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1.
Sci Adv ; 8(14): eabl6579, 2022 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-35385311

RESUMO

Human genetic studies support an inverse causal relationship between leukocyte telomere length (LTL) and coronary artery disease (CAD), but directionally mixed effects for LTL and diverse malignancies. Clonal hematopoiesis of indeterminate potential (CHIP), characterized by expansion of hematopoietic cells bearing leukemogenic mutations, predisposes both hematologic malignancy and CAD. TERT (which encodes telomerase reverse transcriptase) is the most significantly associated germline locus for CHIP in genome-wide association studies. Here, we investigated the relationship between CHIP, LTL, and CAD in the Trans-Omics for Precision Medicine (TOPMed) program (n = 63,302) and UK Biobank (n = 47,080). Bidirectional Mendelian randomization studies were consistent with longer genetically imputed LTL increasing propensity to develop CHIP, but CHIP then, in turn, hastens to shorten measured LTL (mLTL). We also demonstrated evidence of modest mediation between CHIP and CAD by mLTL. Our data promote an understanding of potential causal relationships across CHIP and LTL toward prevention of CAD.

2.
Am Heart J ; 246: 144-151, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-34986393

RESUMO

BACKGROUND: Despite pathophysiological links between endothelin (ET)-1 and hypertension in Black adults, there is no population-based data appraising the association of plasma ET-1 with longitudinal blood pressure (BP) changes in Blacks. METHODS: We analyzed data from 1197 Jackson Heart Study participants without hypertension (mean age 47.8 years [SD: 12.0]; 64.2% women), with plasma ET-1 available at the baseline examination (2000-2004). Poisson regression with robust variance was used to generate risk ratios (RRs) and 95% confidence intervals (CIs) of BP progression (an increase by ≥1 BP category based on the 2017 American College of Cardiology/American Heart Association classification) and incident hypertension (BP ≥ 130/80 mm Hg or use of antihypertensive medication) at follow-up (2005-2008 or 2009-2013). RESULTS: Over a median follow-up of 7 years (range: 4-11), 71.2% (n = 854) progressed to a higher BP stage and 64.6% (n = 773) developed hypertension. After adjusting for possible confounders, each unit increment in baseline log (ET-1) was associated with higher risks of BP progression (RR 1.15 [95% CI 1.03-1.29], P = .016) and incident hypertension (RR 1.15 [95% CI 1.01-1.31], P = .032). Compared to those in the lowest ET-1 quartile, participants in the highest quartile had significantly higher risks of BP progression (RR 1.20 [95% CI 1.05-1.37], P = .007) and incident hypertension (RR 1.16 [95% CI 1.00-1.36], P = .052). CONCLUSIONS: In a large, community-based sample of African Americans, higher plasma ET-1 concentrations were associated with higher risks of BP progression and incident hypertension.


Assuntos
Endotelina-1 , Hipertensão , Adulto , Afro-Americanos , Pressão Sanguínea/fisiologia , Endotelina-1/uso terapêutico , Feminino , Humanos , Hipertensão/tratamento farmacológico , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Estados Unidos/epidemiologia
3.
Am Heart J ; 245: 1-9, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34808103

RESUMO

BACKGROUND: We aimed to investigate the associations of glycemic markers (hemoglobin A1C [HbA1C], fasting plasma glucose [FPG] and glycemic status [normoglycemia, prediabetes and diabetes]) with incident heart failure (HF) and its subtypes, among Blacks. METHODS: We included 2,290 community-dwelling Blacks (64% women, mean age 58 years) without prevalent HF from the Jackson Heart Study who attended the second exam (2005 - 2008). The associations between glycemic markers and incident HF (and subtypes including HF with preserved ejection fraction [HFpEF] and reduced ejection fraction [HFrEF]) were evaluated using Cox proportional hazards regression models, adjusting for risk factors and coronary heart disease. RESULTS: There were 119 incident HF events (48 HFpEF, 58 HFrEF, and 13 unclassified HF events) over a median follow-up of 10.5 years. Higher levels of HbA1C (HR per SD increment, 1.30; 95% CI 1.12, 1.51) and FPG (HR per SD increment FPG: 1.32; 95% CI: 1.17, 1.48) were associated with a higher risk of incident HF. Compared to normal glycemia, diabetes status was associated with a higher risk of incident HF (HR: 1.24; 95%CI: 1.02, 2.05). HbA1C was significantly associated with higher risks of HFpEF (HR per SD increment: 1.41, 95% CI: 1.18, 1.69) and HFrEF (HR per SD increment: 1.32; 95% CI: 1.12, 1.56). FPG was significantly associated with higher risk of HFpEF (HR per SD increment: 1.35, 95% CI: 1.14, 1.62) but not HFrEF (HR per SD increment: 1.12; 95% CI: 0.53, 2.35). CONCLUSIONS: Among community-dwelling Blacks, higher levels of glycemic markers were associated with higher risk of HF subtypes.


