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1.
Circ Genom Precis Med ; 14(4): e003300, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34319147

RESUMO

BACKGROUND: Alterations in electrocardiographic (ECG) intervals are well-known markers for arrhythmia and sudden cardiac death (SCD) risk. While the genetics of arrhythmia syndromes have been studied, relations between electrocardiographic intervals and rare genetic variation at a population level are poorly understood. METHODS: Using a discovery sample of 29 000 individuals with whole-genome sequencing from Trans-Omics in Precision Medicine and replication in nearly 100 000 with whole-exome sequencing from the UK Biobank and MyCode, we examined associations between low-frequency and rare coding variants with 5 routinely measured electrocardiographic traits (RR, P-wave, PR, and QRS intervals and corrected QT interval). RESULTS: We found that rare variants associated with population-based electrocardiographic intervals identify established monogenic SCD genes (KCNQ1, KCNH2, and SCN5A), a controversial monogenic SCD gene (KCNE1), and novel genes (PAM and MFGE8) involved in cardiac conduction. Loss-of-function and pathogenic SCN5A variants, carried by 0.1% of individuals, were associated with a nearly 6-fold increased odds of the first-degree atrioventricular block (P=8.4×10-5). Similar variants in KCNQ1 and KCNH2 (0.2% of individuals) were associated with a 23-fold increased odds of marked corrected QT interval prolongation (P=4×10-25), a marker of SCD risk. Incomplete penetrance of such deleterious variation was common as over 70% of carriers had normal electrocardiographic intervals. CONCLUSIONS: Our findings indicate that large-scale high-depth sequence data and electrocardiographic analysis identifies monogenic arrhythmia susceptibility genes and rare variants with large effects. Known pathogenic variation in conventional arrhythmia and SCD genes exhibited incomplete penetrance and accounted for only a small fraction of marked electrocardiographic interval prolongation.

2.
Nat Commun ; 12(1): 2830, 2021 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-33990564

RESUMO

Coffee and tea are extensively consumed beverages worldwide which have received considerable attention regarding health. Intake of these beverages is consistently linked to, among others, reduced risk of diabetes and liver diseases; however, the mechanisms of action remain elusive. Epigenetics is suggested as a mechanism mediating the effects of dietary and lifestyle factors on disease onset. Here we report the results from epigenome-wide association studies (EWAS) on coffee and tea consumption in 15,789 participants of European and African-American ancestries from 15 cohorts. EWAS meta-analysis of coffee consumption reveals 11 CpGs surpassing the epigenome-wide significance threshold (P-value <1.1×10-7), which annotated to the AHRR, F2RL3, FLJ43663, HDAC4, GFI1 and PHGDH genes. Among them, cg14476101 is significantly associated with expression of the PHGDH and risk of fatty liver disease. Knockdown of PHGDH expression in liver cells shows a correlation with expression levels of genes associated with circulating lipids, suggesting a role of PHGDH in hepatic-lipid metabolism. EWAS meta-analysis on tea consumption reveals no significant association, only two CpGs annotated to CACNA1A and PRDM16 genes show suggestive association (P-value <5.0×10-6). These findings indicate that coffee-associated changes in DNA methylation levels may explain the mechanism of action of coffee consumption in conferring risk of diseases.


Assuntos
Café/efeitos adversos , Metilação de DNA , Epigenoma , Chá/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Ilhas de CpG , Epigênese Genética , Feminino , Técnicas de Silenciamento de Genes , Estudo de Associação Genômica Ampla , Humanos , Fígado/enzimologia , Masculino , Pessoa de Meia-Idade , Fosfoglicerato Desidrogenase/antagonistas & inibidores , Fosfoglicerato Desidrogenase/genética , Fatores de Risco
3.
Am J Epidemiol ; 190(10): 1977-1992, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-33861317

RESUMO

Genotype-phenotype association studies often combine phenotype data from multiple studies to increase statistical power. Harmonization of the data usually requires substantial effort due to heterogeneity in phenotype definitions, study design, data collection procedures, and data-set organization. Here we describe a centralized system for phenotype harmonization that includes input from phenotype domain and study experts, quality control, documentation, reproducible results, and data-sharing mechanisms. This system was developed for the National Heart, Lung, and Blood Institute's Trans-Omics for Precision Medicine (TOPMed) program, which is generating genomic and other -omics data for more than 80 studies with extensive phenotype data. To date, 63 phenotypes have been harmonized across thousands of participants (recruited in 1948-2012) from up to 17 studies per phenotype. Here we discuss challenges in this undertaking and how they were addressed. The harmonized phenotype data and associated documentation have been submitted to National Institutes of Health data repositories for controlled access by the scientific community. We also provide materials to facilitate future harmonization efforts by the community, which include 1) the software code used to generate the 63 harmonized phenotypes, enabling others to reproduce, modify, or extend these harmonizations to additional studies, and 2) the results of labeling thousands of phenotype variables with controlled vocabulary terms.


Assuntos
Estudos de Associação Genética/métodos , Fenômica/métodos , Medicina de Precisão/métodos , Agregação de Dados , Humanos , Disseminação de Informação , National Heart, Lung, and Blood Institute (U.S.) , Fenótipo , Avaliação de Programas e Projetos de Saúde , Estados Unidos
4.
Blood ; 137(17): 2394-2402, 2021 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-33512453

RESUMO

Genetic risk score (GRS) analysis is a popular approach to derive individual risk prediction models for complex diseases. In venous thrombosis (VT), such type of analysis shall integrate information at the ABO blood group locus, which is one of the major susceptibility loci. However, there is no consensus about which single nucleotide polymorphisms (SNPs) must be investigated when properly assessing association between ABO locus and VT risk. Using comprehensive haplotype analyses of ABO blood group tagging SNPs in 5425 cases and 8445 controls from 6 studies, we demonstrate that using only rs8176719 (tagging O1) to correctly assess the impact of ABO locus on VT risk is suboptimal, because 5% of rs8176719-delG carriers do not have an increased risk of developing VT. Instead, we recommend the use of 4 SNPs, rs2519093 (tagging A1), rs1053878 (A2), rs8176743 (B), and rs41302905 (O2), when assessing the impact of ABO locus on VT risk to avoid any risk misestimation. Compared with the O1 haplotype, the A2 haplotype is associated with a modest increase in VT risk (odds ratio, âˆ¼1.2), the A1 and B haplotypes are associated with an âˆ¼1.8-fold increased risk, whereas the O2 haplotype tends to be slightly protective (odds ratio, âˆ¼0.80). In addition, although the A1 and B blood groups are associated with increased von Willebrand factor and factor VIII plasma levels, only the A1 blood group is associated with ICAM levels, but in an opposite direction, leaving additional avenues to be explored to fully understand the spectrum of biological effects mediated by ABO locus on cardiovascular traits.

5.
Pharmacoepidemiol Drug Saf ; 29(9): 1175-1182, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32558036

RESUMO

PURPOSE: Opioids, gabapentinoids, and nonsteroidal anti-inflammatory drugs (NSAIDs) may have adverse cardiovascular effects. We evaluated whether these medications were associated with incident clinically detected atrial fibrillation (AF) or monitor-detected supraventricular ectopy (SVE), including premature atrial contractions (PACs) and supraventricular tachycardia (SVT). METHODS: We used data from the Multi-Ethnic Study of Atherosclerosis (MESA), a cohort study that enrolled 6814 Americans without clinically detected cardiovascular disease in 2000 to 2002. At the 2016 to 2018 examination, 1557 individuals received ambulatory electrocardiographic (ECG) monitoring. Longitudinal analyses investigated time-varying medication exposures at the first five exams (through 2011) in relation to incident clinically detected AF through 2015 using Cox proportional hazards regression models. Cross-sectional analyses investigated medication exposures at 2016 to 2018 examination and the risk of monitor-detected SVE using linear regression models. RESULTS: The longitudinal cohort included 6652 participants. During 12.4 years of mean follow-up, 982 participants (14.7%) experienced incident clinically detected AF. Use of opioids, gabapentinoids, and NSAIDs were not associated with incident AF. The cross-sectional analysis included 1435 participants with ECG monitoring. Gabapentinoid use was associated with an 84% greater average frequency of PACs/hour (95% CI, 25%-171%) and a 44% greater average number of runs of SVT/day (95% CI, 3%-100%). No associations were found with use of opioids or NSAIDs in cross-sectional analyses. CONCLUSIONS: In this study, gabapentinoid use was associated with SVE. Given the rapid increase in gabapentinoid use, additional studies are needed to clarify whether these medications cause cardiovascular complications.

6.
Am J Hypertens ; 32(12): 1146-1153, 2019 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-31545351

RESUMO

BACKGROUND: Only a handful of genetic discovery efforts in apparent treatment-resistant hypertension (aTRH) have been described. METHODS: We conducted a case-control genome-wide association study of aTRH among persons treated for hypertension, using data from 10 cohorts of European ancestry (EA) and 5 cohorts of African ancestry (AA). Cases were treated with 3 different antihypertensive medication classes and had blood pressure (BP) above goal (systolic BP ≥ 140 mm Hg and/or diastolic BP ≥ 90 mm Hg) or 4 or more medication classes regardless of BP control (nEA = 931, nAA = 228). Both a normotensive control group and a treatment-responsive control group were considered in separate analyses. Normotensive controls were untreated (nEA = 14,210, nAA = 2,480) and had systolic BP/diastolic BP < 140/90 mm Hg. Treatment-responsive controls (nEA = 5,266, nAA = 1,817) had BP at goal (<140/90 mm Hg), while treated with one antihypertensive medication class. Individual cohorts used logistic regression with adjustment for age, sex, study site, and principal components for ancestry to examine the association of single-nucleotide polymorphisms with case-control status. Inverse variance-weighted fixed-effects meta-analyses were carried out using METAL. RESULTS: The known hypertension locus, CASZ1, was a top finding among EAs (P = 1.1 × 10-8) and in the race-combined analysis (P = 1.5 × 10-9) using the normotensive control group (rs12046278, odds ratio = 0.71 (95% confidence interval: 0.6-0.8)). Single-nucleotide polymorphisms in this locus were robustly replicated in the Million Veterans Program (MVP) study in consideration of a treatment-responsive control group. There were no statistically significant findings for the discovery analyses including treatment-responsive controls. CONCLUSION: This genomic discovery effort for aTRH identified CASZ1 as an aTRH risk locus.


Assuntos
Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea/genética , Proteínas de Ligação a DNA/genética , Resistência a Medicamentos/genética , Hipertensão/tratamento farmacológico , Hipertensão/genética , Variantes Farmacogenômicos , Polimorfismo de Nucleotídeo Único , Fatores de Transcrição/genética , Afro-Americanos/genética , Idoso , Anti-Hipertensivos/efeitos adversos , Pressão Sanguínea/efeitos dos fármacos , Estudos de Casos e Controles , DNA (Citosina-5-)-Metiltransferases/genética , Proteínas Associadas à Distrofina/genética , Europa (Continente)/epidemiologia , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Loci Gênicos , Estudo de Associação Genômica Ampla , Humanos , Hipertensão/etnologia , Hipertensão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Cadeias Pesadas de Miosina/genética , Miosina Tipo V/genética , Neuropeptídeos/genética , Farmacogenética , Medição de Risco , Fatores de Risco , Estados Unidos/epidemiologia
7.
Mol Genet Genomic Med ; 7(10): e00788, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31407531

RESUMO

BACKGROUND: Left ventricular (LV) hypertrophy affects up to 43% of African Americans (AAs). Antihypertensive treatment reduces LV mass (LVM). However, interindividual variation in LV traits in response to antihypertensive treatments exists. We hypothesized that genetic variants may modify the association of antihypertensive treatment class with LV traits measured by echocardiography. METHODS: We evaluated the main effects of the three most common antihypertensive treatments for AAs as well as the single nucleotide polymorphism (SNP)-by-drug interaction on LVM and relative wall thickness (RWT) in 2,068 participants across five community-based cohorts. Treatments included thiazide diuretics (TDs), angiotensin converting enzyme inhibitors (ACE-Is), and dihydropyridine calcium channel blockers (dCCBs) and were compared in a pairwise manner. We performed fixed effects inverse variance weighted meta-analyses of main effects of drugs and 2.5 million SNP-by-drug interaction estimates. RESULTS: We observed that dCCBs versus TDs were associated with higher LVM after adjusting for covariates (p = 0.001). We report three SNPs at a single locus on chromosome 20 that modified the association between RWT and treatment when comparing dCCBs to ACE-Is with consistent effects across cohorts (smallest p = 4.7 × 10-8 , minor allele frequency range 0.09-0.12). This locus has been linked to LV hypertrophy in a previous study. A marginally significant locus in BICD1 (rs326641) was validated in an external population. CONCLUSIONS: Our study identified one locus having genome-wide significant SNP-by-drug interaction effect on RWT among dCCB users in comparison to ACE-I users. Upon additional validation in future studies, our findings can enhance the precision of medical approaches in hypertension treatment.


Assuntos
Anti-Hipertensivos/uso terapêutico , Variantes Farmacogenômicos , Polimorfismo de Nucleotídeo Único , Disfunção Ventricular Esquerda/genética , Afro-Americanos/genética , Afro-Americanos/estatística & dados numéricos , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Bloqueadores dos Canais de Cálcio/uso terapêutico , Humanos , Estudos Observacionais como Assunto , Inibidores de Simportadores de Cloreto de Sódio/uso terapêutico , Disfunção Ventricular Esquerda/tratamento farmacológico , Disfunção Ventricular Esquerda/epidemiologia
8.
Circulation ; 140(8): 645-657, 2019 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-31424985

RESUMO

BACKGROUND: DNA methylation is implicated in coronary heart disease (CHD), but current evidence is based on small, cross-sectional studies. We examined blood DNA methylation in relation to incident CHD across multiple prospective cohorts. METHODS: Nine population-based cohorts from the United States and Europe profiled epigenome-wide blood leukocyte DNA methylation using the Illumina Infinium 450k microarray, and prospectively ascertained CHD events including coronary insufficiency/unstable angina, recognized myocardial infarction, coronary revascularization, and coronary death. Cohorts conducted race-specific analyses adjusted for age, sex, smoking, education, body mass index, blood cell type proportions, and technical variables. We conducted fixed-effect meta-analyses across cohorts. RESULTS: Among 11 461 individuals (mean age 64 years, 67% women, 35% African American) free of CHD at baseline, 1895 developed CHD during a mean follow-up of 11.2 years. Methylation levels at 52 CpG (cytosine-phosphate-guanine) sites were associated with incident CHD or myocardial infarction (false discovery rate<0.05). These CpGs map to genes with key roles in calcium regulation (ATP2B2, CASR, GUCA1B, HPCAL1), and genes identified in genome- and epigenome-wide studies of serum calcium (CASR), serum calcium-related risk of CHD (CASR), coronary artery calcified plaque (PTPRN2), and kidney function (CDH23, HPCAL1), among others. Mendelian randomization analyses supported a causal effect of DNA methylation on incident CHD; these CpGs map to active regulatory regions proximal to long non-coding RNA transcripts. CONCLUSION: Methylation of blood-derived DNA is associated with risk of future CHD across diverse populations and may serve as an informative tool for gaining further insight on the development of CHD.


Assuntos
Doença das Coronárias/diagnóstico , Ilhas de CpG/genética , Metilação de DNA/fisiologia , Leucócitos/fisiologia , Infarto do Miocárdio/diagnóstico , Adulto , Idoso , Estudos de Coortes , Doença das Coronárias/epidemiologia , Europa (Continente)/epidemiologia , Feminino , Estudo de Associação Genômica Ampla , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/epidemiologia , Grupos Populacionais , Prognóstico , Estudos Prospectivos , Risco , Estados Unidos/epidemiologia
9.
Blood ; 134(19): 1645-1657, 2019 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-31420334

RESUMO

Venous thromboembolism (VTE) is a significant contributor to morbidity and mortality. To advance our understanding of the biology contributing to VTE, we conducted a genome-wide association study (GWAS) of VTE and a transcriptome-wide association study (TWAS) based on imputed gene expression from whole blood and liver. We meta-analyzed GWAS data from 18 studies for 30 234 VTE cases and 172 122 controls and assessed the association between 12 923 718 genetic variants and VTE. We generated variant prediction scores of gene expression from whole blood and liver tissue and assessed them for association with VTE. Mendelian randomization analyses were conducted for traits genetically associated with novel VTE loci. We identified 34 independent genetic signals for VTE risk from GWAS meta-analysis, of which 14 are newly reported associations. This included 11 newly associated genetic loci (C1orf198, PLEK, OSMR-AS1, NUGGC/SCARA5, GRK5, MPHOSPH9, ARID4A, PLCG2, SMG6, EIF5A, and STX10) of which 6 replicated, and 3 new independent signals in 3 known genes. Further, TWAS identified 5 additional genetic loci with imputed gene expression levels differing between cases and controls in whole blood (SH2B3, SPSB1, RP11-747H7.3, RP4-737E23.2) and in liver (ERAP1). At some GWAS loci, we found suggestive evidence that the VTE association signal for novel and previously known regions colocalized with expression quantitative trait locus signals. Mendelian randomization analyses suggested that blood traits may contribute to the underlying risk of VTE. To conclude, we identified 16 novel susceptibility loci for VTE; for some loci, the association signals are likely mediated through gene expression of nearby genes.


Assuntos
Predisposição Genética para Doença/genética , Tromboembolia Venosa/genética , Estudo de Associação Genômica Ampla , Humanos
10.
PLoS One ; 14(6): e0218115, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31242253

RESUMO

AIMS: Statin-related myopathy (SRM), which includes rhabdomyolysis, is an uncommon but important adverse drug reaction because the number of people prescribed statins world-wide is large. Previous association studies of common genetic variants have had limited success in identifying a genetic basis for this adverse drug reaction. We conducted a multi-site whole-exome sequencing study to investigate whether rare coding variants confer an increased risk of SRM. METHODS AND RESULTS: SRM 3-5 cases (N = 505) and statin treatment-tolerant controls (N = 2047) were recruited from multiple sites in North America and Europe. SRM 3-5 was defined as symptoms consistent with muscle injury and an elevated creatine phosphokinase level >4 times upper limit of normal without another likely cause of muscle injury. Whole-exome sequencing and variant calling was coordinated from two analysis centres, and results of single-variant and gene-based burden tests were meta-analysed. No genome-wide significant associations were identified. Given the large number of cases, we had 80% power to identify a variant with minor allele frequency of 0.01 that increases the risk of SRM 6-fold at genome-wide significance. CONCLUSIONS: In this large whole-exome sequencing study of severe statin-related muscle injury conducted to date, we did not find evidence that rare coding variants are responsible for this adverse drug reaction. Larger sample sizes would be required to identify rare variants with small effects, but it is unclear whether such findings would be clinically actionable.


Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Músculo Esquelético , Rabdomiólise , Sequenciamento Completo do Genoma , Estudo de Associação Genômica Ampla , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Rabdomiólise/induzido quimicamente , Rabdomiólise/genética , Rabdomiólise/metabolismo , Rabdomiólise/patologia
11.
PLoS One ; 14(5): e0216222, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31075152

RESUMO

BACKGROUND: Fibrinogen is an essential hemostatic factor and cardiovascular disease risk factor. Early attempts at evaluating the causal effect of fibrinogen on coronary heart disease (CHD) and myocardial infraction (MI) using Mendelian randomization (MR) used single variant approaches, and did not take advantage of recent genome-wide association studies (GWAS) or multi-variant, pleiotropy robust MR methodologies. METHODS AND FINDINGS: We evaluated evidence for a causal effect of fibrinogen on both CHD and MI using MR. We used both an allele score approach and pleiotropy robust MR models. The allele score was composed of 38 fibrinogen-associated variants from recent GWAS. Initial analyses using the allele score used a meta-analysis of 11 European-ancestry prospective cohorts, free of CHD and MI at baseline, to examine incidence CHD and MI. We also applied 2 sample MR methods with data from a prevalent CHD and MI GWAS. Results are given in terms of the hazard ratio (HR) or odds ratio (OR), depending on the study design, and associated 95% confidence interval (CI). In single variant analyses no causal effect of fibrinogen on CHD or MI was observed. In multi-variant analyses using incidence CHD cases and the allele score approach, the estimated causal effect (HR) of a 1 g/L higher fibrinogen concentration was 1.62 (CI = 1.12, 2.36) when using incident cases and the allele score approach. In 2 sample MR analyses that accounted for pleiotropy, the causal estimate (OR) was reduced to 1.18 (CI = 0.98, 1.42) and 1.09 (CI = 0.89, 1.33) in the 2 most precise (smallest CI) models, out of 4 models evaluated. In the 2 sample MR analyses for MI, there was only very weak evidence of a causal effect in only 1 out of 4 models. CONCLUSIONS: A small causal effect of fibrinogen on CHD is observed using multi-variant MR approaches which account for pleiotropy, but not single variant MR approaches. Taken together, results indicate that even with large sample sizes and multi-variant approaches MR analyses still cannot exclude the null when estimating the causal effect of fibrinogen on CHD, but that any potential causal effect is likely to be much smaller than observed in epidemiological studies.


Assuntos
Doença das Coronárias/epidemiologia , Fibrinogênio/farmacologia , Análise da Randomização Mendeliana , Alelos , Doença das Coronárias/etiologia , Pleiotropia Genética , Variação Genética , Estudo de Associação Genômica Ampla , Humanos , Incidência , Modelos Genéticos , Análise Multivariada , Infarto do Miocárdio/epidemiologia , Infarto do Miocárdio/etiologia , Razão de Chances
12.
Genet Epidemiol ; 43(4): 449-457, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30659681

RESUMO

Although recent Genome-Wide Association Studies have identified novel associations for common variants, there has been no comprehensive exome-wide search for low-frequency variants that affect the risk of venous thromboembolism (VTE). We conducted a meta-analysis of 11 studies comprising 8,332 cases and 16,087 controls of European ancestry and 382 cases and 1,476 controls of African American ancestry genotyped with the Illumina HumanExome BeadChip. We used the seqMeta package in R to conduct single variant and gene-based rare variant tests. In the single variant analysis, we limited our analysis to the 64,794 variants with at least 40 minor alleles across studies (minor allele frequency [MAF] ~0.08%). We confirmed associations with previously identified VTE loci, including ABO, F5, F11, and FGA. After adjusting for multiple testing, we observed no novel significant findings in single variant or gene-based analysis. Given our sample size, we had greater than 80% power to detect minimum odds ratios greater than 1.5 and 1.8 for a single variant with MAF of 0.01 and 0.005, respectively. Larger studies and sequence data may be needed to identify novel low-frequency and rare variants associated with VTE risk.


Assuntos
Exoma/genética , Estudo de Associação Genômica Ampla/métodos , Sequenciamento de Nucleotídeos em Larga Escala , Análise em Microsséries/métodos , Tromboembolia Venosa/genética , Afro-Americanos/genética , Alelos , Estudos de Casos e Controles , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Sequenciamento de Nucleotídeos em Larga Escala/estatística & dados numéricos , Humanos , Masculino , Análise em Microsséries/estatística & dados numéricos , Razão de Chances , Polimorfismo de Nucleotídeo Único , Tamanho da Amostra , Tromboembolia Venosa/etnologia
13.
Pharmacogenomics J ; 19(1): 97-108, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-29855607

RESUMO

We evaluated interactions of SNP-by-ACE-I/ARB and SNP-by-TD on serum potassium (K+) among users of antihypertensive treatments (anti-HTN). Our study included seven European-ancestry (EA) (N = 4835) and four African-ancestry (AA) cohorts (N = 2016). We performed race-stratified, fixed-effect, inverse-variance-weighted meta-analyses of 2.5 million SNP-by-drug interaction estimates; race-combined meta-analysis; and trans-ethnic fine-mapping. Among EAs, we identified 11 significant SNPs (P < 5 × 10-8) for SNP-ACE-I/ARB interactions on serum K+ that were located between NR2F1-AS1 and ARRDC3-AS1 on chromosome 5 (top SNP rs6878413 P = 1.7 × 10-8; ratio of serum K+ in ACE-I/ARB exposed compared to unexposed is 1.0476, 1.0280, 1.0088 for the TT, AT, and AA genotypes, respectively). Trans-ethnic fine mapping identified the same group of SNPs on chromosome 5 as genome-wide significant for the ACE-I/ARB analysis. In conclusion, SNP-by-ACE-I /ARB interaction analyses uncovered loci that, if replicated, could have future implications for the prevention of arrhythmias due to anti-HTN treatment-related hyperkalemia. Before these loci can be identified as clinically relevant, future validation studies of equal or greater size in comparison to our discovery effort are needed.


Assuntos
Afro-Americanos/genética , Grupo com Ancestrais do Continente Europeu/genética , Peptidil Dipeptidase A/genética , Polimorfismo de Nucleotídeo Único/genética , Potássio/sangue , Inibidores de Simportadores de Cloreto de Sódio/uso terapêutico , Idoso , Anti-Hipertensivos/uso terapêutico , Cromossomos Humanos Par 5/genética , Europa (Continente) , Feminino , Estudo de Associação Genômica Ampla/métodos , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade
14.
Clin Cardiol ; 41(8): 1049-1054, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29968356

RESUMO

BACKGROUND: Atrial fibrillation (AF) is an important public health problem across race/ethnic groups. Data from US cohort studies initiated in the 1980s suggest a higher prevalence of AF risk factors among African-Americans (AAs) than whites, but lower AF incidence. The Jackson Heart Study (JHS) is a community-based study of 5306 AAs recruited starting in 2000. HYPOTHESIS: Demographic, anthropometric, cardiovascular, and/or electrocardiographic factors are associated with AF incidence in JHS. METHODS: Using baseline participant characteristics and incident AF identified through hospital surveillance, study electrocardiogram, and Medicare claims, we estimated age- and sex-specific AF incidence rates, compared them with rates in AA participants in the Multi-Ethnic Study of Atherosclerosis (MESA) and Cardiovascular Health Study (CHS), and examined associations of cardiovascular risk factors with AF. RESULTS: A total of 66 participants had prevalent AF at baseline. Over an average follow-up of 8.5 years, 242 cases of incident AF were identified. Age- and sex-specific AF incidence rates in JHS were similar to those among AAs in MESA and appeared slightly lower than those among AAs in CHS. In an age- and sex-adjusted model, associations with incident AF were observed for modifiable risk factors: high body weight (HR = 1.23 per 15 kg, 95%CI 1.13-1.35), systolic blood pressure (HR = 1.29 per 20 mmHg, 95%CI 1.13-1.47), and current smoking (HR = 1.80, 95%CI 1.27-2.55). Risk estimates associated with these risk factors were only slightly attenuated after multivariable adjustments. CONCLUSIONS: These findings underscore the potential additional benefits of interventions for weight management, control of hypertension, and smoking cessation for the prevention of AF among AAs.


Assuntos
Afro-Americanos , Fibrilação Atrial/etnologia , Eletrocardiografia , Medição de Risco , Idoso , Fibrilação Atrial/fisiopatologia , Feminino , Seguimentos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Prevalência , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Estados Unidos/epidemiologia
15.
Blood ; 132(17): 1842-1850, 2018 10 25.
Artigo em Inglês | MEDLINE | ID: mdl-30042098

RESUMO

Many hemostatic factors are associated with age and age-related diseases; however, much remains unknown about the biological mechanisms linking aging and hemostatic factors. DNA methylation is a novel means by which to assess epigenetic aging, which is a measure of age and the aging processes as determined by altered epigenetic states. We used a meta-analysis approach to examine the association between measures of epigenetic aging and hemostatic factors, as well as a clotting time measure. For fibrinogen, we performed European and African ancestry-specific meta-analyses which were then combined via a random effects meta-analysis. For all other measures we could not estimate ancestry-specific effects and used a single fixed effects meta-analysis. We found that 1-year higher extrinsic epigenetic age as compared with chronological age was associated with higher fibrinogen (0.004 g/L/y; 95% confidence interval, 0.001-0.007; P = .01) and plasminogen activator inhibitor 1 (PAI-1; 0.13 U/mL/y; 95% confidence interval, 0.07-0.20; P = 6.6 × 10-5) concentrations, as well as lower activated partial thromboplastin time, a measure of clotting time. We replicated PAI-1 associations using an independent cohort. To further elucidate potential functional mechanisms, we associated epigenetic aging with expression levels of the PAI-1 protein encoding gene (SERPINE1) and the 3 fibrinogen subunit-encoding genes (FGA, FGG, and FGB) in both peripheral blood and aorta intima-media samples. We observed associations between accelerated epigenetic aging and transcription of FGG in both tissues. Collectively, our results indicate that accelerated epigenetic aging is associated with a procoagulation hemostatic profile, and that epigenetic aging may regulate hemostasis in part via gene transcription.


Assuntos
Envelhecimento/patologia , Envelhecimento/fisiologia , Metilação de DNA , Hemostasia/fisiologia , Epigênese Genética/fisiologia , Humanos
17.
Clin Cardiol ; 40(12): 1227-1230, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29214653

RESUMO

BACKGROUND: Administrative billing codes for electrical cardioversion and ablation/maze procedures may be useful for atrial fibrillation (AF) research if the codes are accurate relative to medical record documentation. HYPOTHESIS: Administrative billing codes accurately identify occurrence of electrical cardioversion and ablation/maze procedures in AF patients. METHODS: We studied adults ages 30 to 84 who experienced new-onset AF between October 2001 and December 2004 in Group Health Cooperative (acquired by Kaiser Permanente in 2017), an integrated healthcare system in Washington state and northern Idaho. Using medical record review as the gold standard, we calculated sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for 3 administrative billing codes for electrical cardioversion and 3 codes for AF ablation/maze procedures. RESULTS: Of 1953 study participants, during a mean (SD) of 1.5 (0.7) years of follow-up after AF onset, 470 (24%) experienced electrical cardioversion and 44 (2%) experienced ablation/maze procedures, according to medical record review. For electrical cardioversion, individual codes had 7.7% to 76.4% sensitivity, >99% specificity, 83.7% to 96.5% PPV, and 77.3% to 93.0% NPV. Considering any of 3 codes (code 1 or code 2 or code 3) improved sensitivity to 84.9%. For ablation/maze, individual codes had 18.2% to 47.7% sensitivity, >99% specificity, 66.7% to 95.5% PPV, and >98% NPV. Considering any of 3 codes improved sensitivity to 84.1%. CONCLUSIONS: Administrative billing data accurately identified electrical cardioversion and ablation/maze procedures and can be used instead of medical record review. Our findings apply to healthcare settings with available administrative billing databases.


Assuntos
Demandas Administrativas em Assistência à Saúde/estatística & dados numéricos , Fibrilação Atrial/terapia , Ablação por Cateter/economia , Cardioversão Elétrica/economia , Registros Médicos/estatística & dados numéricos , Pericardiectomia/economia , Adulto , Idoso , Idoso de 80 Anos ou mais , Fibrilação Atrial/economia , Ablação por Cateter/estatística & dados numéricos , Cardioversão Elétrica/estatística & dados numéricos , Feminino , Seguimentos , Humanos , Idaho , Masculino , Pessoa de Meia-Idade , Pericardiectomia/estatística & dados numéricos , Estudos Prospectivos , Reprodutibilidade dos Testes , Washington
18.
Circ Cardiovasc Genet ; 10(4): e001632, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28768753

RESUMO

BACKGROUND: PCSK9 loss-of-function (LOF) variants allow for the examination of the effects of lifetime reduced low-density lipoprotein cholesterol (LDL-C) on cardiovascular events. We examined the association of PCSK9 LOF variants with LDL-C and incident coronary heart disease and stroke through a meta-analysis of data from 8 observational cohorts and 1 randomized trial of statin therapy. METHODS AND RESULTS: These 9 studies together included 17 459 blacks with 403 (2.3%) having at least 1 Y142X or C679X variant and 31 306 whites with 955 (3.1%) having at least 1 R46L variant. Unadjusted odds ratios for associations between PCSK9 LOF variants and incident coronary heart disease (851 events in blacks and 2662 events in whites) and stroke (523 events in blacks and 1660 events in whites) were calculated using pooled Mantel-Haenszel estimates with continuity correction factors. Pooling results across studies using fixed-effects inverse-variance-weighted models, PCSK9 LOF variants were associated with 35 mg/dL (95% confidence interval [CI], 32-39) lower LDL-C in blacks and 13 mg/dL (95% CI, 11-16) lower LDL-C in whites. PCSK9 LOF variants were associated with a pooled odds ratio for coronary heart disease of 0.51 (95% CI, 0.28-0.92) in blacks and 0.82 (95% CI, 0.63-1.06) in whites. PCSK9 LOF variants were not associated with incident stroke (odds ratio, 0.84; 95% CI, 0.48-1.47 in blacks and odds ratio, 1.06; 95% CI, 0.80-1.41 in whites). CONCLUSIONS: PCSK9 LOF variants were associated with lower LDL-C and coronary heart disease incidence. PCSK9 LOF variants were not associated with stroke risk.


Assuntos
Grupo com Ancestrais do Continente Africano/genética , Doença das Coronárias/genética , Grupo com Ancestrais do Continente Europeu/genética , Pró-Proteína Convertase 9/genética , Idoso , Idoso de 80 Anos ou mais , LDL-Colesterol/sangue , Estudos de Coortes , Doença das Coronárias/patologia , Doença das Coronárias/prevenção & controle , Feminino , Variação Genética , Genótipo , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Masculino , Razão de Chances , Polimorfismo de Nucleotídeo Único , Modelos de Riscos Proporcionais , Fatores de Risco , Acidente Vascular Cerebral/genética , Acidente Vascular Cerebral/patologia
19.
PLoS Genet ; 13(5): e1006728, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28498854

RESUMO

Hypertension is a leading cause of global disease, mortality, and disability. While individuals of African descent suffer a disproportionate burden of hypertension and its complications, they have been underrepresented in genetic studies. To identify novel susceptibility loci for blood pressure and hypertension in people of African ancestry, we performed both single and multiple-trait genome-wide association analyses. We analyzed 21 genome-wide association studies comprised of 31,968 individuals of African ancestry, and validated our results with additional 54,395 individuals from multi-ethnic studies. These analyses identified nine loci with eleven independent variants which reached genome-wide significance (P < 1.25×10-8) for either systolic and diastolic blood pressure, hypertension, or for combined traits. Single-trait analyses identified two loci (TARID/TCF21 and LLPH/TMBIM4) and multiple-trait analyses identified one novel locus (FRMD3) for blood pressure. At these three loci, as well as at GRP20/CDH17, associated variants had alleles common only in African-ancestry populations. Functional annotation showed enrichment for genes expressed in immune and kidney cells, as well as in heart and vascular cells/tissues. Experiments driven by these findings and using angiotensin-II induced hypertension in mice showed altered kidney mRNA expression of six genes, suggesting their potential role in hypertension. Our study provides new evidence for genes related to hypertension susceptibility, and the need to study African-ancestry populations in order to identify biologic factors contributing to hypertension.


Assuntos
Pressão Sanguínea/genética , Loci Gênicos , Hipertensão/genética , Herança Multifatorial , Afro-Americanos/genética , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Caderinas/genética , Estudos de Casos e Controles , Feminino , Estudo de Associação Genômica Ampla , Humanos , Hipertensão/etnologia , Masculino , Proteínas de Membrana/genética , Camundongos , Polimorfismo de Nucleotídeo Único
20.
Obesity (Silver Spring) ; 25(6): 1115-1121, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28452401

RESUMO

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


Assuntos
Gordura Abdominal/metabolismo , Tecido Adiposo/fisiopatologia , Aterosclerose/etnologia , Fibrilação Atrial/etnologia , Doenças Cardiovasculares/etnologia , Pericárdio/anormalidades , Idoso , Idoso de 80 Anos ou mais , Aterosclerose/terapia , Fibrilação Atrial/terapia , Doenças Cardiovasculares/complicações , Grupos Étnicos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
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