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1.
Syst Rev ; 7(1): 131, 2018 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-30144828

RESUMO

BACKGROUND: Angiotensin-converting enzyme inhibitors (ACEis) and angiotensin II receptor blockers (ARBs) efficaciously reduce systolic blood pressure (BP), a well-established risk factor for myocardial infarction (MI). Both inhibit the renin-angiotensin system, albeit through different mechanisms, and produce similar reductions in BP. However, in parallel meta-analyses of ACEi and ARB trials, ACEis reduce risk of MI whereas ARBs do not-a phenomenon described as the 'ARB-MI paradox'. In addition, ACEis reduce all-cause mortality, whereas ARBs do not, which appears to be independent of BP lowering. The divergent cardiovascular effects of ACE inhibitors and ARBs, despite similar BP reductions, are counter-intuitive. This systematic review aims to ascertain the extent to which clinical outcomes in randomised trials of ACEi and ARBs are attributable to reductions in systolic BP. METHODS: A comprehensive search of bibliographic databases will be performed to identify all randomised studies of agents of the ACEi and ARB class. Placebo and active comparator-controlled studies that report clinical outcomes, with greater than 500 person-years of follow-up in each study arm, will be included. Two independent reviewers will screen study records against a priori-defined eligibility criteria and perform data extraction. The Cochrane Risk of Bias Tool will be applied to all included studies. Studies retracted subsequent to initial publication will be excluded. Primary outcomes of interest include MI and all-cause mortality; secondary outcomes include stroke, heart failure, revascularisation and cardiovascular mortality. Meta-regression will be performed, evaluating the relationship between attained reduction in systolic BP and relative risk of each outcome, stratified by drug class. Where a BP-dependent effect exists (two-tailed p value < 0.05), relative risks, standardised per 10 mmHg difference in BP, will be reported for each study outcome. Publication bias will be examined using Funnel plots, and calculation of Egger's statistic. DISCUSSION: This systematic review will provide a detailed synthesis of evidence regarding the relationship between BP reduction and clinical outcomes with ACEi and ARBs. Greater understanding of the dependency of the effect of each class on BP reduction will advance insight into the nature of the ARB-MI paradox and guide the future usage of these agents. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42017072988.

2.
Heart ; 104(8): 701, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29572276
3.
Can J Diabetes ; 42(2): 124-129, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29277343

RESUMO

The renin angiotensin aldosterone system (RAAS) plays a central role in the pathophysiology of hypertension and vascular disease. Angiotensin-converting enzyme inhibitors (ACEi's) suppress angiotensin II (ANG II) concentrations, whereas angiotensin II type 1 (AT1) receptor blockers (ARBs) block the binding of ANG II to AT1 receptors. ACEi's and ARBs are both effective antihypertensive agents and produce similar risk reductions for stroke, a blood pressure-dependent phenomenon. ACEi's also reduce the risk for myocardial infarction (MI) and all-cause mortality in high-risk hypertensive patients as well as in people with diabetes, vascular disease and congestive heart failure. ARBs, in contrast, do not reduce the risk for MI or death in randomized clinical trials when assessed vs. placebo. Systematic reviews of ARBs that include meta-analyses or metaregression analyses confirm that ARBs lack the cardiovascular-protective effects of ACEi's. Practice guidelines, especially those for high-risk patients, such as those with diabetes mellitus, should reflect the evidence that ACEi's and ARBs have divergent cardiovascular effects: ACEi's reduce mortality, whereas ARBs do not. ACEi's should remain the preferred RAAS inhibitor for patients at high risk.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Doenças Cardiovasculares/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Adulto , Doenças Cardiovasculares/etiologia , Diabetes Mellitus Tipo 2/complicações , Humanos , Prognóstico
5.
Circulation ; 135(24): 2336-2353, 2017 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-28461624

