Carla Lluís-Ganella

Meta-analyses of the association between cytochrome CYP2C19 loss- and gain-of-function polymorphisms and cardiovascular outcomes in patients with coronary artery disease treated with clopidogrel

Aims To perform a meta-analysis of the association between CYP2C19 loss- and gain-of-function variants and cardiovascular outcomes and bleeding in patients with coronary artery disease treated with clopidogrel, and to explore the causes of heterogeneity between studies. Methods A comprehensive literature search was conducted. A random-effects model was used to summarise the results. In the presence of between-study heterogeneity, a meta-regression analysis was performed to identify study characteristics explaining this heterogeneity. Results Patients who carried a loss-of-function allele, mainly CYP2C19*2, did not present an increased risk of a cardiovascular event, HR =1.23 (95% CI 0.97 to 1.55). Substantial heterogeneity was observed between studies (I2 =35.6), which was partially explained by the study sample size: the pooled HR was higher among studies with a sample size <500 patients (HR =3.55; 95% CI 1.66 to 7.56) and lower among studies with a sample size ≥500 (HR =1.06; 95% CI 0.89 to 1.26). CYP2C19*2 was associated with an increased risk of a stent thrombosis (HR =2.24; 95% CI 1.52 to 3.30). The gain-of-function allele, mainly CYP2C19*17, was associated with a lower risk of cardiovascular events (HR =0.75; 95% CI 0.66 to 0.87) and a higher risk of major bleeding (HR =1.26; 95% CI 1.05 to 1.50). Conclusions Not only CYP2C19 loss-of-function but also gain-of-function alleles should be considered to define the pharmacogenetic response to clopidogrel. The results question the relevance of the CYP2C19 loss-of-function alleles in the prediction of major cardiovascular events beyond stent thrombosis in coronary patients treated with clopidogrel. The gain-of-function variant is associated with a lower risk of cardiovascular events but a higher risk of bleeding.

Pathogenesis of coronary artery disease: focus on genetic risk factors and identification of genetic variants

Coronary artery disease (CAD) is the leading cause of death and disability worldwide, and its prevalence is expected to increase in the coming years. CAD events are caused by the interplay of genetic and environmental factors, the effects of which are mainly mediated through cardiovascular risk factors. The techniques used to study the genetic basis of these diseases have evolved from linkage studies to candidate gene studies and genome-wide association studies. Linkage studies have been able to identify genetic variants associated with monogenic diseases, whereas genome-wide association studies have been more successful in determining genetic variants associated with complex diseases. Currently, genome-wide association studies have identified approximately 40 loci that explain 6% of the heritability of CAD. The application of this knowledge to clinical practice is challenging, but can be achieved using various strategies, such as genetic variants to identify new therapeutic targets, personal genetic information to improve disease risk prediction, and pharmacogenomics. The main aim of this narrative review is to provide a general overview of our current understanding of the genetics of coronary artery disease and its potential clinical utility.

Assessment of the value of a genetic risk score in improving the estimation of coronary risk

BACKGROUND The American Heart Association has established criteria for the evaluation of novel markers of cardiovascular risk. In accordance with these criteria, we assessed the association between a multi-locus genetic risk score (GRS) and incident coronary heart disease (CHD), and evaluated whether this GRS improves the predictive capacity of the Framingham risk function. METHODS AND RESULTS Using eight genetic variants associated with CHD but not with classical cardiovascular risk factors (CVRFs), we generated a multi-locus GRS, and found it to be linearly associated with CHD in two population based cohorts: The REGICOR Study (n=2351) and The Framingham Heart Study (n=3537) (meta-analyzed HR [95%CI]: ~1.13 [1.01-1.27], per unit). Inclusion of the GRS in the Framingham risk function improved its discriminative capacity in the Framingham sample (c-statistic: 72.81 vs.72.37, p=0.042) but not in the REGICOR sample. According to both the net reclassification improvement (NRI) index and the integrated discrimination index (IDI), the GRS improved re-classification among individuals with intermediate coronary risk (meta-analysis NRI [95%CI]: 17.44 [8.04; 26.83]), but not overall. CONCLUSIONS A multi-locus GRS based on genetic variants unrelated to CVRFs was associated with a linear increase in risk of CHD events in two distinct populations. This GRS improves risk reclassification particularly in the population at intermediate coronary risk. These results indicate the potential value of the inclusion of genetic information in classical functions for risk assessment in the intermediate risk population group.