Assuntos
Insuficiência Cardíaca , Afro-Americanos , Feminino , Insuficiência Cardíaca/epidemiologia , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Prognóstico , Fatores de Risco , Volume Sistólico , Função Ventricular Esquerda
4.
HGG Adv ; 2(1)2021 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-34734193

RESUMO

Psychological and social factors are known to influence blood pressure (BP) and risk of hypertension and associated cardiovascular diseases. To identify novel BP loci, we carried out genome-wide association meta-analyses of systolic, diastolic, pulse, and mean arterial BP taking into account the interaction effects of genetic variants with three psychosocial factors: depressive symptoms, anxiety symptoms, and social support. Analyses were performed using a two-stage design in a sample of up to 128,894 adults from 5 ancestry groups. In the combined meta-analyses of Stages 1 and 2, we identified 59 loci (p value <5e-8), including nine novel BP loci. The novel associations were observed mostly with pulse pressure, with fewer observed with mean arterial pressure. Five novel loci were identified in African ancestry, and all but one showed patterns of interaction with at least one psychosocial factor. Functional annotation of the novel loci supports a major role for genes implicated in the immune response (PLCL2), synaptic function and neurotransmission (LIN7A, PFIA2), as well as genes previously implicated in neuropsychiatric or stress-related disorders (FSTL5, CHODL). These findings underscore the importance of considering psychological and social factors in gene discovery for BP, especially in non-European populations.

5.
Kidney Med ; 3(5): 702-711.e1, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34693252

RESUMO

RATIONALE & OBJECTIVE: The relation of vascular stiffness, endothelial function, and kidney function is incompletely elucidated in African Americans. Our hypothesis was that increased vascular stiffness and endothelial dysfunction are associated with low estimated glomerular filtration rate (eGFR) and albuminuria in African Americans. STUDY DESIGN: Cross-sectional cohort analysis of data from the Jackson Heart Study. SETTINGS & PATIENTS: 2,244 Jackson Heart Study participants (2012-2017 after Exam 3) who had undergone noninvasive hemodynamic assessment using arterial tonometry. PREDICTORS: Baseline carotid-femoral pulse wave velocity, pulsatile hemodynamics forward wave amplitude, and hyperemic brachial artery flow were measured. Reduced eGFR was defined as eGFR between 15 and 60 mL/min/1.73 m2. OUTCOMES: Prevalent albuminuria, urinary albumin-creatinine ratio. ANALYTICAL APPROACH: 2-sample t test for continuous variables and χ2 test for categorical variables in addition to logistic and linear regression models to assess the risk for chronic kidney disease with each proposed hemodynamic variable. RESULTS: Among 2,244 participants, mean age was 66 ± 11 years and 64% were women. Reduced eGFR was present in 233 (10.4%), and elevated urinary albumin-creatinine ratio, in 232 (10.4%). In multivariable-adjusted analyses, higher carotid-femoral pulse wave velocity was associated with the presence of reduced eGFR (OR, 1.37 [95% CI, 1.08-1.75] per SD; P = 0.01) and with prevalent albuminuria (OR, 1.66 [95% CI, 1.32-2.11]; P < 0.001). Higher forward wave amplitude was significantly associated with prevalent albuminuria (OR, 1.37 [95% CI, 1.14-1.65]; P = 0.001). LIMITATIONS: Cross-sectional analyses cannot inform causality. CONCLUSIONS: Higher arterial stiffness and pulsatility are associated with higher odds of reduced eGFR in African Americans. Future studies should focus on whether improving arterial stiffness contributes to kidney protection in African Americans.