RESUMO

BACKGROUND: Common diseases such as coronary heart disease (CHD) are complex in etiology. The interaction of genetic susceptibility with lifestyle factors may play a prominent role. However, gene-lifestyle interactions for CHD have been difficult to identify. Here, we investigate interaction of smoking behavior, a potent lifestyle factor, with genotypes that have been shown to associate with CHD risk. METHODS: We analyzed data on 60 919 CHD cases and 80 243 controls from 29 studies for gene-smoking interactions for genetic variants at 45 loci previously reported to be associated with CHD risk. We also studied 5 loci associated with smoking behavior. Study-specific gene-smoking interaction effects were calculated and pooled using fixed-effects meta-analyses. Interaction analyses were declared to be significant at a P value of <1.0×10-3 (Bonferroni correction for 50 tests). RESULTS: We identified novel gene-smoking interaction for a variant upstream of the ADAMTS7 gene. Every T allele of rs7178051 was associated with lower CHD risk by 12% in never-smokers (P=1.3×10-16) in comparison with 5% in ever-smokers (P=2.5×10-4), translating to a 60% loss of CHD protection conferred by this allelic variation in people who smoked tobacco (interaction P value=8.7×10-5). The protective T allele at rs7178051 was also associated with reduced ADAMTS7 expression in human aortic endothelial cells and lymphoblastoid cell lines. Exposure of human coronary artery smooth muscle cells to cigarette smoke extract led to induction of ADAMTS7. CONCLUSIONS: Allelic variation at rs7178051 that associates with reduced ADAMTS7 expression confers stronger CHD protection in never-smokers than in ever-smokers. Increased vascular ADAMTS7 expression may contribute to the loss of CHD protection in smokers.


Assuntos
Doença das Coronárias/genética , Doença das Coronárias/prevenção & controle , Loci Gênicos/genética , Predisposição Genética para Doença/genética , Fumar/genética , Proteína ADAMTS7/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Células Cultivadas , Doença das Coronárias/epidemiologia , Vasos Coronários/patologia , Vasos Coronários/fisiologia , Feminino , Interação Gene-Ambiente , Predisposição Genética para Doença/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Fumar/efeitos adversos , Fumar/epidemiologia
6.
Circ Res ; 121(1): 81-88, 2017 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-28506971

RESUMO

RATIONALE: Therapies that inhibit CETP (cholesteryl ester transfer protein) have failed to demonstrate a reduction in risk for coronary heart disease (CHD). Human DNA sequence variants that truncate the CETP gene may provide insight into the efficacy of CETP inhibition. OBJECTIVE: To test whether protein-truncating variants (PTVs) at the CETP gene were associated with plasma lipid levels and CHD. METHODS AND RESULTS: We sequenced the exons of the CETP gene in 58 469 participants from 12 case-control studies (18 817 CHD cases, 39 652 CHD-free controls). We defined PTV as those that lead to a premature stop, disrupt canonical splice sites, or lead to insertions/deletions that shift frame. We also genotyped 1 Japanese-specific PTV in 27561 participants from 3 case-control studies (14 286 CHD cases, 13 275 CHD-free controls). We tested association of CETP PTV carrier status with both plasma lipids and CHD. Among 58 469 participants with CETP gene-sequencing data available, average age was 51.5 years and 43% were women; 1 in 975 participants carried a PTV at the CETP gene. Compared with noncarriers, carriers of PTV at CETP had higher high-density lipoprotein cholesterol (effect size, 22.6 mg/dL; 95% confidence interval, 18-27; P<1.0×10-4), lower low-density lipoprotein cholesterol (-12.2 mg/dL; 95% confidence interval, -23 to -0.98; P=0.033), and lower triglycerides (-6.3%; 95% confidence interval, -12 to -0.22; P=0.043). CETP PTV carrier status was associated with reduced risk for CHD (summary odds ratio, 0.70; 95% confidence interval, 0.54-0.90; P=5.1×10-3). CONCLUSIONS: Compared with noncarriers, carriers of PTV at CETP displayed higher high-density lipoprotein cholesterol, lower low-density lipoprotein cholesterol, lower triglycerides, and lower risk for CHD.