Efecto aditivo de diferentes variantes genéticas en el riesgo de cardiopatía isquémica

Introduccion y objetivos. La cardiopatia isquemica (CI) tiene un componente genetico significativo y en los ultimos anos se han identificado variantes geneticas asociadas con ella. El objetivo de este estudio fue evaluar la magnitud de la asociacion entre una puntuacion individual de riesgo genetico, basada en el numero de alelos de riesgo acumulados en un conjunto de variantes geneticas de interes, y la presencia de CI. Metodos. Estudio de los datos in silico del consorcio de casos y controles del Wellcome Trust. Se incluyo a 1.988 pacientes con CI y 5.380 controles. Se analizo la asociacion entre una puntuacion de riesgo genetica y CI mediante regresion logistica. Resultados. Se seleccionaron nueve variantes geneticas asociadas con CI de forma independiente de los factores de riesgo. Existe una asociacion lineal entre el numero de alelos de riesgo y el riesgo de sufrir CI: odds ratio (OR) por incremento de alelo = 1,18 (intervalo de confianza [IC] del 95%, 1,15-1,22; p = 2 x 10-16). La OR de CI del ultimo quintil del numero de alelos de riesgo acumulados respecto al primero fue 2,21 (IC del 95%, 1,87-2,61; p = 5 x 10-21). Conclusiones. Las nueve variantes geneticas asociadas con CI independientemente de los factores de riesgo cardiovascular permiten crear una puntuacion de riesgo genetico de CI que se asocia con la presencia de la enfermedad. Es necesario realizar estudios de cohorte que analicen si esta puntuacion genetica puede mejorar la capacidad predictiva o la reclasificacion de las funciones de riesgo clasicas.

Identification and validation of seven new loci showing differential DNA methylation related to serum lipid profile: an epigenome-wide approach. The REGICOR study.

Lipid traits (total, low-density and high-density lipoprotein cholesterol, and triglycerides) are risk factors for cardiovascular disease. DNA methylation is not only an inherited but also modifiable epigenetic mark that has been related to cardiovascular risk factors. Our aim was to identify loci showing differential DNA methylation related to serum lipid levels. Blood DNA methylation was assessed using the Illumina Human Methylation 450 BeadChip. A two-stage epigenome-wide association study was performed, with a discovery sample in the REGICOR study (n = 645) and validation in the Framingham Offspring Study (n = 2,542). Fourteen CpG sites located in nine genes (SREBF1, SREBF2, PHOSPHO1, SYNGAP1, ABCG1, CPT1A, MYLIP, TXNIP and SLC7A11) and 2 intergenic regions showed differential methylation in association with lipid traits. Six of these genes and 1 intergenic region were new discoveries showing differential methylation related to total cholesterol (SREBF2), HDL-cholesterol (PHOSPHO1, SYNGAP1 and an intergenic region in chromosome 2) and triglycerides (MYLIP, TXNIP and SLC7A11). These CpGs explained 0.7%, 9.5% and 18.9% of the variability of total cholesterol, HDL cholesterol and triglycerides in the Framingham Offspring Study, respectively. The expression of the genes SREBF2 and SREBF1 was inversely associated with methylation of their corresponding CpGs (P-value = 0.0042 and 0.0045, respectively) in participants of the GOLDN study (n = 98). In turn, SREBF1 expression was directly associated with HDL cholesterol (P-value = 0.0429). Genetic variants in SREBF1, PHOSPHO1, ABCG1 and CPT1A were also associated with lipid profile. Further research is warranted to functionally validate these new loci and assess the causality of new and established associations between these differentially methylated loci and lipid metabolism.

Additive Effects of Multiple Genetic Variants on the Risk of Coronary Artery Disease

–21 ). Conclusions. A genetic risk score based on nine genetic variants independently associated with CAD irrespective of other cardiovascular risk factors was associated with the presence of the disease. Cohort studies are needed to determine whether this genetic risk score can improve the predictive capacity or the risk classification of classical risk functions.

Hypothesis-based analysis of gene-gene interactions and risk of myocardial infarction

The genetic loci that have been found by genome-wide association studies to modulate risk of coronary heart disease explain only a fraction of its total variance, and gene-gene interactions have been proposed as a potential source of the remaining heritability. Given the potentially large testing burden, we sought to enrich our search space with real interactions by analyzing variants that may be more likely to interact on the basis of two distinct hypotheses: a biological hypothesis, under which MI risk is modulated by interactions between variants that are known to be relevant for its risk factors; and a statistical hypothesis, under which interacting variants individually show weak marginal association with MI. In a discovery sample of 2,967 cases of early-onset myocardial infarction (MI) and 3,075 controls from the MIGen study, we performed pair-wise SNP interaction testing using a logistic regression framework. Despite having reasonable power to detect interaction effects of plausible magnitudes, we observed no statistically significant evidence of interaction under these hypotheses, and no clear consistency between the top results in our discovery sample and those in a large validation sample of 1,766 cases of coronary heart disease and 2,938 controls from the Wellcome Trust Case-Control Consortium. Our results do not support the existence of strong interaction effects as a common risk factor for MI. Within the scope of the hypotheses we have explored, this study places a modest upper limit on the magnitude that epistatic risk effects are likely to have at the population level (odds ratio for MI risk 1.3–2.0, depending on allele frequency and interaction model).