6.
Am J Hypertens ; 2021 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-34166486

RESUMO

BACKGROUND: Little is known on the association of plasma adiponectin with blood pressure (BP) changes in African Americans (AAs). We evaluated the associations between plasma adiponectin and BP progression among AAs. METHODS: We analyzed data from 1184 participants without hypertension at baseline (2000-2004) with ≥1 follow-up visits in the Jackson Heart Study. We used robust Poisson regression to generate risk ratios (RR) for BP progression (an increase by ≥1 BP stage) and incident hypertension. RESULTS: Over a median of 7 years, 71 % progressed to higher BP stage and 65% developed hypertension. We found evidence of interaction by sex (P-interaction=0.088). Compared to those in the lowest quartile (Q1), male participants in the highest adiponectin quartile (Q4) had reduced risks of BP progression (Risk Ratio [RR] 0.76 [95% CI 0.60-0.96]) and incident hypertension (RR 0.74 [95% CI 0.56-0.97]). After accounting for body mass index, this relation persisted among obese men (RR for the highest (vs. lowest) adiponectin quartile: 0.59 (95% CI 0.36-0.97) for incident hypertension, and 0.69 (95% CI 0.45-1.06) for BP progression). Among women, adiponectin was not associated with BP outcomes (RR [95% CI] for Q4 vs Q1: 1.03 [0.86-1.23], and 1.01[0.83-1.23] for BP progression and incident hypertension respectively). Our findings were consistent across both the ACC/AHA and JNC-7 BP categories. CONCLUSIONS: In a large, community-based sample of African Americans, higher adiponectin concentrations were associated with lower risks of BP progression and incident hypertension in men, but no significant association was observed in women.

7.
J Hypertens ; 39(11): 2200-2209, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34173799

RESUMO

OBJECTIVE: There is a paucity of data on the relations of insulin resistance with incident blood pressure (BP) changes among Blacks. We investigated the associations of insulin resistance and metabolic syndrome (MetS) with BP progression in a community-based sample of African Americans. METHODS: We analyzed 1064 participants without hypertension at baseline (2000-2004) who attended at least one follow-up visit in 2005-2008 or 2009-2013. Four insulin resistance indices [fasting insulin, insulin-to-glucose ratio (IGR), homeostasis model assessment of insulin resistance (HOMA-IR), and quantitative insulin sensitivity check index (QUICKI)] and MetS (excluding hypertension in the definition) were assessed at baseline. Robust Poisson regression was used to generate risk ratios (RRs) and 95% confidence intervals (CI) for BP progression and incident hypertension. RESULTS: Over a median of 7 years, 69.6% progressed to a higher BP category and 62.7% developed hypertension. After multivariable adjustment, participants in the highest quartile of HOMA-IR had higher risks of BP progression [RR 1.25 (95% CI 1.09-1.43), Ptrend = 0.004] and hypertension [RR 1.35 (95% CI 1.16-1.58), Ptrend < 0.001] compared with those in the lowest quartile. A similar positive association of insulin resistance with BP outcomes was noted with insulin resistance assessed using IGR, fasting insulin, and QUICKI. MetS was associated with increased risks of BP progression [RR 1.15 (95% CI 1.02-1.30), P = 0.02] and incident hypertension [RR 1.23 [95% CI 1.08-1.41], P = 0.002]. These associations were present across baseline BP categories. CONCLUSION: Our findings support the notion that higher insulin resistance levels are associated with greater risks of BP progression and incident hypertension among Blacks.


Assuntos
Resistência à Insulina , Síndrome Metabólica , Afro-Americanos , Glicemia , Pressão Sanguínea , Índice de Massa Corporal , Humanos , Insulina , Estudos Longitudinais
8.
BMC Med Genomics ; 14(1): 136, 2021 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-34020621

