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1.
Arterioscler Thromb Vasc Biol ; : ATVBAHA120314965, 2020 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-33115273

RESUMO

OBJECTIVE: Lp(a) (lipoprotein[a]) is an independent risk factor for cardiovascular diseases and plasma levels are primarily determined by variation at the LPA locus. We performed a genome-wide association study in the UK Biobank to determine whether additional loci influence Lp(a) levels. Approach and Results: We included 293 274 White British individuals in the discovery analysis. Approximately 93 095 623 variants were tested for association with natural log-transformed Lp(a) levels using linear regression models adjusted for age, sex, genotype batch, and 20 principal components of genetic ancestry. After quality control, 131 independent variants were associated at genome-wide significance (P≤5×10-8). In addition to validating previous associations at LPA, APOE, and CETP, we identified a novel variant at the APOH locus, encoding ß2GPI (beta2-glycoprotein I). The APOH variant rs8178824 was associated with increased Lp(a) levels (ß [95% CI] [ln nmol/L], 0.064 [0.047-0.081]; P=2.8×10-13) and demonstrated a stronger effect after adjustment for variation at the LPA locus (ß [95% CI] [ln nmol/L], 0.089 [0.076-0.10]; P=3.8×10-42). This association was replicated in a meta-analysis of 5465 European-ancestry individuals from the Framingham Offspring Study and Multi-Ethnic Study of Atherosclerosis (ß [95% CI] [ln mg/dL], 0.16 [0.044-0.28]; P=0.0071). CONCLUSIONS: In a large-scale genome-wide association study of Lp(a) levels, we identified APOH as a novel locus for Lp(a) in individuals of European ancestry. Additional studies are needed to determine the precise role of ß2GPI in influencing Lp(a) levels as well as its potential as a therapeutic target.

2.
Diabetes Care ; 43(12): 3086-3093, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33033069

RESUMO

OBJECTIVE: To assess the relation of type 2 diabetes occurring earlier (age <55 years) versus later in life to the risk of cardiovascular death and to diabetes in offspring. RESEARCH DESIGN AND METHODS: In the Framingham Heart Study, a community-based prospective cohort study, glycemic status was ascertained at serial examinations over six decades among 5,571 first- and second-generation participants with mortality data and 2,123 second-generation participants who initially did not have diabetes with data on parental diabetes status. We assessed cause of death in a case (cardiovascular death)-control (noncardiovascular death) design and incident diabetes in offspring in relation to parental early-onset diabetes. RESULTS: Among the participants in two generations (N = 5,571), there were 1,822 cardiovascular deaths (including 961 coronary deaths). The odds of cardiovascular versus noncardiovascular death increased with decreasing age of diabetes onset (P < 0.001 trend). Compared with never developing diabetes, early-onset diabetes conferred a 1.81-fold odds (95% CI 1.10-2.97, P = 0.02) of cardiovascular death and 1.75-fold odds (0.96-3.21, P = 0.07) of coronary death, whereas later-onset diabetes was not associated with greater risk for either (P = 0.09 for cardiovascular death; P = 0.51 for coronary death). In second-generation participants, having a parent with early-onset diabetes increased diabetes risk by 3.24-fold (1.73-6.07), whereas having one or both parents with late-onset diabetes increased diabetes risk by 2.19-fold (1.50-3.19). CONCLUSIONS: Our findings provide evidence for a diabetes subgroup with an early onset, a stronger association with cardiovascular death, and higher transgenerational transmission.

3.
J Am Heart Assoc ; 9(18): e014711, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32892691

RESUMO

Background Elevated lipoprotein(a) is a well-established risk factor for atherosclerotic vascular disease but is not measured in routine clinical care. Screening of high lipoprotein(a) in individuals with moderate elevations of low-density lipoprotein cholesterol (LDL-C) may identify individuals at high risk of cardiovascular disease. Methods and Results We examined 2606 Framingham Offspring participants (median age, 54 years; 45% men) prospectively with a median follow-up of 15 years (n=392 incident cardiovascular events). Individuals with higher (≥100 nmol/L) versus lower lipoprotein(a) were divided into groups based on LDL-C <135 mg/dL versus ≥135 mg/dL. In Cox models, after adjustment for known risk factors, high lipoprotein(a) (≥100 nmol/L) and LDL-C ≥135 mg/dL were each significant predictors of cardiovascular disease (LDL-C ≥135 mg/dL: hazard ratio [HR], 1.34; 95% CI, 1.09-1.64; P=0.006; high lipoprotein (a): HR, 1.31; 95% CI, 1.03-1.66; P=0.026). Across the groups of high/low lipoprotein (a) and LDL-C ≥135 mg/dL or <135 mg/dL, the absolute cardiovascular disease risks at 15 years were 22.6% (high lipoprotein(a)/LDL-C ≥135 mg/dL, n=248), 17.3% (low lipoprotein(a)/LDL-C ≥135 mg/dL, n=758), 12.7% (high lipoprotein(a)/LDL-C <135 mg/dL, n=275) and 11.5% (low lipoprotein(a)/LDL-C <135 mg/dL, n=1328, reference group). Among individuals with LDL-C ≥135 mg/dL, those with high lipoprotein(a) had a 43% higher risk (HR, 1.43; 95% CI, 1.05-1.97; P=0.02). Presence of high lipoprotein(a) with moderate LDL-C levels (135-159 mg/dL) yielded absolute risks equivalent to those with LDL-C ≥160 mg/dL (23.5%, 95% CI, 17.4%-31.3%; and 20.7%, 95% CI, 16.8%-25.3%, respectively). Conclusions Concomitant elevation of LDL-C ≥135 mg/dL and lipoprotein(a) ≥100 nmol/L is associated with a high absolute risk of incident cardiovascular disease. lipoprotein(a) measurement in individuals with moderate elevations in LDL-C, who do not otherwise meet criteria for statins, may identify individuals at high cardiovascular risk.