Assuntos
Proteínas de Transferência de Ésteres de Colesterol/genética , Doença das Coronárias/diagnóstico , Doença das Coronárias/genética , Variação Genética/genética , Adulto , Idoso , Estudos de Casos e Controles , Proteínas de Transferência de Ésteres de Colesterol/sangue , Doença das Coronárias/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco
7.
JAMA ; 317(9): 937-946, 2017 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-28267856

RESUMO

Importance: The activity of lipoprotein lipase (LPL) is the rate-determining step in clearing triglyceride-rich lipoproteins from the circulation. Mutations that damage the LPL gene (LPL) lead to lifelong deficiency in enzymatic activity and can provide insight into the relationship of LPL to human disease. Objective: To determine whether rare and/or common variants in LPL are associated with early-onset coronary artery disease (CAD). Design, Setting, and Participants: In a cross-sectional study, LPL was sequenced in 10 CAD case-control cohorts of the multinational Myocardial Infarction Genetics Consortium and a nested CAD case-control cohort of the Geisinger Health System DiscovEHR cohort between 2010 and 2015. Common variants were genotyped in up to 305 699 individuals of the Global Lipids Genetics Consortium and up to 120 600 individuals of the CARDIoGRAM Exome Consortium between 2012 and 2014. Study-specific estimates were pooled via meta-analysis. Exposures: Rare damaging mutations in LPL included loss-of-function variants and missense variants annotated as pathogenic in a human genetics database or predicted to be damaging by computer prediction algorithms trained to identify mutations that impair protein function. Common variants in the LPL gene region included those independently associated with circulating triglyceride levels. Main Outcomes and Measures: Circulating lipid levels and CAD. Results: Among 46 891 individuals with LPL gene sequencing data available, the mean (SD) age was 50 (12.6) years and 51% were female. A total of 188 participants (0.40%; 95% CI, 0.35%-0.46%) carried a damaging mutation in LPL, including 105 of 32 646 control participants (0.32%) and 83 of 14 245 participants with early-onset CAD (0.58%). Compared with 46 703 noncarriers, the 188 heterozygous carriers of an LPL damaging mutation displayed higher plasma triglyceride levels (19.6 mg/dL; 95% CI, 4.6-34.6 mg/dL) and higher odds of CAD (odds ratio = 1.84; 95% CI, 1.35-2.51; P < .001). An analysis of 6 common LPL variants resulted in an odds ratio for CAD of 1.51 (95% CI, 1.39-1.64; P = 1.1 × 10-22) per 1-SD increase in triglycerides. Conclusions and Relevance: The presence of rare damaging mutations in LPL was significantly associated with higher triglyceride levels and presence of coronary artery disease. However, further research is needed to assess whether there are causal mechanisms by which heterozygous lipoprotein lipase deficiency could lead to coronary artery disease.


Assuntos
Doença da Artéria Coronariana/genética , Lipase Lipoproteica/genética , Mutação , Adulto , Idade de Início , Estudos de Casos e Controles , Estudos Transversais , Feminino , Genótipo , Heterozigoto , Humanos , Lipoproteínas/sangue , Masculino , Pessoa de Meia-Idade , Razão de Chances , Triglicerídeos/sangue
8.
J Am Coll Cardiol ; 68(25): 2761-2772, 2016 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-28007139

RESUMO

BACKGROUND: Genomic analyses have suggested that the LPA gene and its associated plasma biomarker, lipoprotein(a) (Lp[a]), represent a causal risk factor for coronary heart disease (CHD). As such, lowering Lp(a) levels has emerged as a therapeutic strategy. Beyond target identification, human genetics may contribute to the development of new therapies by defining the full spectrum of beneficial and adverse consequences and by developing a dose-response curve of target perturbation. OBJECTIVES: The goal of this study was to establish the full phenotypic impact of LPA gene variation and to estimate a dose-response curve between genetically altered plasma Lp(a) and risk for CHD. METHODS: We leveraged genetic variants at the LPA gene from 3 data sources: individual-level data from 112,338 participants in the U.K. Biobank; summary association results from large-scale genome-wide association studies; and LPA gene sequencing results from case subjects with CHD and control subjects free of CHD. RESULTS: One SD genetically lowered Lp(a) level was associated with a 29% lower risk of CHD (odds ratio [OR]: 0.71; 95% confidence interval [CI]: 0.69 to 0.73), a 31% lower risk of peripheral vascular disease (OR: 0.69; 95% CI: 0.59 to 0.80), a 13% lower risk of stroke (OR: 0.87; 95% CI: 0.79 to 0.96), a 17% lower risk of heart failure (OR: 0.83; 95% CI: 0.73 to 0.94), and a 37% lower risk of aortic stenosis (OR: 0.63; 95% CI: 0.47 to 0.83). We observed no association with 31 other disorders, including type 2 diabetes and cancer. Variants that led to gain of LPA gene function increased the risk for CHD, whereas those that led to loss of gene function reduced the CHD risk. CONCLUSIONS: Beyond CHD, genetically lowered Lp(a) levels are associated with a lower risk of peripheral vascular disease, stroke, heart failure, and aortic stenosis. As such, pharmacological lowering of plasma Lp(a) may influence a range of atherosclerosis-related diseases.