RESUMO

BACKGROUND: Melatonin is a hormone that is secreted at night by the pineal gland. It exerts its function by binding to the MT1 and MT2 receptors, which are encoded by the MTNR1A and MTNR1B genes, respectively. Previous studies reveal that MTNR1B variants are associated with insulin secretion impairments and an increased body mass index (BMI) in individuals of European and Asian ancestries. Obesity is highly prevalent in the US and disproportionately affects African Americans. Here, we hypothesized that common single nucleotide polymorphisms (SNPs) imputed in 1000 Genomes in the MTNR1B gene are associated with adiposity in African American adult men and women and that the association is modified by insomnia. METHODS: We used an additive genetic model to describe the association between the adiposity traits (BMI and waist circumference) and selected MTNR1B variants in 3,029 Jackson Heart Study participants, with an average age of 55.13 ± 12.84 years, and 62% were women. We regressed the adiposity measures on the estimated allelic or genotypic dosage at every selected SNP and adjusted for age, sex, population stratification, and insomnia. Thirty common SNPs, spanning the MTNR1B gene, with a minor allele frequency ≥ 5%, a call rate ≥ 90%, a Hardy-Weinberg equilibrium p value > 10-6, were available for the analysis. RESULTS: The allele T of rs76371840 was associated with adiposity (OR = 1.47 [1.13-1.82]; PFDR-adjusted = 0.0499), and the allele A of rs8192552 showed a significant association with waist circumference (ß = 0.023 ± 0.007; PFDR-adjusted = 0.0077) after correcting for multiple testing. When insomnia was included in the adiposity analysis model, the following four variants became significantly associated with adiposity: rs6483208; rs4388843; rs4601728; and rs12804291. CONCLUSIONS: Our data indicate that polymorphisms in the MTNR1B gene are associated with obesity traits in African Americans. To the best of our knowledge, this is the first study to explore the effect of insomnia on the association between the circadian MTNR1B genetic variants and metabolic traits in an African American sample population. We observed that insomnia affected the association between the MTNR1B variants and adiposity.


Assuntos
Obesidade
9.
Eur Heart J Digit Health ; 2(1): 137-151, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34048510

RESUMO

AIMS: Almost half of African American (AA) men and women have cardiovascular disease (CVD). Detection of prevalent CVD in community settings would facilitate secondary prevention of CVD. We sought to develop a tool for automated CVD detection. METHODS AND RESULTS: Participants from the Jackson Heart Study (JHS) with analysable electrocardiograms (ECGs) (n=3679; age, 6212 years; 36% men) were included. Vectorcardiographic (VCG) metrics QRS, T, and spatial ventricular gradient vectors magnitude and direction, and traditional ECG metrics were measured on 12-lead ECG. Random forests, convolutional neural network (CNN), lasso, adaptive lasso, plugin lasso, elastic net, ridge, and logistic regression models were developed in 80% and validated in 20% samples. We compared models with demographic, clinical, and VCG input (43 predictors) and those after the addition of ECG metrics (695 predictors). Prevalent CVD was diagnosed in 411 out of 3679 participants (11.2%). Machine learning models detected CVD with the area under the receiver operator curve (ROC AUC) 0.690.74. There was no difference in CVD detection accuracy between models with VCG and VCG + ECG input. Models with VCG input were better calibrated than models with ECG input. Plugin-based lasso model consisting of only two predictors (age and peak QRS-T angle) detected CVD with AUC 0.687 [95% confidence interval (CI) 0.6250.749], which was similar (P=0.394) to the CNN (0.660; 95% CI 0.5970.722) and better (P<0.0001) than random forests (0.512; 95% CI 0.4930.530). CONCLUSIONS: Simple model (age and QRS-T angle) can be used for prevalent CVD detection in limited-resources community settings, which opens an avenue for secondary prevention of CVD in underserved communities.

11.
J Am Heart Assoc ; 10(9): e016524, 2021 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-33880930

RESUMO

Background Black individuals have a higher burden of risk factors for heart failure (HF) and subclinical left ventricular remodeling. Methods and Results We evaluated 1871 Black participants in the Atherosclerosis Risk in Communities Study cohort who attended a routine examination (1993-1996, median age 58 years) when they underwent echocardiography. We estimated the prevalences of 4 HF stages: (1) Stage 0: no risk factors; (2) Stage A: presence of HF risk factors (hypertension, diabetes mellitus, obesity, smoking, dyslipidemia, coronary artery disease without clinical myocardial infarction), no cardiac structural/functional abnormality; (3) Stage B: presence of prior myocardial infarction, systolic dysfunction, left ventricular hypertrophy, regional wall motion abnormality, or left ventricular enlargement; and (4) Stage C/D: prevalent HF. We assessed the incidence of clinical HF, atherosclerotic cardiovascular disease events, and all-cause mortality on follow-up according to HF stage. The prevalence of HF Stages 0, A, B, and C/D were 3.8%, 20.6%, 67.0%, and 8.6%, respectively, at baseline. On follow-up (median 19.0 years), 309 participants developed overt HF, 390 incurred new-onset cardiovascular disease events, and 651 individuals died. Incidence rates per 1000 person-years for overt HF, cardiovascular disease events, and death, respectively, were Stage 0, 2.4, 0.8, and 7.6; Stage A, 7.4, 9.7, and 13.5; Stage B 13.6, 15.9, and 22.0. Stage B HF was associated with a 1.5- to 2-fold increased adjusted risk of HF, cardiovascular disease events and death compared with Stages 0/A. Conclusions In our large community-based sample of Black individuals, we observed a strikingly high prevalence of Stage B HF in middle age that was a marker of high cardiovascular morbidity and mortality.