4.
ESC Heart Fail ; 2020 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-32909388

RESUMO

AIMS: Heart failure (HF) is associated with several metabolic changes, but it is unknown whether distinct components of the circulating metabolome may be related to cardiac structure and function, and with incident HF in the community. METHODS AND RESULTS: We assayed 217 circulating metabolites in 2336 Framingham Study participants (mean age 55 ± 10 years, 53% women) without HF at baseline. We used linear and Cox regression to relate concentrations of metabolites to left ventricular (LV) diastolic dimension, LV wall thickness, LV ejection fraction, left atrial dimension, LV ventricular mass, and aortic root size cross-sectionally and to incident HF prospectively. Bonferroni-adjusted P-values <0.05 denoted statistical significance. Circulating concentrations of kynurenine [ß = -0.12 cm per standard deviation (SD) increment in normalized residual of metabolite, P = 7.3 × 10-8 ] and aminoadipate (-0.11 cm per SD increment, P = 2.61 × 10-5 ) were associated with left ventricular diastolic dimension, phosphatidylcholine (carbon:double bound = 38:6) with left atrial dimension (0.10 cm per SD increment, P = 9.7 × 10-6 ), and cholesterol ester (carbon:double bound = 20:5) with left atrial dimension (0.10 cm per SD increment, P = 1.4 × 10-5 ) in multivariable-adjusted models. During an average follow-up of 15.8 (range 0.02-23.2) years, 113 participants (5%) were diagnosed with HF with reduced ejection fraction and 106 individuals (5%) with HF with preserved ejection fraction. In multivariable analyses, concentrations of phosphatidylcholine (hazard ratio 0.63, P = 1.3 × 10-5 ) and ornithine (hazard ratio 1.44, P = 0.00014) were associated with HF with reduced ejection fraction. CONCLUSIONS: Several metabolites, including the vasoactive metabolite kynurenine, were related to cardiac structure and function in our sample. Additional research is warranted to confirm our observations and investigate if these metabolites can risk stratify ambulatory individuals.

5.
J Am Heart Assoc ; 9(19): e017598, 2020 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-32975162

RESUMO

Background Epidemiological and animal studies have associated systemic inflammation with blood pressure (BP). However, the mechanistic factors linking inflammation and BP remain unknown. Fatty acid-derived eicosanoids serve as mediators of inflammation and have been suggested to regulate renal vascular tone, peripheral resistance, renin-angiotensin system, and endothelial function. We hypothesize that specific proinflammatory and anti-inflammatory eicosanoids are linked with BP. Methods and Results We studied a population sample of 8099 FINRISK 2002 participants randomly drawn from the Finnish population register (53% women; mean age, 48±13 years) and, for external validation, a sample of 2859 FHS (Framingham Heart Study) Offspring study participants (55% women; mean age, 66±9 years). Using nontargeted liquid chromatography-mass spectrometry, we profiled 545 distinct high-quality eicosanoids and related oxylipin mediators in plasma. Adjusting for conventional hypertension risk factors, we observed 187 (34%) metabolites that were significantly associated with systolic BP (P

6.
J Am Coll Cardiol ; 76(12): 1455-1465, 2020 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-32943164

RESUMO

BACKGROUND: Whether cardiovascular (CV) disease risk factors and biomarkers associate differentially with heart failure (HF) risk in men and women is unclear. OBJECTIVES: The purpose of this study was to evaluate sex-specific associations of CV risk factors and biomarkers with incident HF. METHODS: The analysis was performed using data from 4 community-based cohorts with 12.5 years of follow-up. Participants (recruited between 1989 and 2002) were free of HF at baseline. Biomarker measurements included natriuretic peptides, cardiac troponins, plasminogen activator inhibitor-1, D-dimer, fibrinogen, C-reactive protein, sST2, galectin-3, cystatin-C, and urinary albumin-to-creatinine ratio. RESULTS: Among 22,756 participants (mean age 60 ± 13 years, 53% women), HF occurred in 2,095 participants (47% women). Age, smoking, type 2 diabetes mellitus, hypertension, body mass index, atrial fibrillation, myocardial infarction, left ventricular hypertrophy, and left bundle branch block were strongly associated with HF in both sexes (p < 0.001), and the combined clinical model had good discrimination in men (C-statistic = 0.80) and in women (C-statistic = 0.83). The majority of biomarkers were strongly and similarly associated with HF in both sexes. The clinical model improved modestly after adding natriuretic peptides in men (ΔC-statistic = 0.006; likelihood ratio chi-square = 146; p < 0.001), and after adding cardiac troponins in women (ΔC-statistic = 0.003; likelihood ratio chi-square = 73; p < 0.001). CONCLUSIONS: CV risk factors are strongly and similarly associated with incident HF in both sexes, highlighting the similar importance of risk factor control in reducing HF risk in the community. There are subtle sex-related differences in the predictive value of individual biomarkers, but the overall improvement in HF risk estimation when included in a clinical HF risk prediction model is limited in both sexes.