Assuntos
Doença das Coronárias/genética , Terapia Genética/métodos , Estudo de Associação Genômica Ampla/métodos , Lipoproteína(a)/sangue , Biomarcadores , Doença das Coronárias/sangue , Doença das Coronárias/terapia , DNA/genética , Feminino , Humanos , Lipoproteína(a)/genética , Masculino , Fenótipo , Polimorfismo de Nucleotídeo Único , Prognóstico , Fatores de Risco
9.
Sci Rep ; 6: 35278, 2016 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-27731410

RESUMO

In recent years, genome-wide association studies have identified 58 independent risk loci for coronary artery disease (CAD) on the autosome. However, due to the sex-specific data structure of the X chromosome, it has been excluded from most of these analyses. While females have 2 copies of chromosome X, males have only one. Also, one of the female X chromosomes may be inactivated. Therefore, special test statistics and quality control procedures are required. Thus, little is known about the role of X-chromosomal variants in CAD. To fill this gap, we conducted a comprehensive X-chromosome-wide meta-analysis including more than 43,000 CAD cases and 58,000 controls from 35 international study cohorts. For quality control, sex-specific filters were used to adequately take the special structure of X-chromosomal data into account. For single study analyses, several logistic regression models were calculated allowing for inactivation of one female X-chromosome, adjusting for sex and investigating interactions between sex and genetic variants. Then, meta-analyses including all 35 studies were conducted using random effects models. None of the investigated models revealed genome-wide significant associations for any variant. Although we analyzed the largest-to-date sample, currently available methods were not able to detect any associations of X-chromosomal variants with CAD.


Assuntos
Cromossomos Humanos X , Doença da Artéria Coronariana/genética , Estudos de Coortes , Feminino , Humanos , Internacionalidade , Masculino
11.
N Engl J Med ; 374(22): 2131-41, 2016 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-27192541

RESUMO

BACKGROUND: Several sequence variants are known to have effects on serum levels of non-high-density lipoprotein (HDL) cholesterol that alter the risk of coronary artery disease. METHODS: We sequenced the genomes of 2636 Icelanders and found variants that we then imputed into the genomes of approximately 398,000 Icelanders. We tested for association between these imputed variants and non-HDL cholesterol levels in 119,146 samples. We then performed replication testing in two populations of European descent. We assessed the effects of an implicated loss-of-function variant on the risk of coronary artery disease in 42,524 case patients and 249,414 controls from five European ancestry populations. An augmented set of genomes was screened for additional loss-of-function variants in a target gene. We evaluated the effect of an implicated variant on protein stability. RESULTS: We found a rare noncoding 12-base-pair (bp) deletion (del12) in intron 4 of ASGR1, which encodes a subunit of the asialoglycoprotein receptor, a lectin that plays a role in the homeostasis of circulating glycoproteins. The del12 mutation activates a cryptic splice site, leading to a frameshift mutation and a premature stop codon that renders a truncated protein prone to degradation. Heterozygous carriers of the mutation (1 in 120 persons in our study population) had a lower level of non-HDL cholesterol than noncarriers, a difference of 15.3 mg per deciliter (0.40 mmol per liter) (P=1.0×10(-16)), and a lower risk of coronary artery disease (by 34%; 95% confidence interval, 21 to 45; P=4.0×10(-6)). In a larger set of sequenced samples from Icelanders, we found another loss-of-function ASGR1 variant (p.W158X, carried by 1 in 1850 persons) that was also associated with lower levels of non-HDL cholesterol (P=1.8×10(-3)). CONCLUSIONS: ASGR1 haploinsufficiency was associated with reduced levels of non-HDL cholesterol and a reduced risk of coronary artery disease. (Funded by the National Institutes of Health and others.).