Assuntos
Afro-Americanos , Aterosclerose/etnologia , Insuficiência Cardíaca/etnologia , Ventrículos do Coração/diagnóstico por imagem , Medição de Risco/métodos , Função Ventricular Esquerda/fisiologia , Aterosclerose/complicações , Aterosclerose/fisiopatologia , Progressão da Doença , Ecocardiografia , Feminino , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/fisiopatologia , Ventrículos do Coração/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Morbidade/tendências , Prognóstico , Fatores de Risco , Taxa de Sobrevida/tendências , Estados Unidos/epidemiologia
12.
Mol Psychiatry ; 26(11): 6293-6304, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-33859359

RESUMO

Long and short sleep duration are associated with elevated blood pressure (BP), possibly through effects on molecular pathways that influence neuroendocrine and vascular systems. To gain new insights into the genetic basis of sleep-related BP variation, we performed genome-wide gene by short or long sleep duration interaction analyses on four BP traits (systolic BP, diastolic BP, mean arterial pressure, and pulse pressure) across five ancestry groups in two stages using 2 degree of freedom (df) joint test followed by 1df test of interaction effects. Primary multi-ancestry analysis in 62,969 individuals in stage 1 identified three novel gene by sleep interactions that were replicated in an additional 59,296 individuals in stage 2 (stage 1 + 2 Pjoint < 5 × 10-8), including rs7955964 (FIGNL2/ANKRD33) that increases BP among long sleepers, and rs73493041 (SNORA26/C9orf170) and rs10406644 (KCTD15/LSM14A) that increase BP among short sleepers (Pint < 5 × 10-8). Secondary ancestry-specific analysis identified another novel gene by long sleep interaction at rs111887471 (TRPC3/KIAA1109) in individuals of African ancestry (Pint = 2 × 10-6). Combined stage 1 and 2 analyses additionally identified significant gene by long sleep interactions at 10 loci including MKLN1 and RGL3/ELAVL3 previously associated with BP, and significant gene by short sleep interactions at 10 loci including C2orf43 previously associated with BP (Pint < 10-3). 2df test also identified novel loci for BP after modeling sleep that has known functions in sleep-wake regulation, nervous and cardiometabolic systems. This study indicates that sleep and primary mechanisms regulating BP may interact to elevate BP level, suggesting novel insights into sleep-related BP regulation.


Assuntos
Estudo de Associação Genômica Ampla , Hipertensão , Pressão Sanguínea/genética , Loci Gênicos/genética , Humanos , Hipertensão/genética , Polimorfismo de Nucleotídeo Único/genética , Sono/genética
13.
Hum Mol Genet ; 30(15): 1443-1456, 2021 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-33856023

RESUMO

Nonalcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver disease and is highly correlated with metabolic disease. NAFLD results from environmental exposures acting on a susceptible polygenic background. This study performed the largest multiethnic investigation of exonic variation associated with NAFLD and correlated metabolic traits and diseases. An exome array meta-analysis was carried out among eight multiethnic population-based cohorts (n = 16 492) with computed tomography (CT) measured hepatic steatosis. A fixed effects meta-analysis identified five exome-wide significant loci (P < 5.30 × 10-7); including a novel signal near TOMM40/APOE. Joint analysis of TOMM40/APOE variants revealed the TOMM40 signal was attributed to APOE rs429358-T; APOE rs7412 was not associated with liver attenuation. Moreover, rs429358-T was associated with higher serum alanine aminotransferase, liver steatosis, cirrhosis, triglycerides and obesity; as well as, lower cholesterol and decreased risk of myocardial infarction and Alzheimer's disease (AD) in phenome-wide association analyses in the Michigan Genomics Initiative, United Kingdom Biobank and/or public datasets. These results implicate APOE in imaging-based identification of NAFLD. This association may or may not translate to nonalcoholic steatohepatitis; however, these results indicate a significant association with advanced liver disease and hepatic cirrhosis. These findings highlight allelic heterogeneity at the APOE locus and demonstrate an inverse link between NAFLD and AD at the exome level in the largest analysis to date.


Assuntos
Apolipoproteínas E/genética , Hepatopatia Gordurosa não Alcoólica/genética , Obesidade/genética , Alanina Transaminase , Alelos , Doença de Alzheimer/genética , Apolipoproteínas E/metabolismo , Bases de Dados Genéticas , Exoma/genética , Frequência do Gene/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Fígado , Cirrose Hepática/genética , Infarto do Miocárdio/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , Obesidade/metabolismo , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Prognóstico , Fatores de Risco , Triglicerídeos
15.
J Am Heart Assoc ; 10(7): e016947, 2021 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-33728932

RESUMO

Background Metabolic dyslipidemia (high triglyceride) and low high-density lipoprotein cholesterol (HDL-C) is highly prevalent in type 2 diabetes mellitus (T2DM). The extent to which diabetes mellitus-related abnormalities in the triglyceride-HDL-C profile associates with cardiovascular disease (CVD) risk is incompletely understood. We evaluated the associations of triglyceride and HDL-C status with CVD outcomes in individuals with T2DM. Methods and Results We analyzed data from 4199 overweight/obese adults with T2DM free of CVD with available data on triglyceride and HDL-C at baseline (2001-2004) in the Look AHEAD (Action for Health in Diabetes) study. We used Cox proportional models to estimate hazard ratios (HRs) and 95% CIs of: (1) composite CVD outcome (myocardial infarction, stroke, hospitalization for angina, and/or death from cardiovascular causes); (2) coronary artery disease events; and (3) cerebrovascular accidents (stroke). Of the 4199 participants, 62% (n=2600) were women, with a mean age of 58 years (SD, 7), and 40% (n=1659) had metabolic dyslipidemia at baseline. Over a median follow-up of 9.5 years (interquartile range, 8.7-10.3), 500 participants experienced the composite CVD outcome, 396 experienced coronary artery disease events, and 100 experienced stroke. Low HDL-C was associated with higher hazards of the composite CVD outcome (HR, 1.36; 95% CI, 1.12-1.64 [P=0.002]) and coronary artery disease events (HR, 1.46; 95% CI, 1.18-1.81 [P=0.001]) but not stroke (HR, 1.38; 95% CI, 0.90-2.11 [P=0.140]). Compared with patients with normal triglyceride and normal HDL, participants with metabolic dyslipidemia had higher risks of the composite CVD outcome (HR, 1.30; 95% CI, 1.03-1.63 [P=0.025]) and coronary artery disease events (HR, 1.48; 95% CI, 1.14-1.93 [P=0.003]) but not stroke (HR, 1.23; 95% CI, 0.74-2.05 [P=0.420]). Conclusions In a large sample of overweight/obese individuals with T2DM, metabolic dyslipidemia was associated with higher risks of CVD outcomes. Our findings highlight the necessity to account for metabolic dyslipidemia in CVD risk stratification among patients with T2DM. Registration URL: https://www.lookaheadtrial.org; Unique identifier: NCT00017953.


Assuntos
Doenças Cardiovasculares , HDL-Colesterol , Diabetes Mellitus Tipo 2 , Dislipidemias , Obesidade , Triglicerídeos , Doenças Cardiovasculares/classificação , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/mortalidade , HDL-Colesterol/sangue , HDL-Colesterol/metabolismo , Comorbidade , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/psicologia , Dislipidemias/sangue , Dislipidemias/diagnóstico , Dislipidemias/epidemiologia , Feminino , Seguimentos , Fatores de Risco de Doenças Cardíacas , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/diagnóstico , Obesidade/epidemiologia , Obesidade/metabolismo , Prognóstico , Modelos de Riscos Proporcionais , Medição de Risco/métodos , Comportamento de Redução do Risco , Triglicerídeos/sangue , Triglicerídeos/metabolismo
16.
Nat Med ; 27(4): 653-658, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33619371

RESUMO

Malaria and iron deficiency (ID) are common and interrelated public health problems in African children. Observational data suggest that interrupting malaria transmission reduces the prevalence of ID1. To test the hypothesis that malaria might cause ID, we used sickle cell trait (HbAS, rs334 ), a genetic variant that confers specific protection against malaria2, as an instrumental variable in Mendelian randomization analyses. HbAS was associated with a 30% reduction in ID among children living in malaria-endemic countries in Africa (n = 7,453), but not among individuals living in malaria-free areas (n = 3,818). Genetically predicted malaria risk was associated with an odds ratio of 2.65 for ID per unit increase in the log incidence rate of malaria. This suggests that an intervention that halves the risk of malaria episodes would reduce the prevalence of ID in African children by 49%.


Assuntos
Malária/complicações , Absorção Fisiológica , Adolescente , África , Criança , Pré-Escolar , Feminino , Geografia , Hepcidinas/metabolismo , Humanos , Lactente , Masculino , Análise da Randomização Mendeliana , Traço Falciforme/complicações
17.
EBioMedicine ; 63: 103157, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33418499

RESUMO

BACKGROUND: Genetic factors that influence kidney traits have been understudied for low frequency and ancestry-specific variants. METHODS: We combined whole genome sequencing (WGS) data from 23,732 participants from 10 NHLBI Trans-Omics for Precision Medicine (TOPMed) Program multi-ethnic studies to identify novel loci for estimated glomerular filtration rate (eGFR). Participants included European, African, East Asian, and Hispanic ancestries. We applied linear mixed models using a genetic relationship matrix estimated from the WGS data and adjusted for age, sex, study, and ethnicity. FINDINGS: When testing single variants, we identified three novel loci driven by low frequency variants more commonly observed in non-European ancestry (PRKAA2, rs180996919, minor allele frequency [MAF] 0.04%, P = 6.1 × 10-11; METTL8, rs116951054, MAF 0.09%, P = 4.5 × 10-9; and MATK, rs539182790, MAF 0.05%, P = 3.4 × 10-9). We also replicated two known loci for common variants (rs2461702, MAF=0.49, P = 1.2 × 10-9, nearest gene GATM, and rs71147340, MAF=0.34, P = 3.3 × 10-9, CDK12). Testing aggregated variants within a gene identified the MAF gene. A statistical approach based on local ancestry helped to identify replication samples for ancestry-specific variants. INTERPRETATION: This study highlights challenges in studying variants influencing kidney traits that are low frequency in populations and more common in non-European ancestry.


Assuntos
Genômica , Taxa de Filtração Glomerular , Medicina de Precisão , Sequenciamento Completo do Genoma , Alelos , Frequência do Gene , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genômica/métodos , Humanos , Masculino , National Heart, Lung, and Blood Institute (U.S.) , Polimorfismo de Nucleotídeo Único , Medicina de Precisão/métodos , Vigilância em Saúde Pública , Característica Quantitativa Herdável , Estados Unidos/epidemiologia
18.
Mol Psychiatry ; 26(6): 2111-2125, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-32372009

RESUMO

Educational attainment is widely used as a surrogate for socioeconomic status (SES). Low SES is a risk factor for hypertension and high blood pressure (BP). To identify novel BP loci, we performed multi-ancestry meta-analyses accounting for gene-educational attainment interactions using two variables, "Some College" (yes/no) and "Graduated College" (yes/no). Interactions were evaluated using both a 1 degree of freedom (DF) interaction term and a 2DF joint test of genetic and interaction effects. Analyses were performed for systolic BP, diastolic BP, mean arterial pressure, and pulse pressure. We pursued genome-wide interrogation in Stage 1 studies (N = 117 438) and follow-up on promising variants in Stage 2 studies (N = 293 787) in five ancestry groups. Through combined meta-analyses of Stages 1 and 2, we identified 84 known and 18 novel BP loci at genome-wide significance level (P < 5 × 10-8). Two novel loci were identified based on the 1DF test of interaction with educational attainment, while the remaining 16 loci were identified through the 2DF joint test of genetic and interaction effects. Ten novel loci were identified in individuals of African ancestry. Several novel loci show strong biological plausibility since they involve physiologic systems implicated in BP regulation. They include genes involved in the central nervous system-adrenal signaling axis (ZDHHC17, CADPS, PIK3C2G), vascular structure and function (GNB3, CDON), and renal function (HAS2 and HAS2-AS1, SLIT3). Collectively, these findings suggest a role of educational attainment or SES in further dissection of the genetic architecture of BP.


