Computadorizada por Raios X , Circunferência da Cintura , Relação Cintura-Quadril
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA