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1.
J Am Heart Assoc ; 10(18): e020809, 2021 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-34514816

RESUMO

Background Individual blood cell count abnormalities have been associated with cardiovascular disease and increased mortality. In this study, we defined a "cytopenia phenotype," reflecting bone marrow hypoproliferation, to determine if peripheral blood cytopenia is associated with increased cardiovascular disease and mortality risk. Methods and Results Study participants were derived from a biracial observational cohort study, REGARDS (Reasons for Geographic and Racial Differences in Stroke), that enrolled 30 239 Black and White participants aged ≥45 years between 2003 and 2007. Median follow up was ≈9 years. The current study included 19 864 participants from REGARDS study (37.9% men, 40% Black participants) who have complete blood count available at study enrollment. We defined a cytopenia phenotype based on age-, sex-, and race-adjusted lowest fifth percentile of blood counts. Multivariable Cox proportional hazards models estimated the hazard ratios (HR) and 95% CI of cytopenia for mortality and incident cardiovascular disease in adjusted models. Mean age of the study participants was 64 years (SD:9.7). The prevalence of cytopenia was 1.9% (n=378). Cytopenia was associated with increased risk of all-cause mortality (HR, 1.73; 95% CI, 1.34-2.22) and cardiovascular disease mortality (HR, 1.56; 95% CI, 1.11-2.29). Cytopenia was associated with stroke risk in Black but not White participants (HR, 1.96 versus 0.86; P-interaction for race=0.08) and was not associated with coronary heart disease risk. Conclusions We defined a cytopenia phenotype with clinical implications for mortality and stroke risk in a large biracial and geographically diverse population. Whether generated through somatic mutations or decreased organ function, cytopenia was associated with mortality risk and was a race-specific risk factor for stroke.

2.
Curr Atheroscler Rep ; 23(11): 71, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34468868

RESUMO

PURPOSE OF REVIEW: Epigenetic modifications via DNA methylation have previously been linked to blood lipid levels, dyslipidemias, and atherosclerosis. The purpose of this review is to discuss current literature on the role of DNA methylation on lipid traits and their associated pathologies. RECENT FINDINGS: Candidate gene and epigenome-wide approaches have identified differential methylation of genes associated with lipid traits (particularly CPT1A, ABCG1, SREBF1), and novel approaches are being implemented to further characterize these relationships. Moreover, studies on environmental factors have shown that methylation variations at lipid-related genes are associated with diet and pollution exposure. Further investigation is needed to elucidate the directionality of the associations between the environment, lipid traits, and epigenome. Future studies should also seek to increase the diversity of cohorts, as European and Asian ancestry populations are the predominant study populations in the current literature.

3.
Medicine (Baltimore) ; 100(30): e26588, 2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34397689

RESUMO

ABSTRACT: High cardiovascular disease risk in people living with HIV is partly attributed to antiretroviral therapy (ART). Lipid response to ART has been extensively studied, yet, little is known how small molecule lipids respond to Integrase inhibitor-based (INSTI-based) compared to Protease inhibitor-based (PI-based) ART regimens.Ancillary study to a phase 3, randomized, open-label trial [AIDS Clinical Trial Group A5257 Study] in treatment-naive HIV-infected patients randomized in a 1:1:1 ratio to receive ritonavir-boosted atazanavir (ATV/r), ritonavir-boosted darunavir (DRV/r) (both PI-based), or raltegravir with Tenofovir Disoproxil Fumarate-TDF plus emtricitabine (RAL, INSTI-based).We examined small molecule lipid response in a subcohort of 75 participants. Lipidomic assays of plasma samples collected pre- and post-ART treatment (48 weeks) were conducted using ultra-performance liquid chromatography coupled to time-of-flight mass spectrometry. The effect of ART regimens was regressed on lipid species response adjusting for the baseline covariates (lipids, age, sex, race, CD4 level, BMI, and smoking). Results were validated in the Centers for AIDS Research Network of Integrated Clinical Systems study (N = 16).Out of 417 annotated lipids, glycerophospholipids (P = .007) and sphingolipids (P = .028) had a higher response to ATV/r and DRV/r compared to RAL. The lysophosphatidylcholine (LPCs(16:1),(17:1),(20:3)) and phosphophatidylcholine species (PCs(40:7),(38:4)) had an opposite response to RAL versus ATV/r in the discovery and validation cohort. The INSTI-based regimen had an opposite response of ceramide species ((d38:1), (d42:2)), PCs((35:2), (38:4)), phosphatidylethanolamines (PEs(38:4), (38:6)), and sphingomyelin(SMd38:1) species compared with the PI-based regimens. There were no differences observed between 2 PI-based regimens.We observed differences in response of small molecule lipid species by ART regimens in treatment-naive people living with HIV.


Assuntos
Antirretrovirais/efeitos adversos , Lipidômica/métodos , Adulto , Antirretrovirais/uso terapêutico , Sulfato de Atazanavir/efeitos adversos , Sulfato de Atazanavir/uso terapêutico , Distribuição de Qui-Quadrado , Darunavir/efeitos adversos , Darunavir/uso terapêutico , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/fisiopatologia , Humanos , Lipidômica/estatística & dados numéricos , Lipídeos , Masculino , Espectrometria de Massas/métodos , Pessoa de Meia-Idade , Plasma/efeitos dos fármacos , Raltegravir Potássico/efeitos adversos , Raltegravir Potássico/uso terapêutico , Tenofovir/efeitos adversos , Tenofovir/uso terapêutico
4.
Clin Pharmacol Ther ; 110(3): 723-732, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34231218

RESUMO

We sought to identify genome-wide variants influencing antihypertensive drug response and adverse cardiovascular outcomes, utilizing data from four randomized controlled trials in the International Consortium for Antihypertensive Pharmacogenomics Studies (ICAPS). Genome-wide antihypertensive drug-single nucleotide polymorphism (SNP) interaction tests for four drug classes (ß-blockers, n = 9,195; calcium channel blockers (CCBs), n = 10,511; thiazide/thiazide-like diuretics, n = 3,516; ACE-inhibitors/ARBs, n = 2,559) and cardiovascular outcomes (incident myocardial infarction, stroke, or death) were analyzed among patients with hypertension of European ancestry. Top SNPs from the meta-analyses were tested for replication of cardiovascular outcomes in an independent Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) study (n = 21,267), blood pressure (BP) response in independent ICAPS studies (n = 1,552), and ethnic validation in African Americans from the Genetics of Hypertension Associated Treatment study (GenHAT; n = 5,115). One signal reached genome-wide significance in the ß-blocker-SNP interaction analysis (rs139945292, Interaction P = 1.56 × 10-8 ). rs139945292 was validated through BP response to ß-blockers, with the T-allele associated with less BP reduction (systolic BP response P = 6 × 10-4 , Beta = 3.09, diastolic BP response P = 5 × 10-3 , Beta = 1.53). The T-allele was also associated with increased adverse cardiovascular risk within the ß-blocker treated patients' subgroup (P = 2.35 × 10-4 , odds ratio = 1.57, 95% confidence interval = 1.23-1.99). The locus showed nominal replication in CHARGE, and consistent directional trends in ß-blocker treated African Americans. rs139945292 is an expression quantitative trait locus for the 50 kb upstream gene NTM (neurotrimin). No SNPs attained genome-wide significance for any other drugs classes. Top SNPs were located near CALB1 (CCB), FLJ367777 (ACE-inhibitor), and CES5AP1 (thiazide). The NTM region is associated with increased risk for adverse cardiovascular outcomes and less BP reduction in ß-blocker treated patients. Further investigation into this region is warranted.


Assuntos
Anti-Hipertensivos/uso terapêutico , Doenças Cardiovasculares/induzido quimicamente , Doenças Cardiovasculares/genética , Sistema Cardiovascular/efeitos dos fármacos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/genética , Hipertensão/tratamento farmacológico , Afro-Americanos/genética , Idoso , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/genética , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Feminino , Estudo de Associação Genômica Ampla/métodos , Humanos , Hipertensão/genética , Masculino , Pessoa de Meia-Idade , Testes Farmacogenômicos/métodos , Polimorfismo de Nucleotídeo Único/genética
5.
PLoS One ; 16(7): e0253611, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34214102

RESUMO

Handgrip strength is a widely used measure of muscle strength and a predictor of a range of morbidities including cardiovascular diseases and all-cause mortality. Previous genome-wide association studies of handgrip strength have focused on common variants primarily in persons of European descent. We aimed to identify rare and ancestry-specific genetic variants associated with handgrip strength by conducting whole-genome sequence association analyses using 13,552 participants from six studies representing diverse population groups from the Trans-Omics in Precision Medicine (TOPMed) Program. By leveraging multiple handgrip strength measures performed in study participants over time, we increased our effective sample size by 7-12%. Single-variant analyses identified ten handgrip strength loci among African-Americans: four rare variants, five low-frequency variants, and one common variant. One significant and four suggestive genes were identified associated with handgrip strength when aggregating rare and functional variants; all associations were ancestry-specific. We additionally leveraged the different ancestries available in the UK Biobank to further explore the ancestry-specific association signals from the single-variant association analyses. In conclusion, our study identified 11 new loci associated with handgrip strength with rare and/or ancestry-specific genetic variations, highlighting the added value of whole-genome sequencing in diverse samples. Several of the associations identified using single-variant or aggregate analyses lie in genes with a function relevant to the brain or muscle or were reported to be associated with muscle or age-related traits. Further studies in samples with sequence data and diverse ancestries are needed to confirm these findings.