7.
Proc Natl Acad Sci U S A ; 117(40): 25026-25035, 2020 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-32958645

RESUMO

In addition to their fundamental role in clearance, the kidneys release select molecules into the circulation, but whether any of these anabolic functions provides insight on kidney health is unknown. Using aptamer-based proteomics, we characterized arterial (A)-to-renal venous (V) gradients for >1,300 proteins in 22 individuals who underwent invasive sampling. Although most of the proteins that changed significantly decreased from A to V, consistent with renal clearance, several were found to increase, the most significant of which was testican-2. To assess the clinical implications of these physiologic findings, we examined proteomic data in the Jackson Heart Study (JHS), an African-American cohort (n = 1,928), with replication in the Framingham Heart Study (FHS), a White cohort (n = 1,621). In both populations, testican-2 had a strong, positive correlation with estimated glomerular filtration rate (eGFR). In addition, higher baseline testican-2 levels were associated with a lower rate of eGFR decline in models adjusted for age, gender, hypertension, type 2 diabetes, body mass index, baseline eGFR, and albuminuria. Glomerular expression of testican-2 in human kidneys was demonstrated by immunohistochemistry, immunofluorescence, and electron microscopy, while single-cell RNA sequencing of human kidneys showed expression of the cognate gene, SPOCK2, exclusively in podocytes. In vitro, testican-2 increased glomerular endothelial tube formation and motility, raising the possibility that its secretion has a functional role within the glomerulus. Taken together, our findings identify testican-2 as a podocyte-derived biomarker of kidney health and prognosis.

8.
Circulation ; 142(20): 1905-1924, 2020 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-32927962

RESUMO

BACKGROUND: Whereas regular exercise is associated with lower risk of cardiovascular disease and mortality, mechanisms of exercise-mediated health benefits remain less clear. We used metabolite profiling before and after acute exercise to delineate the metabolic architecture of exercise response patterns in humans. METHODS: Cardiopulmonary exercise testing and metabolite profiling was performed on Framingham Heart Study participants (age 53±8 years, 63% women) with blood drawn at rest (n=471) and at peak exercise (n=411). RESULTS: We observed changes in circulating levels for 502 of 588 measured metabolites from rest to peak exercise (exercise duration 11.9±2.1 minutes) at a 5% false discovery rate. Changes included reductions in metabolites implicated in insulin resistance (glutamate, -29%; P=1.5×10-55; dimethylguanidino valeric acid [DMGV], -18%; P=5.8×10-18) and increases in metabolites associated with lipolysis (1-methylnicotinamide, +33%; P=6.1×10-67), nitric oxide bioavailability (arginine/ornithine + citrulline, +29%; P=2.8×10-169), and adipose browning (12,13-dihydroxy-9Z-octadecenoic acid +26%; P=7.4×10-38), among other pathways relevant to cardiometabolic risk. We assayed 177 metabolites in a separate Framingham Heart Study replication sample (n=783, age 54±8 years, 51% women) and observed concordant changes in 164 metabolites (92.6%) at 5% false discovery rate. Exercise-induced metabolite changes were variably related to the amount of exercise performed (peak workload), sex, and body mass index. There was attenuation of favorable excursions in some metabolites in individuals with higher body mass index and greater excursions in select cardioprotective metabolites in women despite less exercise performed. Distinct preexercise metabolite levels were associated with different physiologic dimensions of fitness (eg, ventilatory efficiency, exercise blood pressure, peak Vo2). We identified 4 metabolite signatures of exercise response patterns that were then analyzed in a separate cohort (Framingham Offspring Study; n=2045, age 55±10 years, 51% women), 2 of which were associated with overall mortality over median follow-up of 23.1 years (P≤0.003 for both). CONCLUSIONS: In a large sample of community-dwelling individuals, acute exercise elicits widespread changes in the circulating metabolome. Metabolic changes identify pathways central to cardiometabolic health, cardiovascular disease, and long-term outcome. These findings provide a detailed map of the metabolic response to acute exercise in humans and identify potential mechanisms responsible for the beneficial cardiometabolic effects of exercise for future study.

9.
Eur J Heart Fail ; 2020 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-32462760

RESUMO

AIMS: We sought to describe the frequency, type and timing of clinical events, and delineate patterns in their transitions, after a first episode of heart failure (HF). METHODS AND RESULTS: In 1036 Framingham participants with new-onset HF (mean age 79 years; 53% women), we used mixture models to estimate probabilities of, and time to cardiac death, other cardiovascular disease (CVD) death, recurrent HF, cardiac events and other CVD events, accounting for age, sex, HF type (preserved vs. reduced ejection fraction), and prevalent cardiac/CVD events. The most common first events after new-onset HF were cardiac (36%), recurrent HF (28%) and death (29%). Compared with recurrent HF (referent transition state), prevalent cardiac events were associated with higher odds of fatal [odds ratio (OR) 1.90, 95% confidence interval (CI) 1.11-3.23] and non-fatal (OR 2.13, 95% CI 1.52-3.00) cardiac events; prevalent CVD increased odds of other CVD death (OR 1.90, 95% CI 1.04-3.47). Among 715 participants without a fatal initial event, there were 3337 distinct epochs (inter-event time periods), with median 3.0 epochs/participant [49% cardiac (n = 1639); 27% recurrent HF (n = 912)]. Median inter-event times varied between 12 to 285 days (recurrent HF to other CVD death and non-fatal other CVD, respectively). Prior HF, cardiac and other CVD events significantly increased odds of developing the same event-type (OR ∼ 5-7-fold), with shortened time to recurrence, indicating 'rapid cycling loops' of the same event type. HF type did not impact the nature or timing of future events. CONCLUSIONS: Comorbidities but not HF type impact clinical course of HF by influencing the type and timing of subsequent events, denoting 'natural history loops' within the overall HF population.

10.
Circ Heart Fail ; 13(5): e006729, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32362167

RESUMO

BACKGROUND: Ventilatory efficiency (minute ventilation required to eliminate carbon dioxide, VE/VCO2) during exercise potently predicts outcomes in advanced heart failure with reduced ejection fraction, but its prognostic significance for at-risk individuals with preserved left ventricular systolic function is unclear. We aimed to characterize mechanistic determinants and prognostic implications of VE/VCO2 in a single-center dyspneic referral cohort (MGH-ExS [Massachusetts General Hospital Exercise Study]) and in a large sample of community-dwelling participants in the FHS (Framingham Heart Study). METHODS: Maximum incremental cardiopulmonary exercise tests were performed. VE/VCO2 was assessed as the slope pre- and post-ventilatory anaerobic threshold (VE/VCO2pre-VATslope, VE/VCO2post-VATslope), the slope throughout exercise (VE/VCO2overall-slope), and as the lowest 30-second value (VE/VCO2nadir). RESULTS: In the MGH-ExS (N=493, age 56±15 years, 61% women, left ventricular ejection fraction 64±8%), higher VE/VCO2nadir was associated with lower peak exercise cardiac output and steeper increases in exercise pulmonary capillary wedge pressure (both P<0.0001). VE/VCO2nadir (hazard ratio, 1.34 per 1-SD unit [95% CI, 1.10-1.62] P=0.003) was associated with future cardiovascular hospitalization/death and outperformed classical VE/VCO2 measures used in heart failure with reduced ejection fraction (VE/VCO2overall-slope). In FHS (N=1936, age 54±9 years, 53% women), VE/VCO2 measures taken in low-to-moderate intensity exercise (including VE/VCO2pre-VATslope, VE/VCO2nadir) were directly associated with cardiovascular risk factor burden (smoking, Framingham cardiovascular disease risk score, and lower fitness; all P<0.001). CONCLUSIONS: Impaired ventilatory efficiency is associated with cardiovascular risk in the community and with adverse hemodynamic profiles and future hospitalizations/death in a referral population, highlighting the prognostic importance of easily acquired submaximum exercise ventilatory gas exchange measurements in broad populations with preserved left ventricular systolic function.


Assuntos
Dispneia/fisiopatologia , Insuficiência Cardíaca/fisiopatologia , Hemodinâmica , Pulmão/fisiopatologia , Ventilação Pulmonar , Função Ventricular Esquerda , Adulto , Idoso , Aptidão Cardiorrespiratória , Dispneia/diagnóstico , Dispneia/etiologia , Teste de Esforço , Tolerância ao Exercício , Feminino , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Sístole , Fatores de Tempo
11.
Circ Heart Fail ; 13(5): e006749, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32408813

RESUMO

BACKGROUND: We used a large-scale, high-throughput DNA aptamer-based discovery proteomic platform to identify circulating biomarkers of cardiac remodeling and incident heart failure (HF) in community-dwelling individuals. METHODS: We evaluated 1895 FHS (Framingham Heart Study) participants (age 55±10 years, 54% women) who underwent proteomic profiling and echocardiography. Plasma levels of 1305 proteins were related to echocardiographic traits and to incident HF using multivariable regression. Statistically significant protein-HF associations were replicated in the HUNT (Nord-Trøndelag Health) study (n=2497, age 63±10 years, 43% women), and results were meta-analyzed. Genetic variants associated with circulating protein levels (pQTLs) were related to echocardiographic traits in the EchoGen (n=30 201) and to incident HF in the CHARGE (n=20 926) consortia. RESULTS: Seventeen proteins associated with echocardiographic traits in cross-sectional analyses (false discovery rate <0.10), and 8 of these proteins had pQTLs associated with echocardiographic traits in EchoGen (P<0.0007). In Cox models adjusted for clinical risk factors, 29 proteins demonstrated associations with incident HF in FHS (174 HF events, mean follow-up 19 [limits, 0.2-23.7] years). In meta-analyses of FHS and HUNT, 6 of these proteins were associated with incident HF (P<3.8×10-5; 3 with higher risk: NT-proBNP [N-terminal proB-type natriuretic peptide], TSP2 [thrombospondin-2], MBL [mannose-binding lectin]; and 3 with lower risk: ErbB1 [epidermal growth factor receptor], GDF-11/8 [growth differentiation factor-11/8], and RGMC [hemojuvelin]). For 5 of the 6 proteins, pQTLs were associated with echocardiographic traits (P<0.0006) in EchoGen, and for RGMC, a protein quantitative trait loci was associated with incident HF (P=0.001). CONCLUSIONS: A large-scale proteomics approach identified new predictors of cardiac remodeling and incident HF. Future studies are warranted to elucidate how biological pathways represented by these proteins may mediate cardiac remodeling and HF risk and to assess if these proteins can improve HF risk prediction.