Assuntos
Receptor de Asialoglicoproteína/genética , Colesterol/sangue , Doença da Artéria Coronariana/genética , Haploinsuficiência , Adulto , Idoso , Idoso de 80 Anos ou mais , Sequência de Bases , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Predisposição Genética para Doença , Humanos , Islândia , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Infarto do Miocárdio/genética , Risco , Análise de Sequência de DNA
12.
Heart ; 102(10): 735-40, 2016 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-26857212

RESUMO

OBJECTIVE: Define the real-world performance of recently updated National Institute for Health and Care Excellence guidelines (TA314) on implantable cardioverter-defibrillator (ICD) use in people with chronic heart failure. METHODS: Multicentre prospective cohort study of 1026 patients with stable chronic heart failure, associated with left ventricular ejection fraction (LVEF) ≤45% recruited in cardiology outpatient departments of four UK hospitals. We assessed the capacity of TA314 to identify patients at increased risk of sudden cardiac death (SCD) or appropriate ICD shock. RESULTS: The overall risk of SCD or appropriate ICD shock was 2.1 events per 100 patient-years (95% CI 1.7 to 2.6). Patients meeting TA314 ICD criteria (31.1%) were 2.5-fold (95% CI 1.6 to 3.9) more likely to suffer SCD or appropriate ICD shock; they were also 1.5-fold (95% CI 1.1 to 2.2) more likely to die from non-cardiovascular causes and 1.6-fold (95% CI 1.1 to 2.3) more likely to die from progressive heart failure. Patients with diabetes not meeting TA314 criteria experienced comparable absolute risk of SCD or appropriate ICD shock to patients without diabetes who met TA314 criteria. Patients with ischaemic cardiomyopathy not meeting TA314 criteria experienced comparable absolute risk of SCD or appropriate ICD shock to patients with non-ischaemic cardiomyopathy who met TA314 criteria. CONCLUSIONS: TA314 can identify patients with reduced LVEF who are at increased relative risk of sudden death. Clinicians should also consider clinical context and the absolute risk of SCD when advising patients about the potential risks and benefits of ICD therapy.


Assuntos
Morte Súbita Cardíaca/prevenção & controle , Técnicas de Apoio para a Decisão , Cardioversão Elétrica/instrumentação , Insuficiência Cardíaca/terapia , Guias de Prática Clínica como Assunto , Idoso , Causas de Morte , Doença Crônica , Desfibriladores Implantáveis/efeitos adversos , Desfibriladores Implantáveis/normas , Cardioversão Elétrica/efeitos adversos , Cardioversão Elétrica/mortalidade , Cardioversão Elétrica/normas , Inglaterra , Feminino , Fidelidade a Diretrizes , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/mortalidade , Insuficiência Cardíaca/fisiopatologia , Humanos , Estimativa de Kaplan-Meier , Masculino , Seleção de Pacientes , Guias de Prática Clínica como Assunto/normas , Modelos de Riscos Proporcionais , Falha de Prótese , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Volume Sistólico , Fatores de Tempo , Resultado do Tratamento , Função Ventricular Esquerda
13.
Int J Cardiol ; 203: 141-4, 2016 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-26512829

RESUMO

BACKGROUND: Diabetes mellitus (DM) is an established adverse prognostic factor in patients sustaining myocardial infarction (MI). However, its impact on long-term survival remains less clear. The aim of this observational study was to quantify lifetime mortality and years of life lost after MI in patients with and without DM. METHODS: In 1995, 2153 individuals with MI were recruited from 20 adjacent hospitals within Yorkshire, UK. Median survival, all-cause mortality at 20 years and lost years of life when compared to actuarial predictions were compared in patients with and without DM. Landmark analyses were conducted to define the ongoing impact of DM beyond specified time points. RESULTS: 13% (279/2153) had known DM. They experienced higher mortality at 30 days (33.1% vs 24.6%; p<0.0001) and at 20 years (84.9% vs 75.7%; p<0.0001). Overall, there was a 48% increased risk of death (p<0.0001), which persisted after adjustment for potential confounders. There was no interaction between DM and prior MI in predicting mortality (p=0.67). Median survival decreased by 3.3 years (p<0.0001). The adverse impact of DM persisted in sequential landmark analyses at 1, 5 and 10 years. Presence of DM conferred 2 extra years of life lost when compared with actuarial predictions (8 vs 6 years; p<0.0001). CONCLUSIONS: DM remains an independent adverse prognostic factor in the long-term after MI. Persistently diverging survival curves support enduring efforts to reduce mortality late after MI.


Assuntos
Diabetes Mellitus/mortalidade , Previsões , Infarto do Miocárdio/mortalidade , Sistema de Registros , Medição de Risco/métodos , Adulto , Distribuição por Idade , Idoso , Feminino , Seguimentos , Humanos , Expectativa de Vida/tendências , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/complicações , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Distribuição por Sexo , Taxa de Sobrevida/tendências , Reino Unido/epidemiologia
14.
Prog Cardiovasc Dis ; 58(5): 473-82, 2016 Mar-Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26586276

RESUMO

The renin angiotensin aldosterone system (RAAS) plays a central role in the pathophysiology of hypertension and vascular disease. Angiotensin converting enzyme inhibitors (ACEis) suppress angiotensin II (ANG II) concentrations, whereas angiotensin receptor blockers (ARBs) block the binding of ANG II to AT1 receptors. ACEis and ARBs are both effective anti-hypertensive agents and have similar risk reductions in stroke - a blood pressure dependent phenomenon. ACEis also reduce the risk of myocardial infarction (MI) and mortality in high risk hypertensive patients, as well as in diabetics, the elderly, those with vascular disease, and in congestive heart failure. ARBs, in contrast, do not reduce the risk of MI or death in clinical trials where the comparator has been another active therapy or even a placebo. Systematic reviews of ARBs that include meta-analyses or meta-regression analyses confirm that ARBs lack the cardiovascular protective effects of ACEis, which in part are "independent" of blood pressure lowering. Practice guidelines, especially those in high risk hypertensive patients, should reflect the evidence that ACEis and ARBs have divergent cardiovascular effects - ACEis reduce mortality, whereas ARBs do not. ACEis should be the preferred RAAS inhibitor in high risk patients.


Assuntos
Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Infarto do Miocárdio/prevenção & controle , Sistema Renina-Angiotensina/efeitos dos fármacos , Comorbidade , Humanos , Hipertensão/diagnóstico , Hipertensão/mortalidade , Hipertensão/fisiopatologia , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/mortalidade , Infarto do Miocárdio/fisiopatologia , Seleção de Pacientes , Medição de Risco , Fatores de Risco , Resultado do Tratamento
15.
Int J Cardiol Heart Vasc ; 7: 88-91, 2015 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-26114160

RESUMO

BACKGROUND: Genome-wide association studies and candidate-gene based approaches have identified multiple common variants associated with increased risk of sudden cardiac death (SCD). However, the independent contribution of these individual loci to disease risk is modest. OBJECTIVE: To investigate the cumulative effects of genetic variants previously associated with SCD risk. METHODS: A total of 966 SCD cases from the Oregon-Sudden Unexpected Death Study and 1,926 coronary artery disease controls from the Wellcome Trust Case-Control Consortium were investigated. We generated genetic risk scores (GRS) for each trait composed of variants previously associated with SCD or with abnormalities in specific electrocardiographic traits such as QRS duration, QTc interval and heart rate. GRSs were calculated using a weighted approach based on the number of risk alleles weighted by the beta coefficients derived from the original studies. We also compared the highest and lowest quintiles for the GRS composed of SCD SNPs. RESULTS: Increased cumulative risk was observed for a GRS composed of 14 SCD-SNPs (OR=1.17 [1.05-1.29], P = 0.002). The risk for SCD was 1.5 fold higher in the highest quintile when compared to the lowest quintile (OR = 1.46[1.11-1.92]). We did not observe significant associations with SCD for SNPs that determine electrocardiographic traits. CONCLUSIONS: A modest but significant effect on SCD risk was identified for a GRS composed of 14 previously associated SCD SNPs. While next generation sequencing methodology will continue to identify additional novel variants, these findings represent proof of concept for the additive effects of gene variants on SCD risk.

16.
Int J Epidemiol ; 44(2): 578-86, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26016847

RESUMO

BACKGROUND: Adiposity, as indicated by body mass index (BMI), has been associated with risk of cardiovascular diseases in epidemiological studies. We aimed to investigate if these associations are causal, using Mendelian randomization (MR) methods. METHODS: The associations of BMI with cardiovascular outcomes [coronary heart disease (CHD), heart failure and ischaemic stroke], and associations of a genetic score (32 BMI single nucleotide polymorphisms) with BMI and cardiovascular outcomes were examined in up to 22,193 individuals with 3062 incident cardiovascular events from nine prospective follow-up studies within the ENGAGE consortium. We used random-effects meta-analysis in an MR framework to provide causal estimates of the effect of adiposity on cardiovascular outcomes. RESULTS: There was a strong association between BMI and incident CHD (HR = 1.20 per SD-increase of BMI, 95% CI, 1.12-1.28, P = 1.9.10(-7)), heart failure (HR = 1.47, 95% CI, 1.35-1.60, P = 9.10(-19)) and ischaemic stroke (HR = 1.15, 95% CI, 1.06-1.24, P = 0.0008) in observational analyses. The genetic score was robustly associated with BMI (ß = 0.030 SD-increase of BMI per additional allele, 95% CI, 0.028-0.033, P = 3.10(-107)). Analyses indicated a causal effect of adiposity on development of heart failure (HR = 1.93 per SD-increase of BMI, 95% CI, 1.12-3.30, P = 0.017) and ischaemic stroke (HR = 1.83, 95% CI, 1.05-3.20, P = 0.034). Additional cross-sectional analyses using both ENGAGE and CARDIoGRAMplusC4D data showed a causal effect of adiposity on CHD. CONCLUSIONS: Using MR methods, we provide support for the hypothesis that adiposity causes CHD, heart failure and, previously not demonstrated, ischaemic stroke.


Assuntos
Adiposidade/genética , Doenças Cardiovasculares/genética , Polimorfismo de Nucleotídeo Único/genética , Índice de Massa Corporal , Estudos Transversais , Feminino , Humanos , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Estudos Prospectivos
18.
N Engl J Med ; 372(17): 1608-18, 2015 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-25853659

RESUMO

BACKGROUND: The nature and underlying mechanisms of an inverse association between adult height and the risk of coronary artery disease (CAD) are unclear. METHODS: We used a genetic approach to investigate the association between height and CAD, using 180 height-associated genetic variants. We tested the association between a change in genetically determined height of 1 SD (6.5 cm) with the risk of CAD in 65,066 cases and 128,383 controls. Using individual-level genotype data from 18,249 persons, we also examined the risk of CAD associated with the presence of various numbers of height-associated alleles. To identify putative mechanisms, we analyzed whether genetically determined height was associated with known cardiovascular risk factors and performed a pathway analysis of the height-associated genes. RESULTS: We observed a relative increase of 13.5% (95% confidence interval [CI], 5.4 to 22.1; P<0.001) in the risk of CAD per 1-SD decrease in genetically determined height. There was a graded relationship between the presence of an increased number of height-raising variants and a reduced risk of CAD (odds ratio for height quartile 4 versus quartile 1, 0.74; 95% CI, 0.68 to 0.84; P<0.001). Of the 12 risk factors that we studied, we observed significant associations only with levels of low-density lipoprotein cholesterol and triglycerides (accounting for approximately 30% of the association). We identified several overlapping pathways involving genes associated with both development and atherosclerosis. CONCLUSIONS: There is a primary association between a genetically determined shorter height and an increased risk of CAD, a link that is partly explained by the association between shorter height and an adverse lipid profile. Shared biologic processes that determine achieved height and the development of atherosclerosis may explain some of the association. (Funded by the British Heart Foundation and others.).