6.
Genome Med ; 13(1): 74, 2021 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-33931109

RESUMO

BACKGROUND: DNA methylation (DNAm) is associated with gene regulation and estimated glomerular filtration rate (eGFR), a measure of kidney function. Decreased eGFR is more common among US Hispanics and African Americans. The causes for this are poorly understood. We aimed to identify trans-ethnic and ethnic-specific differentially methylated positions (DMPs) associated with eGFR using an agnostic, genome-wide approach. METHODS: The study included up to 5428 participants from multi-ethnic studies for discovery and 8109 participants for replication. We tested the associations between whole blood DNAm and eGFR using beta values from Illumina 450K or EPIC arrays. Ethnicity-stratified analyses were performed using linear mixed models adjusting for age, sex, smoking, and study-specific and technical variables. Summary results were meta-analyzed within and across ethnicities. Findings were assessed using integrative epigenomics methods and pathway analyses. RESULTS: We identified 93 DMPs associated with eGFR at an FDR of 0.05 and replicated 13 and 1 DMPs across independent samples in trans-ethnic and African American meta-analyses, respectively. The study also validated 6 previously published DMPs. Identified DMPs showed significant overlap enrichment with DNase I hypersensitive sites in kidney tissue, sites associated with the expression of proximal genes, and transcription factor motifs and pathways associated with kidney tissue and kidney development. CONCLUSIONS: We uncovered trans-ethnic and ethnic-specific DMPs associated with eGFR, including DMPs enriched in regulatory elements in kidney tissue and pathways related to kidney development. These findings shed light on epigenetic mechanisms associated with kidney function, bridging the gap between population-specific eGFR-associated DNAm and tissue-specific regulatory context.

7.
Nat Commun ; 12(1): 2182, 2021 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-33846329

RESUMO

Autosomal genetic analyses of blood lipids have yielded key insights for coronary heart disease (CHD). However, X chromosome genetic variation is understudied for blood lipids in large sample sizes. We now analyze genetic and blood lipid data in a high-coverage whole X chromosome sequencing study of 65,322 multi-ancestry participants and perform replication among 456,893 European participants. Common alleles on chromosome Xq23 are strongly associated with reduced total cholesterol, LDL cholesterol, and triglycerides (min P = 8.5 × 10-72), with similar effects for males and females. Chromosome Xq23 lipid-lowering alleles are associated with reduced odds for CHD among 42,545 cases and 591,247 controls (P = 1.7 × 10-4), and reduced odds for diabetes mellitus type 2 among 54,095 cases and 573,885 controls (P = 1.4 × 10-5). Although we observe an association with increased BMI, waist-to-hip ratio adjusted for BMI is reduced, bioimpedance analyses indicate increased gluteofemoral fat, and abdominal MRI analyses indicate reduced visceral adiposity. Co-localization analyses strongly correlate increased CHRDL1 gene expression, particularly in adipose tissue, with reduced concentrations of blood lipids.


Assuntos
Fatores de Risco Cardiometabólico , Cromossomos Humanos X/genética , Lipídeos/sangue , Proteínas do Olho/metabolismo , Feminino , Regulação da Expressão Gênica , Estudos de Associação Genética , Loci Gênicos , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/metabolismo , Fenômica , Polimorfismo de Nucleotídeo Único/genética , Tela Subcutânea/metabolismo , Sequenciamento Completo do Genoma
8.
Am J Hypertens ; 34(3): 267-273, 2021 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-33821945

RESUMO

Genetic studies of DNA have been unable to explain a significant portion of the variance of the estimated heritability of blood pressure (BP). Epigenetic mechanisms, particularly DNA methylation, have helped explain additional biological processes linked to BP phenotypes and diseases. Candidate gene methylation studies and genome-wide methylation studies of BP have highlighted impactful cytosine-phosphate-guanine (CpG) markers across different ethnicities. Furthermore, many of these BP-related CpG sites are also linked to metabolism-related phenotypes. Integrating epigenome-wide association study data with other layers of molecular data such as genotype data (from single nucleotide polymorphism arrays or sequencing), other epigenetic data, and/or transcriptome data can provide additional information about the significance and complexity of these relationships. Recent data suggest that epigenetic changes can be consequences rather than causes of BP variation. Finally, these data can give insight into downstream effects of long-standing high BP (due to target organ damage (TOD)). The current review provides a literature overview of epigenetic modifications in BP and TOD. Recent studies strongly support the importance of epigenetic modifications, such as DNA methylation, in BP and TOD for relevant biological insights, reliable biomarkers, and possible future therapeutics.

9.
Lipids Health Dis ; 20(1): 30, 2021 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-33812378

RESUMO

BACKGROUND: Developing an understanding of the biochemistry of aging in both sexes is critical for managing disease throughout the lifespan. Lipidomic associations with age and sex have been reported, but prior studies are limited by measurements in serum rather than plasma or by participants taking lipid-lowering medications. METHODS: Our study included lipidomic data from 980 participants aged 18-87 years old from the Genetics of Lipid-Lowering Drugs and Diet Network (GOLDN). Participants were off lipid-lowering medications for at least 4 weeks, and signal intensities of 413 known lipid species were measured in plasma. We examined linear age and sex associations with signal intensity of (a) 413 lipid species; (b) 6 lipid classes (glycerolipids, glycerophospholipids, sphingolipids, sterol lipids, fatty acids, and acylcarnitines); and (c) 15 lipid subclasses; as well as with the particle sizes of three lipoproteins. RESULTS: Significant age associations were identified in 4 classes, 11 subclasses, 147 species, and particle size of one lipoprotein while significant sex differences were identified in 5 classes, 12 subclasses, 248 species, and particle sizes of two lipoproteins. For many lipid species (n = 97), age-related associations were significantly different between males and females. Age*sex interaction effects were most prevalent among phosphatidylcholines, sphingomyelins, and triglycerides. CONCLUSION: We identified several lipid species, subclasses, and classes that differ by age and sex; these lipid phenotypes may serve as useful biomarkers for lipid changes and associated cardiovascular risk with aging in the future. Future studies of age-related changes throughout the adult lifespan of both sexes are warranted. TRIAL REGISTRATION: ClinicalTrials.gov NCT00083369 ; May 21, 2004.