Qualitative assessment of previous evidence and an updated meta-analysis confirms lack of association between the ESR1 rs2234693 (PvuII) variant and coronary heart disease in men and women.

BACKGROUND Coronary heart disease (CHD) is the leading cause of mortality worldwide. CHD clusters in families but this familial aggregation remains largely unexplained. ESR1 is a candidate gene for CHD although recent meta-analyses of the rs2234693 variant reported inconsistent evidence for association with myocardial infarction (MI) in men. The objectives of this study were to perform a qualitative and a quantitative assessment of all evidence to date regarding this association. METHODS We performed structured literature searches for studies addressing the association between the ESR1 rs2234693 and CHD. We assessed the quality of these studies collectively and individually according to recently published guidelines on the reporting and interpretation of genetic association studies. We also performed a meta-analysis of all studies to date, including a sample of MI cases and controls from our region. RESULTS The qualitative assessment indicated that many studies met a low proportion of the criteria proposed by the current guidelines. No significant association between ESR1 rs2234693 and MI was observed in our sample or in the meta-analysis (16 studies; N approximately 32,000; OR approximately 1). Strong between-study heterogeneity was largely explained by a quality score based on the quality criteria. Studies that reported significant associations were generally of poorer quality. CONCLUSION We confirm the lack of association between the ESR1 rs223469 and CHD, and show that inconsistencies between previous studies is explained by differences in their quality.

Clinical Utility of Multi-marker Genetic Risk Scores for Prediction of Incident Coronary Heart Disease: A Cohort Study among over 51 Thousand Individuals of European Ancestry

Background—We evaluated whether including multilocus genetic risk scores (GRSs) into the Framingham Risk Equation improves the predictive capacity, discrimination, and reclassification of asymptomatic individuals with respect to coronary heart disease (CHD) risk. Methods and Results—We performed a cohort study among 51 954 European-ancestry members of a Northern California integrated healthcare system (67% female; mean age 59) free of CHD at baseline (2007–2008). Four GRSs were constructed using between 8 and 51 previously identified genetic variants. After a mean (±SD) follow-up of 5.9 (±1.5) years, 1864 incident CHD events were documented. All GRSs were linearly associated with CHD in a model adjusted by individual risk factors: hazard ratio (95% confidence interval) per SD unit: 1.21 (1.15–1.26) for GRS_8, 1.20 (1.15–1.26) for GRS_12, 1.23 (1.17–1.28) for GRS_36, and 1.23 (1.17–1.28) for GRS_51. Inclusion of the GRSs improved the C statistic (&Dgr;C statistic =0.008 for GRS_8 and GRS_36; 0.007 for GRS_12; and 0.009 for GRS_51; all P<0.001). The net reclassification improvement was 5% for GRS_8, GRS_12, and GRS_36 and 4% for GRS_51 in the entire cohort and was (after correcting for bias) 9% for GRS_8 and GRS_12 and 7% for GRS_36 and GRS_51 when analyzing those classified as intermediate Framingham risk (10%–20%). The number required to treat to prevent 1 CHD after selectively treating with statins up-reclassified subjects on the basis of genetic information was 36 for GRS_8 and GRS_12, 41 for GRS_36, and 43 for GRS_51. Conclusions—Our results demonstrate significant and clinically relevant incremental discriminative/predictive capability of 4 multilocus GRSs for incident CHD among subjects of European ancestry.

Update in Cardiology: Vascular Risk and Cardiac Rehabilitation

Cardiovascular disease develops in a slow and subclinical manner over decades, only to manifest suddenly and unexpectedly. The role of prevention is crucial, both before and after clinical appearance, and there is ample evidence of the effectiveness and usefulness of the early detection of at-risk individuals and lifestyle modifications or pharmacological approaches. However, these approaches require time, perseverance, and continuous development. The present article reviews the developments in 2013 in epidemiological aspects related to prevention, includes relevant contributions in areas such as diet, weight control methods (obesity is now considered a disease), and physical activity recommendations (with warnings about the risk of strenuous exercise), deals with habit-related psychosocial factors such as smoking, provides an update on emerging issues such as genetics, addresses the links between cardiovascular disease and other pathologies such as kidney disease, summarizes the contributions of new, updated guidelines (3 of which have recently been released on topics of considerable clinical importance: hypertension, diabetes mellitus, and chronic kidney disease), analyzes the pharmacological advances (largely mediocre except for promising lipid-related results), and finishes by outlining developments in the oft-neglected field of cardiac rehabilitation. This article provides a briefing on controversial issues, presents interesting and somewhat surprising developments, updates established knowledge with undoubted application in clinical practice, and sheds light on potential future contributions.