Assuntos
Aptâmeros de Nucleotídeos , Proteínas Sanguíneas/análise , Ecocardiografia , Variação Genética , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/diagnóstico por imagem , Proteômica , Idoso , Biomarcadores/sangue , Proteínas Sanguíneas/genética , Estudos Transversais , Feminino , Predisposição Genética para Doença , Insuficiência Cardíaca/epidemiologia , Insuficiência Cardíaca/genética , Ensaios de Triagem em Larga Escala , Humanos , Incidência , Masculino , Massachusetts/epidemiologia , Pessoa de Meia-Idade , Noruega/epidemiologia , Fenótipo , Valor Preditivo dos Testes , Estudos Prospectivos , Medição de Risco , Fatores de Risco , Remodelação Ventricular/genética
12.
PLoS One ; 15(4): e0231254, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32275698

RESUMO

BACKGROUND: Heart failure (HF) is a clinical syndrome where diagnostic certainty varies. The prognosis of individuals with some clinical features of HF, but without the fully overt syndrome, is unclear. Therefore, we sought to evaluate their natural history. METHODS AND RESULTS: Between 1990 and 2009, all suspected HF cases in the Framingham Heart Study were adjudicated into 3 groups reflecting varying diagnostic certainty: definite (meeting HF diagnostic criteria; n = 479), possible (meeting HF criteria but with an alternative explanation for findings; n = 135), and probable (insufficient criteria for definite HF; n = 121) HF. Age-and-sex-matched individuals (n = 1112) without HF or cardiovascular disease (CVD) were controls. Using multivariable-adjusted Cox regression, we compared the possible/probable HF groups with controls regarding risk of incident definite HF, coronary heart disease (CHD), other CVD or death; and with definite HF regarding risk of latter three outcomes. During follow-up (mean 8.6 years), ~90% of individuals with possible, probable and definite HF experienced CVD events or died. Compared with controls, those with possible or probable HF experienced higher hazards for definite HF, CHD, other CVD and death (hazards ratios [HR] 1.35-9.31; p<0.05). The possible/probable groups did not differ from the definite HF group for risk of any outcome. Compared with the possible HF group, the probable HF group had a higher propensity for definite HF (HR 1.64, with a higher proportion of ischemic HF) but lower risk of death (HR 0.69). CONCLUSIONS: Individuals meeting partial criteria for HF are at a substantial risk for progression to HF, CVD, and mortality.


Assuntos
Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/patologia , Idoso , Estudos de Casos e Controles , Feminino , Seguimentos , Insuficiência Cardíaca/epidemiologia , Humanos , Incidência , Estimativa de Kaplan-Meier , Masculino , Fenótipo , Prognóstico , Fatores de Risco , Incerteza
13.
JAMA Cardiol ; 5(6): 694-702, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32186652

RESUMO

Importance: Aortic stenosis (AS) has no approved medical treatment. Identifying etiological pathways for AS could identify pharmacological targets. Objective: To identify novel genetic loci and pathways associated with AS. Design, Setting, and Participants: This genome-wide association study used a case-control design to evaluate 44 703 participants (3469 cases of AS) of self-reported European ancestry from the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort (from January 1, 1996, to December 31, 2015). Replication was performed in 7 other cohorts totaling 256 926 participants (5926 cases of AS), with additional analyses performed in 6942 participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Follow-up biomarker analyses with aortic valve calcium (AVC) were also performed. Data were analyzed from May 1, 2017, to December 5, 2019. Exposures: Genetic variants (615 643 variants) and polyunsaturated fatty acids (ω-6 and ω-3) measured in blood samples. Main Outcomes and Measures: Aortic stenosis and aortic valve replacement defined by electronic health records, surgical records, or echocardiography and the presence of AVC measured by computed tomography. Results: The mean (SD) age of the 44 703 GERA participants was 69.7 (8.4) years, and 22 019 (49.3%) were men. The rs174547 variant at the FADS1/2 locus was associated with AS (odds ratio [OR] per C allele, 0.88; 95% CI, 0.83-0.93; P = 3.0 × 10-6), with genome-wide significance after meta-analysis with 7 replication cohorts totaling 312 118 individuals (9395 cases of AS) (OR, 0.91; 95% CI, 0.88-0.94; P = 2.5 × 10-8). A consistent association with AVC was also observed (OR, 0.91; 95% CI, 0.83-0.99; P = .03). A higher ratio of arachidonic acid to linoleic acid was associated with AVC (OR per SD of the natural logarithm, 1.19; 95% CI, 1.09-1.30; P = 6.6 × 10-5). In mendelian randomization, increased FADS1 liver expression and arachidonic acid were associated with AS (OR per unit of normalized expression, 1.31 [95% CI, 1.17-1.48; P = 7.4 × 10-6]; OR per 5-percentage point increase in arachidonic acid for AVC, 1.23 [95% CI, 1.01-1.49; P = .04]; OR per 5-percentage point increase in arachidonic acid for AS, 1.08 [95% CI, 1.04-1.13; P = 4.1 × 10-4]). Conclusions and Relevance: Variation at the FADS1/2 locus was associated with AS and AVC. Findings from biomarker measurements and mendelian randomization appear to link ω-6 fatty acid biosynthesis to AS, which may represent a therapeutic target.