10.
Front Public Health ; 9: 611895, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33598444

RESUMO

The built environment (BE) has been associated with health outcomes in prior studies. Few have investigated the association between neighborhood walkability, a component of BE, and hypertension. We examined the association between neighborhood walkability and incident hypertension in the REasons for Geographic and Racial Differences in Stroke (REGARDS) Study. Walkability was measured using Street Smart Walk Score based on participants' residential information at baseline (collected between 2003 and 2007) and was dichotomized as more (score ≥70) and less (score <70) walkable. The primary outcome was incident hypertension defined at the second visit (collected between 2013 and 2017). We derived risk ratios (RR) using modified Poisson regression adjusting for age, race, sex, geographic region, income, alcohol use, smoking, exercise, BMI, dyslipidemia, diabetes, and baseline blood pressure (BP). We further stratified by race, age, and geographic region. Among 6,894 participants, 6.8% lived in more walkable areas and 38% (N = 2,515) had incident hypertension. In adjusted analysis, neighborhood walkability (Walk Score ≥70) was associated with a lower risk of incident hypertension (RR [95%CI]: 0.85[0.74, 0.98], P = 0.02), with similar but non-significant trends in race and age strata. In secondary analyses, living in a more walkable neighborhood was protective against being hypertensive at both study visits (OR [95%CI]: 0.70[0.59, 0.84], P < 0.001). Neighborhood walkability was associated with incident hypertension in the REGARDS cohort, with the relationship consistent across race groups. The results of this study suggest increased neighborhood walkability may be protective for high blood pressure in black and white adults from the general US population.


Assuntos
Planejamento Ambiental , Hipertensão , Adulto , Estudos de Coortes , Humanos , Hipertensão/epidemiologia , Características de Residência , Caminhada
11.
JAMA Netw Open ; 4(1): e2030435, 2021 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-33399855

RESUMO

Importance: The incidence of and mortality from coronary heart disease (CHD) are substantially higher among African American individuals compared with non-Hispanic White individuals, even after adjusting for traditional factors associated with CHD. The unexplained excess risk might be due to genetic factors related to African ancestry that are associated with a higher risk of CHD, such as the heterozygous state for the sickle cell variant or sickle cell trait (SCT). Objective: To evaluate whether there is an association between SCT and the incidence of myocardial infarction (MI) or composite CHD outcomes in African American individuals. Design, Setting, and Participants: This cohort study included 5 large, prospective, population-based cohorts of African American individuals in the Women's Health Initiative (WHI) study, the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, the Multi-Ethnic Study of Atherosclerosis (MESA), the Jackson Heart Study (JHS), and the Atherosclerosis Risk in Communities (ARIC) study. The follow-up periods included in this study were 1993 and 1998 to 2014 for the WHI study, 2003 to 2014 for the REGARDS study, 2002 to 2016 for the MESA, 2002 to 2015 for the JHS, and 1987 to 2016 for the ARIC study. Data analysis began in October 2013 and was completed in October 2020. Exposures: Sickle cell trait status was evaluated by either direct genotyping or high-quality imputation of rs334 (the sickle cell variant). Participants with sickle cell disease and those with a history of CHD were excluded from the analyses. Main Outcomes and Measures: Incident MI, defined as adjudicated nonfatal or fatal MI, and incident CHD, defined as adjudicated nonfatal MI, fatal MI, coronary revascularization procedures, or death due to CHD. Cox proportional hazards regression models were used to estimate the hazard ratio for incident MI or CHD comparing SCT carriers with noncarriers. Models were adjusted for age, sex (except for the WHI study), study site or region of residence, hypertension status or systolic blood pressure, type 1 or 2 diabetes, serum high-density lipoprotein level, total cholesterol level, and global ancestry (estimated from principal components analysis). Results: A total of 23 197 African American men (29.8%) and women (70.2%) were included in the combined sample, of whom 1781 had SCT (7.7% prevalence). Mean (SD) ages at baseline were 61.2 (6.9) years in the WHI study (n = 5904), 64.0 (9.3) years in the REGARDS study (n = 10 714), 62.0 (10.0) years in the MESA (n = 1556), 50.3 (12.0) years in the JHS (n = 2175), and 53.2 (5.8) years in the ARIC study (n = 2848). There were no significant differences in the distribution of traditional factors associated with cardiovascular disease by SCT status within cohorts. A combined total of 1034 participants (76 with SCT) had incident MI, and 1714 (137 with SCT) had the composite CHD outcome. The meta-analyzed crude incidence rate of MI did not differ by SCT status and was 3.8 per 1000 person-years (95% CI, 3.3-4.5 per 1000 person-years) among those with SCT and 3.6 per 1000 person-years (95% CI, 2.7-5.1 per 1000 person-years) among those without SCT. For the composite CHD outcome, these rates were 7.3 per 1000 person-years (95% CI, 5.5-9.7 per 1000 person-years) among those with SCT and 6.0 per 1000 person-years (95% CI, 4.9-7.4 per 1000 person-years) among those without SCT. Meta-analysis of the 5 study results showed that SCT status was not significantly associated with MI (hazard ratio, 1.03; 95% CI, 0.81-1.32) or the composite CHD outcome (hazard ratio, 1.16; 95% CI, 0.92-1.47). Conclusions and Relevance: In this cohort study, there was not an association between SCT and increased risk of MI or CHD in African American individuals. These disorders may not be associated with sickle cell trait-related sudden death in this population.


Assuntos
Afro-Americanos/estatística & dados numéricos , Doença das Coronárias , Traço Falciforme , Idoso , Estudos de Coortes , Doença das Coronárias/complicações , Doença das Coronárias/epidemiologia , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Traço Falciforme/complicações , Traço Falciforme/epidemiologia
12.
Hypertension ; 76(6): 1953-1961, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33131312

RESUMO

Almost 1 in 5 US adults with hypertension has apparent treatment resistant hypertension (aTRH). Identifying modifiable risk factors for incident aTRH may guide interventions to reduce the need for additional antihypertensive medication. We evaluated the association between cardiovascular health and incident aTRH among participants with hypertension and controlled blood pressure (BP) at baseline in the Jackson Heart Study (N=800) and the Reasons for Geographic and Racial Differences in Stroke study (N=2316). Body mass index, smoking, physical activity, diet, BP, cholesterol and glucose, categorized as ideal, intermediate, or poor according to the American Heart Association's Life's Simple 7 were assessed at baseline and used to define cardiovascular health. Incident aTRH was defined by uncontrolled BP, systolic BP ≥130 mm Hg or diastolic BP ≥80 mm Hg, while taking ≥3 classes of antihypertensive medication or controlled BP, systolic BP <130 mm Hg and diastolic BP <80 mm Hg, while taking ≥4 classes of antihypertensive medication at a follow-up visit. Over a median 9 years of follow-up, 605 (19.4%) participants developed aTRH. Incident aTRH developed among 25.8%, 18.2%, and 15.7% of participants with 0 to 1, 2, and 3 to 5 ideal Life's Simple 7 components, respectively. No participants had 6 or 7 ideal Life's Simple 7 components at baseline. The multivariable adjusted hazard ratios (95% CIs) for incident aTRH associated with 2 and 3 to 5 versus 0 to 1 ideal components were 0.75 (0.61-0.92) and 0.67 (0.54-0.82), respectively. These findings suggest optimizing cardiovascular health may reduce the pill burden and high cardiovascular risk associated with aTRH among individuals with hypertension.


Assuntos
Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Sistema Cardiovascular/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Idoso , American Heart Association , Pressão Sanguínea/fisiologia , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/fisiopatologia , Sistema Cardiovascular/fisiopatologia , Resistência a Medicamentos , Exercício Físico/fisiologia , Feminino , Inquéritos Epidemiológicos/métodos , Inquéritos Epidemiológicos/estatística & dados numéricos , Humanos , Hipertensão/fisiopatologia , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Fatores de Risco , Estados Unidos
13.
Epigenetics ; : 1-14, 2020 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-33100131

RESUMO

Target organ damage (TOD) manifests as vascular injuries in the body organ systems associated with long-standing hypertension. DNA methylation in peripheral blood leukocytes can capture inflammatory processes and gene expression changes underlying TOD. We investigated the association between epigenome-wide DNA methylation and five measures of TOD (estimated glomerular filtration rate (eGFR), urinary albumin-creatinine ratio (UACR), left ventricular mass index (LVMI), relative wall thickness (RWT), and white matter hyperintensity (WMH)) in 961 African Americans from hypertensive sibships. A multivariate (multi-trait) model of eGFR, UACR, LVMI, and RWT identified seven CpGs associated with at least one of the traits (cg21134922, cg04816311 near C7orf50, cg09155024, cg10254690 near OAT, cg07660512, cg12661888 near IFT43, and cg02264946 near CATSPERD) at FDR q < 0.1. Adjusting for blood pressure, body mass index, and type 2 diabetes attenuated the association for four CpGs. DNA methylation was associated with cis-gene expression for some CpGs, but no significant mediation by gene expression was detected. Mendelian randomization analyses suggested causality between three CpGs and eGFR (cg04816311, cg10254690, and cg07660512). We also assessed whether the identified CpGs were associated with TOD in 614 African Americans in the Hypertension Genetic Epidemiology Network (HyperGEN) study. Out of three CpGs available for replication, cg04816311 was significantly associated with eGFR (p = 0.0003), LVMI (p = 0.0003), and RWT (p = 0.002). This study found evidence of an association between DNA methylation and TOD in African Americans and highlights the utility of using a multivariate-based model that leverages information across related traits in epigenome-wide association studies.