Assuntos
Estudo de Associação Genômica Ampla , Hipertensão , Pressão Sanguínea/genética , Epistasia Genética , Loci Gênicos , Humanos , Hipertensão/genética , Polimorfismo de Nucleotídeo Único
19.
Ann Behav Med ; 55(3): 266-279, 2021 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-32686818

RESUMO

BACKGROUND: Metabolic syndrome (MetS) is a risk factor for the development of cardiovascular disease and type 2 diabetes. Although the development of MetS is attributed to known lifestyle factors, perceived discrimination may also contribute to MetS development and severity. PURPOSE: We examined the associations of perceived discrimination with MetS severity among African American adults at baseline and 8-year follow-up. METHODS: Three thousand eight hundred and seventy participants (mean age 53.8 ± 13.0; 63.1% female) without diabetes and no missing MetS severity scores at baseline were included. Each self-reported measure of discrimination at baseline (everyday, lifetime, and burden of lifetime) was classified into tertiles (low, medium, high). After adjustment for demographics and MetS risk factors, associations of discrimination were examined with a sex- and race/ethnicity-specific MetS severity Z-score. We employed a mixed model approach that allowed for the assessment of an overall association between reported discrimination at baseline and MetS severity, and for the possible change over time. RESULTS: Sex and age differences were observed in experiences with discrimination, such that men reported higher levels of all aspects of discrimination relative to women. Everyday discrimination decreased with age, whereas lifetime discrimination increased with age (p < .05). Independent of lifestyle and demographic factors, everyday and lifetime discrimination were significantly associated with MetS severity (p = .003 and p = .017, respectively) and the associations remained constant over the 8 years (i.e., no interaction with time). CONCLUSIONS: Our results suggest that, in a large community-based sample of African Americans, discrimination is a salient psychosocial risk factor for severity of MetS.


Assuntos
Afro-Americanos/psicologia , Síndrome Metabólica/psicologia , Racismo/psicologia , Adulto , Afro-Americanos/estatística & dados numéricos , Idoso , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Racismo/estatística & dados numéricos , Fatores de Risco , Índice de Gravidade de Doença
20.
Diabet Med ; 38(5): e14465, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33236370

RESUMO

AIM: To evaluate the association between plasma biomarkers including leptin, adiponectin, adiponectin-to-leptin ratio and high-sensitivity C-reactive protein (hsCRP) with risk of glycaemic progression and incident dysglycaemia (pre-diabetes or diabetes) in a community-based sample of African American (AAs). METHODS: We analysed data from 3223 participants without type 2 diabetes at baseline (2000-2004) who attended ≥1 follow-up visit. Poisson regression was used to generate risk ratios (RRs) for glycaemic progression and incident dysglycaemia. RESULTS: Over a median of 7 years, 46.4% developed glycaemic progression (n=1495). After adjusting for demographic and lifestyle variables, the RRs (95% CI) for glycaemic progression comparing highest (Q4) to lowest (Q1) quartiles were 1.30 (1.10-1.54), 0.74 (0.65-0.84), 0.70 (0.62-0.80) and 1.22 (1.07-1.38) for leptin, adiponectin, adiponectin-leptin ratio and hsCRP, respectively. Upon additional adjustment for BMI, the corresponding RRs (95% CIs) were 1.15 (0.94-1.42), 0.76 (0.67-0.86), 0.72 (0.62-0.84) and 1.14 (0.99-1.31) respectively. Among participants with normal glycaemia, the RRs (95% CIs) for incident pre-diabetes in Q4 vs Q1 were 1.37 (1.13-1.67), 0.73 (0.63-0.85), 0.70 (0.59-0.82) and 1.28 (1.10-1.48) for leptin, adiponectin, adiponectin-leptin ratio and hsCRP, respectively; equivalent RRs for incident diabetes were 5.15 (2.63-10.10), 0.36 (0.20-0.68), 0.21 (0.12-0.38) and 3.04 (1.70-5.44), respectively. CONCLUSIONS: In this large community-based cohort of AAs, our results suggest that high plasma leptin and hsCRP, as well as low adiponectin and adiponectin-to-leptin ratio, are associated with higher risks of glycaemic progression. The findings point to the potential utility of these biomarkers in predicting and preventing glycaemic progression in this high-risk population.


Assuntos
Adipocinas/sangue , Afro-Americanos , Glicemia/metabolismo , Adulto , Afro-Americanos/estatística & dados numéricos , Idoso , Idoso de 80 Anos ou mais , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/etnologia , Diabetes Mellitus Tipo 2/patologia , Progressão da Doença , Feminino , Controle Glicêmico/estatística & dados numéricos , Humanos , Incidência , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Estado Pré-Diabético/sangue , Estado Pré-Diabético/etnologia , Estado Pré-Diabético/patologia , Estados Unidos/epidemiologia , Adulto Jovem
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