14.
J Am Soc Echocardiogr ; 33(1): 72-81.e6, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31624026

RESUMO

BACKGROUND: In recent decades, novel echocardiographic measures have constantly emerged. It is still unclear which echocardiographic measures have the most significant prognostic value in the general population. Accordingly, the aim of this study was to compare the prognostic value of a large panel of echocardiographic measures to identify the most promising measures. METHODS: A total of 1,497 Framingham study participants (mean age, 65 years; 55.4% women) who underwent echocardiographic measurements of left ventricular ejection fraction, left ventricular mass index, global longitudinal strain, global circumferential strain, mitral annular plane systolic excursion, mitral E/e' ratio, maximum and minimum left atrial (LA) volume index, LA emptying fraction, and left ventricular longitudinal synchrony were evaluated. These measures were related to the incidence of two composite outcomes: cardiovascular disease (CVD) or death and atrial fibrillation (AF) or congestive heart failure (CHF). RESULTS: On follow-up (mean, 8.3 years), there were 241 CVD events or deaths and 139 AF or CHF events. In multivariate-adjusted Cox models, higher LA emptying fraction was associated with a lower risk (hazard ratios per SD, 0.80 and 0.70 for CVD or death and AF or CHF, respectively; P ≤ .001 for both) while higher minimum LA volume index (hazard ratios per SD, 1.32 and 1.70 for CVD or death and AF or CHF, respectively; P ≤ .001 for both) and maximum LA volume index (hazard ratios per SD, 1.26 and 1.54 for CVD or death and AF or CHF, respectively; P ≤ .002 for both) were associated with a higher risk for both composite outcomes. CONCLUSIONS: In this community-based sample, LA volumes and function were the best echocardiographic predictors of clinical outcomes. Therefore, these values should be considered for inclusion in standard echocardiographic assessments for the purpose of risk stratification.

15.
Epigenetics ; 15(1-2): 183-198, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31282290

RESUMO

DNA methylation (DNAm) and microRNAs (miRNAs) have been implicated in a wide-range of human diseases. While often studied in isolation, DNAm and miRNAs are not independent. We analyzed associations of expression of 283 miRNAs with DNAm at >400K CpG sites in whole blood obtained from 3565 individuals and identified 227 CpGs at which differential methylation was associated with the expression of 40 nearby miRNAs (cis-miR-eQTMs) at FDR<0.01, including 91 independent CpG sites at r2 < 0.2. cis-miR-eQTMs were enriched for CpGs in promoter and polycomb-repressed state regions, and 60% were inversely associated with miRNA expression. Bidirectional Mendelian randomization (MR) analysis further identified 58 cis-miR-eQTMCpG-miRNA pairs where DNAm changes appeared to drive miRNA expression changes and opposite directional effects were unlikely. Integration of genetic variants in joint analyses revealed an average partial between cis-miR-eQTM CpGs and miRNAs of 2% after conditioning on site-specific genetic variation, suggesting that DNAm is an important epigenetic regulator of miRNA expression. Finally, two-step MR analysis was performed to identify putatively causal CpGs driving miRNA expression in relation to human complex traits. We found that an imprinted region on 14q32 that was previously identified in relation to age at menarche is enriched with cis-miR-eQTMs. Nine CpGs and three miRNAs at this locus tested causal for age at menarche, reflecting novel epigenetic-driven molecular pathways underlying this complex trait. Our study sheds light on the joint genetic and epigenetic regulation of miRNA expression and provides insights into the relations of miRNAs to their targets and to complex phenotypes.