14.
Genes (Basel) ; 11(11)2020 10 27.
Artigo em Inglês | MEDLINE | ID: mdl-33121163

RESUMO

In this work, we proposed a process to select informative genetic variants for identifying clinically meaningful subtypes of hypertensive patients. We studied 575 African American (AA) and 612 Caucasian hypertensive participants enrolled in the Hypertension Genetic Epidemiology Network (HyperGEN) study and analyzed each race-based group separately. All study participants underwent GWAS (Genome-Wide Association Studies) and echocardiography. We applied a variety of statistical methods and filtering criteria, including generalized linear models, F statistics, burden tests, deleterious variant filtering, and others to select the most informative hypertension-related genetic variants. We performed an unsupervised learning algorithm non-negative matrix factorization (NMF) to identify hypertension subtypes with similar genetic characteristics. Kruskal-Wallis tests were used to demonstrate the clinical meaningfulness of genetic-based hypertension subtypes. Two subgroups were identified for both African American and Caucasian HyperGEN participants. In both AAs and Caucasians, indices of cardiac mechanics differed significantly by hypertension subtypes. African Americans tend to have more genetic variants compared to Caucasians; therefore, using genetic information to distinguish the disease subtypes for this group of people is relatively challenging, but we were able to identify two subtypes whose cardiac mechanics have statistically different distributions using the proposed process. The research gives a promising direction in using statistical methods to select genetic information and identify subgroups of diseases, which may inform the development and trial of novel targeted therapies.

15.
Am J Clin Nutr ; 112(5): 1200-1211, 2020 11 11.
Artigo em Inglês | MEDLINE | ID: mdl-32930325

RESUMO

BACKGROUND: Epigenome-wide association studies identified the cg00574958 DNA methylation site at the carnitine palmitoyltransferase-1A (CPT1A) gene to be associated with reduced risk of metabolic diseases (hypertriglyceridemia, obesity, type 2 diabetes, hypertension, metabolic syndrome), but the mechanism underlying these associations is unknown. OBJECTIVES: We aimed to elucidate whether carbohydrate and fat intakes modulate cg00574958 methylation and the risk of metabolic diseases. METHODS: We examined associations between carbohydrate (CHO) and fat (FAT) intake, as percentages of total diet energy, and the CHO/FAT ratio with CPT1A-cg00574958, and the risk of metabolic diseases in 3 populations (Genetics of Lipid Lowering Drugs and Diet Network, n = 978; Framingham Heart Study, n = 2331; and REgistre GIroní del COR study, n = 645) while adjusting for confounding factors. To understand possible causal effects of dietary intake on the risk of metabolic diseases, we performed meta-analysis, CPT1A transcription analysis, and mediation analysis with CHO and FAT intakes as exposures and cg00574958 methylation as the mediator. RESULTS: We confirmed strong associations of cg00574958 methylation with metabolic phenotypes (BMI, triglyceride, glucose) and diseases in all 3 populations. Our results showed that CHO intake and CHO/FAT ratio were positively associated with cg00574958 methylation, whereas FAT intake was negatively correlated with cg00574958 methylation. Meta-analysis further confirmed this strong correlation, with ß = 58.4 ± 7.27, P = 8.98 x 10-16 for CHO intake; ß = -36.4 ± 5.95, P = 9.96 x 10-10 for FAT intake; and ß = 3.30 ± 0.49, P = 1.48 x 10-11 for the CHO/FAT ratio. Furthermore, CPT1A mRNA expression was negatively associated with CHO intake, and positively associated with FAT intake, and metabolic phenotypes. Mediation analysis supports the hypothesis that CHO intake induces CPT1A methylation, hence reducing the risk of metabolic diseases, whereas FAT intake inhibits CPT1A methylation, thereby increasing the risk of metabolic diseases. CONCLUSIONS: Our results suggest that the proportion of total energy supplied by CHO and FAT can have a causal effect on the risk of metabolic diseases via the epigenetic status of CPT1A.Study registration at https://www.clinicaltrials.gov/: the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN)-NCT01023750; and the Framingham Heart Study (FHS)-NCT00005121.


Assuntos
Carnitina O-Palmitoiltransferase/metabolismo , Carboidratos da Dieta/efeitos adversos , Gorduras na Dieta/efeitos adversos , Epigênese Genética , Adulto , Idoso , Carnitina O-Palmitoiltransferase/genética , Epigenoma , Feminino , Regulação Enzimológica da Expressão Gênica , Variação Genética , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade
16.
Nat Genet ; 52(9): 969-983, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32839606

RESUMO

Large-scale whole-genome sequencing studies have enabled the analysis of rare variants (RVs) associated with complex phenotypes. Commonly used RV association tests have limited scope to leverage variant functions. We propose STAAR (variant-set test for association using annotation information), a scalable and powerful RV association test method that effectively incorporates both variant categories and multiple complementary annotations using a dynamic weighting scheme. For the latter, we introduce 'annotation principal components', multidimensional summaries of in silico variant annotations. STAAR accounts for population structure and relatedness and is scalable for analyzing very large cohort and biobank whole-genome sequencing studies of continuous and dichotomous traits. We applied STAAR to identify RVs associated with four lipid traits in 12,316 discovery and 17,822 replication samples from the Trans-Omics for Precision Medicine Program. We discovered and replicated new RV associations, including disruptive missense RVs of NPC1L1 and an intergenic region near APOC1P1 associated with low-density lipoprotein cholesterol.


Assuntos
Predisposição Genética para Doença/genética , Variação Genética/genética , Genoma/genética , LDL-Colesterol/genética , Simulação por Computador , Estudo de Associação Genômica Ampla/métodos , Humanos , Modelos Genéticos , Anotação de Sequência Molecular/métodos , Fenótipo , Sequenciamento Completo do Genoma/métodos
17.
J Nutr ; 150(10): 2635-2645, 2020 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-32840624

RESUMO

BACKGROUND: Excess sodium intake and insufficient potassium intake are risk factors for hypertension, but there is limited knowledge regarding genetic factors that influence intake. Twenty-hour or half-day urine samples provide robust estimates of sodium and potassium intake, outperforming other measures such as spot urine samples and dietary self-reporting. OBJECTIVE: The aim of this study was to investigate genomic regions associated with sodium intake, potassium intake, and sodium-to-potassium ratio measured from 24-h or half-day urine samples. METHODS: Using samples of European ancestry (mean age: 54.2 y; 52.3% women), we conducted a meta-analysis of genome-wide association studies in 4 cohorts with 24-h or half-day urine samples (n = 6,519), followed by gene-based analysis. Suggestive loci (P < 10-6) were examined in additional European (n = 844), African (n = 1,246), and Asian (n = 2,475) ancestry samples. RESULTS: We found suggestive loci (P < 10-6) for all 3 traits, including 7 for 24-h sodium excretion, 4 for 24-h potassium excretion, and 4 for sodium-to-potassium ratio. The most significant locus was rs77958157 near cocaine- and amphetamine-regulated transcript prepropeptide (CARTPT) , a gene involved in eating behavior and appetite regulation (P = 2.3 × 10-8 with sodium-to-potassium ratio). Two suggestive loci were replicated in additional samples: for sodium excretion, rs12094702 near zinc finger SWIM-type containing 5 (ZSWIM5) was replicated in the Asian ancestry sample reaching Bonferroni-corrected significance (P = 0.007), and for potassium excretion rs34473523 near sodium leak channel (NALCN) was associated at a nominal P value with potassium excretion both in European (P = 0.043) and African (P = 0.043) ancestry cohorts. Gene-based tests identified 1 significant gene for sodium excretion, CDC42 small effector 1 (CDC42SE1), which is associated with blood pressure regulation. CONCLUSIONS: We identified multiple suggestive loci for sodium and potassium intake near genes associated with eating behavior, nervous system development and function, and blood pressure regulation in individuals of European ancestry. Further research is needed to replicate these findings and to provide insight into the underlying genetic mechanisms by which these genomic regions influence sodium and potassium intake.


Assuntos
Grupo com Ancestrais do Continente Europeu/genética , Comportamento Alimentar , Estudo de Associação Genômica Ampla , Potássio na Dieta/administração & dosagem , Sódio na Dieta/administração & dosagem , Adulto , Idoso , Dieta , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Potássio/metabolismo , Potássio/urina , Sódio/metabolismo , Sódio/urina
18.
Lipids Health Dis ; 19(1): 153, 2020 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-32586392

RESUMO

BACKGROUND: The lipoprotein insulin resistance (LPIR) score was shown to predict insulin resistance (IR) and type 2 diabetes (T2D) in healthy adults. However, the molecular basis underlying the LPIR utility for classification remains unclear. OBJECTIVE: To identify small molecule lipids associated with variation in the LPIR score, a weighted index of lipoproteins measured by nuclear magnetic resonance, in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study (n = 980). METHODS: Linear mixed effects models were used to test the association between the LPIR score and 413 lipid species and their principal component analysis-derived groups. Significant associations were tested for replication with homeostatic model assessment-IR (HOMA-IR), a phenotype correlated with the LPIR score (r = 0.48, p <  0.001), in the Heredity and Phenotype Intervention (HAPI) Heart Study (n = 590). RESULTS: In GOLDN, 319 lipids were associated with the LPIR score (false discovery rate-adjusted p-values ranging from 4.59 × 10- 161 to 49.50 × 10- 3). Factors 1 (triglycerides and diglycerides/storage lipids) and 3 (mixed lipids) were positively (ß = 0.025, p = 4.52 × 10- 71 and ß = 0.021, p = 5.84 × 10- 41, respectively) and factor 2 (phospholipids/non-storage lipids) was inversely (ß = - 0.013, p = 2.28 × 10- 18) associated with the LPIR score. These findings were replicated for HOMA-IR in the HAPI Heart Study (ß = 0.10, p = 1.21 × 10- 02 for storage, ß = - 0.13, p = 3.14 × 10- 04 for non-storage, and ß = 0.19, p = 8.40 × 10- 07 for mixed lipids). CONCLUSIONS: Non-storage lipidomics species show a significant inverse association with the LPIR metabolic dysfunction score and present a promising focus for future therapeutic and prevention studies.