Assuntos
Estatura/genética , Doença da Artéria Coronariana/genética , Variação Genética , Adulto , LDL-Colesterol/sangue , Doença da Artéria Coronariana/etiologia , Humanos , Hiperlipidemias/complicações , Razão de Chances , Fatores de Risco , Triglicerídeos/sangue
19.
PLoS One ; 10(2): e0117684, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25658981

RESUMO

OBJECTIVE: Only a small fraction of coronary artery disease (CAD) heritability has been explained by common variants identified to date. Interactions between genes of importance to cardiovascular regulation may account for some of the missing heritability of CAD. This study aimed to investigate the role of gene-gene interactions in common variants in candidate cardiovascular genes in CAD. APPROACH AND RESULTS: 2,101 patients with CAD from the British Heart Foundation Family Heart Study and 2,426 CAD-free controls were included in the discovery cohort. All subjects were genotyped with the Illumina HumanCVD BeadChip enriched for genes and pathways relevant to the cardiovascular system and disease. The primary analysis in the discovery cohort examined pairwise interactions among 913 common (minor allele frequency >0.1) independent single nucleotide polymorphisms (SNPs) with at least nominal association with CAD in single locus analysis. A secondary exploratory interaction analysis was performed among all 11,332 independent common SNPs surviving quality control criteria. Replication analyses were conducted in 2,967 patients and 3,075 controls from the Myocardial Infarction Genetics Consortium. None of the interactions amongst 913 SNPs analysed in the primary analysis was statistically significant after correction for multiple testing (required P<1.2x10-7). Similarly, none of the pairwise gene-gene interactions in the secondary analysis reached statistical significance after correction for multiple testing (required P = 7.8x10-10). None of 36 suggestive interactions from the primary analysis or 31 interactions from the secondary analysis was significant in the replication cohort. Our study had 80% power to detect odds ratios > 1.7 for common variants in the primary analysis. CONCLUSIONS: Moderately large additive interactions between common SNPs in genes relevant to cardiovascular disease do not appear to play a major role in genetic predisposition to CAD. The role of genetic interactions amongst less common SNPs and with medium and small magnitude effects remain to be investigated.


Assuntos
Doença da Artéria Coronariana/genética , Epistasia Genética , Polimorfismo de Nucleotídeo Único , Adulto , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reino Unido
20.
Neurol Genet ; 1(1): e10, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27066539

RESUMO

OBJECTIVE: To apply genetic analysis of genome-wide association data to study the extent and nature of a shared biological basis between migraine and coronary artery disease (CAD). METHODS: Four separate methods for cross-phenotype genetic analysis were applied on data from 2 large-scale genome-wide association studies of migraine (19,981 cases, 56,667 controls) and CAD (21,076 cases, 63,014 controls). The first 2 methods quantified the extent of overlapping risk variants and assessed the load of CAD risk loci in migraineurs. Genomic regions of shared risk were then identified by analysis of covariance patterns between the 2 phenotypes and by querying known genome-wide significant loci. RESULTS: We found a significant overlap of genetic risk loci for migraine and CAD. When stratified by migraine subtype, this was limited to migraine without aura, and the overlap was protective in that patients with migraine had a lower load of CAD risk alleles than controls. Genes indicated by 16 shared risk loci point to mechanisms with potential roles in migraine pathogenesis and CAD, including endothelial dysfunction (PHACTR1) and insulin homeostasis (GIP). CONCLUSIONS: The results suggest that shared biological processes contribute to risk of migraine and CAD, but surprisingly this commonality is restricted to migraine without aura and the impact is in opposite directions. Understanding the mechanisms underlying these processes and their opposite relationship to migraine and CAD may improve our understanding of both disorders.

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