16.
Am J Hum Genet ; 106(1): 112-120, 2020 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-31883642

RESUMO

Whole-genome sequencing (WGS) can improve assessment of low-frequency and rare variants, particularly in non-European populations that have been underrepresented in existing genomic studies. The genetic determinants of C-reactive protein (CRP), a biomarker of chronic inflammation, have been extensively studied, with existing genome-wide association studies (GWASs) conducted in >200,000 individuals of European ancestry. In order to discover novel loci associated with CRP levels, we examined a multi-ancestry population (n = 23,279) with WGS (∼38× coverage) from the Trans-Omics for Precision Medicine (TOPMed) program. We found evidence for eight distinct associations at the CRP locus, including two variants that have not been identified previously (rs11265259 and rs181704186), both of which are non-coding and more common in individuals of African ancestry (∼10% and ∼1% minor allele frequency, respectively, and rare or monomorphic in 1000 Genomes populations of East Asian, South Asian, and European ancestry). We show that the minor (G) allele of rs181704186 is associated with lower CRP levels and decreased transcriptional activity and protein binding in vitro, providing a plausible molecular mechanism for this African ancestry-specific signal. The individuals homozygous for rs181704186-G have a mean CRP level of 0.23 mg/L, in contrast to individuals heterozygous for rs181704186 with mean CRP of 2.97 mg/L and major allele homozygotes with mean CRP of 4.11 mg/L. This study demonstrates the utility of WGS in multi-ethnic populations to drive discovery of complex trait associations of large effect and to identify functional alleles in noncoding regulatory regions.


Assuntos
Grupo com Ancestrais do Continente Africano/genética , Grupo com Ancestrais do Continente Asiático/genética , Proteína C-Reativa/genética , Grupo com Ancestrais do Continente Europeu/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Sequenciamento Completo do Genoma/métodos , Estudos de Coortes , Frequência do Gene , Estudo de Associação Genômica Ampla , Humanos , Desequilíbrio de Ligação
17.
EBioMedicine ; 51: 102520, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31877415

RESUMO

BACKGROUND: Metabolic syndrome (MetS), the clustering of metabolic risk factors, is associated with cardiovascular disease risk. We sought to determine if dysregulation of the lipidome may contribute to metabolic risk factors. METHODS: We measured 154 circulating lipid species in 658 participants from the Framingham Heart Study (FHS) using liquid chromatography-tandem mass spectrometry and tested for associations with obesity, dysglycemia, and dyslipidemia. Independent external validation was sought in three independent cohorts. Follow-up data from the FHS were used to test for lipid metabolites associated with longitudinal changes in metabolic risk factors. RESULTS: Thirty-nine lipids were associated with obesity and eight with dysglycemia in the FHS. Of 32 lipids that were available for replication for obesity and six for dyslipidemia, 28 (88%) replicated for obesity and five (83%) for dysglycemia. Four lipids were associated with longitudinal changes in body mass index and four were associated with changes in fasting blood glucose in the FHS. CONCLUSIONS: We identified and replicated several novel lipid biomarkers of key metabolic traits. The lipid moieties identified in this study are involved in biological pathways of metabolic risk and can be explored for prognostic and therapeutic utility.


Assuntos
Biomarcadores , Metabolismo dos Lipídeos , Lipidômica , Lipídeos/sangue , Síndrome Metabólica/sangue , Síndrome Metabólica/etiologia , Adulto , Idoso , Animais , Estudos Transversais , Suscetibilidade a Doenças , Feminino , Humanos , Lipidômica/métodos , Estudos Longitudinais , Masculino , Síndrome Metabólica/diagnóstico , Síndrome Metabólica/epidemiologia , Pessoa de Meia-Idade , Medição de Risco , Fatores de Risco
18.
Circ Genom Precis Med ; 12(12): e002489, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31703168

RESUMO

BACKGROUND: Heart failure (HF) may arise from alterations in metabolic, structural, and signaling pathways, but its genetic architecture is incompletely understood. To elucidate potential genetic contributors to cardiac remodeling and HF, we integrated genome-wide single-nucleotide polymorphisms, gene expression, and DNA methylation using a transomics analytical approach. METHODS: We used robust rank aggregation (where the position of a certain gene in a rank order list [based on statistical significance level] is tested against a randomly shuffled rank order list) to derive an integrative transomic score for each annotated gene associated with a HF trait. RESULTS: We evaluated ≤8372 FHS (Framingham Heart Study) participants (54% women; mean age, 55±17 years). Of these, 62 (0.7%) and 35 (0.4%) had prevalent HF with reduced ejection fraction and HF with preserved left ventricular ejection fraction, respectively. During a mean follow-up of 8.5 years (minimum-maximum, 0.005-18.6 years), 223 (2.7%) and 234 (2.8%) individuals developed incident HF with reduced ejection fraction and HF with reduced ejection fraction, respectively. Top genes included MMP20 and MTSS1 (promotes actin assembly at intercellular junctions) for left ventricular systolic function; ITGA9 (receptor for VCAM1 [vascular cell protein 1]) and C5 for left ventricular remodeling; NUP210 (expressed during myogenic differentiation) and ANK1 (cytoskeletal protein) for diastolic function; TSPAN16 and RAB11FIP3 (involved in regulation of actin cytoskeleton) for prevalent HF with reduced ejection fraction; ANKRD13D and TRIM69 for incident HF with reduced ejection fraction; HPCAL1 and PTTG1IP for prevalent HF with reduced ejection fraction; and ZNF146 (close to the COX7A1 enzyme) and ZFP3 (close to SLC52A1-the riboflavin transporter) for incident HF with reduced ejection fraction. We tested the HF-related top single-nucleotide polymorphisms in the UK biobank, where rs77059055 in TPM1 (minor allele frequency, 0.023; odds ratio, 0.83; P=0.002) remained statistically significant upon Bonferroni correction. CONCLUSIONS: Our integrative transomics approach offers insights into potential molecular and genetic contributors to HF and its precursors. Although several of our candidate genes have been implicated in HF in animal models, independent replication is warranted.