Assuntos
Resistência à Insulina/fisiologia , Lipídeos/sangue , Adulto , Idoso , Índice de Massa Corporal , Diabetes Mellitus Tipo 2/sangue , Feminino , Humanos , Lipidômica , Lipoproteínas/sangue , Masculino , Pessoa de Meia-Idade , Triglicerídeos/sangue , Circunferência da Cintura
19.
J Am Heart Assoc ; 9(6): e014241, 2020 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-32157955

RESUMO

Background Soluble CD14 (sCD14), a circulating pattern recognition receptor, has been suggested as a cardiovascular disease risk factor. Prospective studies evaluating sCD14 with incident cardiovascular disease events are limited, particularly among racially diverse populations. Methods and Results Between 2003 and 2007, the REGARDS (Reasons for Geographic and Racial Differences in Stroke) study recruited 30 239 black and white participants across the United States. In a nested case-cohort study, sCD14 was measured in baseline serum from 548 cases of incident ischemic stroke, 612 cases of incident coronary heart disease (CHD), and a cohort random sample (n=1039). Cox models estimated hazards ratios (HR) of incident ischemic stroke or CHD per 1 SD higher sCD14, adjusting for cardiovascular disease risk factors. There was a differential association of sCD14 with ischemic stroke and CHD risk by race. Among blacks, the adjusted HR of stroke per SD increment of sCD14 was 1.42 (95% CI: 1.12, 1.80), with no association among whites (HR 1.02 [95% CI: 0.82, 1.27]). Higher sCD14 was associated with increased CHD risk in blacks but not whites, and relationships between sCD14 and CHD were stronger at younger ages. Adjusted for risk factors, the HR of CHD per SD higher sCD14 among blacks at age 45 years was 2.30 (95% CI: 1.45, 3.65) compared with 1.56 (95% CI: 0.94, 2.57) among whites. At age 65 years, the CHD HR was 1.51 (95% CI: 1.20, 1.91) among blacks and 1.02 (95% CI: 0.80, 1.31) among whites. Conclusions sCD14 may be a race-specific stroke and CHD risk marker.


Assuntos
Doença das Coronárias/sangue , AVC Isquêmico/sangue , Receptores de Lipopolissacarídeos/sangue , Afro-Americanos , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Doença das Coronárias/diagnóstico , Doença das Coronárias/etnologia , Grupo com Ancestrais do Continente Europeu , Feminino , Humanos , Incidência , AVC Isquêmico/diagnóstico , AVC Isquêmico/etnologia , Masculino , Pessoa de Meia-Idade , Fatores Raciais , Medição de Risco , Fatores de Risco , Estados Unidos/epidemiologia , Regulação para Cima
20.
J Thromb Haemost ; 18(6): 1335-1347, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-31985870

RESUMO

BACKGROUND: Prospective studies have suggested higher factor VIII (FVIII) levels are an independent risk factor for coronary heart disease (CHD) and stroke. However, limited information, including on genetic and epigenetic contributors to FVIII variation, is available specifically among African Americans (AAs), who have higher FVIII levels than Europeans. OBJECTIVES: We measured FVIII levels in ~3400 AAs from the community-based Jackson Heart Study and assessed genetic, epigenetic, and epidemiological correlates of FVIII, as well as incident cardiovascular disease (CVD) associations. METHODS: We assessed cross-sectional associations of FVIII with CVD risk factors as well as incident CHD, stroke, heart failure, and mortality associations. We additionally assessed associations with TOPMed whole genome sequencing data and an epigenome-wide methylation array. RESULTS: Our results confirmed associations between FVIII and risk of incident CHD events and total mortality in AAs; mortality associations were largely independent of traditional risk factors. We also demonstrate an association of FVIII with incident heart failure, independent of B-type natriuretic peptide. Two genomic regions were strongly associated with FVIII (ABO and VWF). The index variant at VWF is specific to individuals of African descent and is distinct from the previously reported European VWF association signal. Epigenome-wide association analysis showed significant FVIII associations with several CpG sites in the ABO region. However, after adjusting for ABO genetic variants, ABO CpG sites were not significant. CONCLUSIONS: Larger sample sizes of AAs will be required to discover additional genetic and epigenetic contributors to FVIII phenotypic variation, which may have consequences for CVD health disparities.


Assuntos
Doenças Cardiovasculares , Fator VIII , Afro-Americanos/genética , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/genética , Estudos Transversais , Epigenoma , Fator VIII/genética , Humanos , Estudos Prospectivos , Fator de von Willebrand/genética
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