19.
Nat Med ; 25(11): 1739-1747, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31700183

RESUMO

Type 2 diabetes is characterized by insulin resistance and a gradual loss of pancreatic beta cell mass and function1,2. Currently, there are no therapies proven to prevent beta cell loss and some, namely insulin secretagogues, have been linked to accelerated beta cell failure, thereby limiting their use in type 2 diabetes3,4. The adipokine adipsin/complement factor D controls the alternative complement pathway and generation of complement component C3a, which acts to augment beta cell insulin secretion5. In contrast to other insulin secretagogues, we show that chronic replenishment of adipsin in diabetic db/db mice ameliorates hyperglycemia and increases insulin levels while preserving beta cells by blocking dedifferentiation and death. Mechanistically, we find that adipsin/C3a decreases the phosphatase Dusp26; forced expression of Dusp26 in beta cells decreases expression of core beta cell identity genes and sensitizes to cell death. In contrast, pharmacological inhibition of DUSP26 improves hyperglycemia in diabetic mice and protects human islet cells from cell death. Pertaining to human health, we show that higher concentrations of circulating adipsin are associated with a significantly lower risk of developing future diabetes among middle-aged adults after adjusting for body mass index (BMI). Collectively, these data suggest that adipsin/C3a and DUSP26-directed therapies may represent a novel approach to achieve beta cell health to treat and prevent type 2 diabetes.


Assuntos
Complemento C3a/genética , Fator D do Complemento/farmacologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Fosfatases de Especificidade Dupla/genética , Células Secretoras de Insulina/efeitos dos fármacos , Fosfatases da Proteína Quinase Ativada por Mitógeno/genética , Animais , Índice de Massa Corporal , Desdiferenciação Celular/efeitos dos fármacos , Fator D do Complemento/genética , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/patologia , Glucose/metabolismo , Humanos , Hiperglicemia/tratamento farmacológico , Hiperglicemia/genética , Hiperglicemia/patologia , Insulina/genética , Resistência à Insulina/genética , Células Secretoras de Insulina/patologia , Camundongos , Camundongos Endogâmicos NOD
20.
PLoS One ; 14(10): e0222886, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31613888

RESUMO

BACKGROUND: Heart failure (HF) is a heterogeneous clinical syndrome with varying prognosis. Subphenotyping of HF is a research priority to advance our understanding of the syndrome. We formulated a subphenotyping schema and compared long-term mortality risk among the HF subphenotypes in the community-based Framingham Study. METHODS AND RESULTS: In hierarchical order, we grouped participants with new-onset HF (stratified by HF with reduced [HFrEF] vs. preserved ejection fraction [HFpEF]) according to the presence of: (1) coronary heart disease (CHD), (2) metabolic syndrome (MetS), (3) hypertension, and (4) 'other' causes. Age at HF onset was lowest in people with the MetS (mean 76 vs. 77 years for HFrEF and HFpEF, respectively) and highest in those with hypertension only (mean 82 and 85 years for HFrEF and HFpEF, respectively). For HFrEF, 10-year cumulative mortality and hazards ratios [HR] were 87% for CHD (n = 219; referent group), 88% for MetS (n = 105; HR 0.95 [95% CI 0.73-1.23]), 82% for hypertension (n = 104; HR 0.71 [0.55-0.91]), and 78% for other (n = 37; HR 0.81 [0.55-1.19]). Corresponding 10-year cumulative mortality and HR data for HFpEF were: 85% for CHD (n = 84; referent), 83% for MetS (n = 118; HR 0.98 [0.72-1.33]), 81% for hypertension (n = 127; HR 0.71 [0.52-0.95]), and 76% for other (n = 43; HR 0.76 [0.50-1.14]). In a sample without overt heart failure (n = 5536), several echocardiographic and vascular indices showed graded worsening of age- and sex adjusted-values among those having CHD, MetS, hypertension, or obesity, compared with individuals not having these risk factors. CONCLUSIONS: HF subphenotypes characterized by the presence of CHD or metabolic syndrome present at a younger age and are marked by greater mortality risk. The clinical utility of the proposed subphenotyping schema warrants further research.


Assuntos
Doença das Coronárias/diagnóstico por imagem , Insuficiência Cardíaca/diagnóstico por imagem , Hipertensão/diagnóstico por imagem , Síndrome Metabólica/diagnóstico por imagem , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Doença das Coronárias/complicações , Doença das Coronárias/mortalidade , Doença das Coronárias/fisiopatologia , Ecocardiografia , Feminino , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/mortalidade , Insuficiência Cardíaca/fisiopatologia , Humanos , Hipertensão/complicações , Hipertensão/mortalidade , Hipertensão/fisiopatologia , Masculino , Síndrome Metabólica/complicações , Síndrome Metabólica/mortalidade , Síndrome Metabólica/fisiopatologia , Fenótipo , Prognóstico , Modelos de Riscos Proporcionais , Fatores de Risco , Fatores Sexuais , Volume Sistólico/fisiologia
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