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Multi-nucleotide variants (MNVs), defined as two or more nearby variants existing on the same haplotype in an individual, are a clinically and biologically important class of genetic variation. However, existing tools typically do not accurately classify MNVs, and understanding of their mutational origins remains limited. Here, we systematically survey MNVs in 125,748 whole exomes and 15,708 whole genomes from the Genome Aggregation Database (gnomAD). We identify 1,792,248 MNVs across the genome with constituent variants falling within 2 bp distance of one another, including 18,756 variants with a novel combined effect on protein sequence. Finally, we estimate the relative impact of known mutational mechanisms - CpG deamination, replication error by polymerase zeta, and polymerase slippage at repeat junctions - on the generation of MNVs. Our results demonstrate the value of haplotype-aware variant annotation, and refine our understanding of genome-wide mutational mechanisms of MNVs., Multi-nucleotide variants (MNV) are genetic variants in close proximity of each other on the same haplotype whose functional impact is difficult to predict if they reside in the same codon. Here, Wang et al. use the gnomAD dataset to assemble a catalogue of MNVs and estimate their global mutation rate.

INTRODUCTION: DNA methylation may be one of the biological mechanisms underlying the health benefits of physical activity (PA). Our objective was to determine the association between PA and genome-wide DNA methylation at CpG level. METHODS: We designed a two-stage epigenome wide association study. In the discovery stage, we used 619 individuals from the REGICOR cohort. Next, we validated the CpGs suggestively associated with PA (p-value

Resumen Introduccion y objetivos Se considera que los individuos con disminucion leve-moderada de la tasa de filtrado glomerular estimada (TFGe, 30-59 ml/min/1,73 m 2 ) estan en alto riesgo de enfermedad cardiovascular (ECV). Ningun estudio ha comparado este riesgo con TFGe 30-59, diabetes mellitus (DM) y enfermedad coronaria (EC) en regiones con baja incidencia de EC. Metodos Se realizo un estudio de cohortes retrospectivo en 122.443 individuos de 60-84 anos de una region de baja incidencia de EC con creatinina determinada entre el 1 de enero de 2010 y 31 de diciembre de 2011. Se identificaron los ingresos por EC (infarto de miocardio, angina de pecho) o ECV (EC, accidente cerebrovascular o accidente isquemico transitorio) hasta el 31 de diciembre de 2013 segun registros electronicos. Se estimaron las tasas de incidencia y la subdistribution hazard ratio (sHR) ajustadas mediante regresion de Cox considerando los riesgos competitivos en individuos con TFGe 30-59, DM y EC o combinaciones, respecto a individuos sin estas afecciones. Resultados La mediana de seguimiento fue de 38,3 [intervalo intercuartilico, 33,8-42,7] meses. Las sHR de EC de los individuos con TFGe 30-59, DM, TFGe 30-59 mas DM, EC previa, EC mas DM y EC mas TFGe 30-59 mas DM fueron, respectivamente, 1,34 (IC95%, 1,04-1,74), 1,61 (IC95%, 1,36-1,90), 1,96 (IC95%, 1,42-2,70), 4,33 (IC95%, 3,58-5,25), 7,05 (IC95%, 5,80-8,58) y 7,72 (IC95%, 5,72-10,41), y las sHR de ECV, 1,25 (IC95%, 1,06-1,46), 1,56 (IC95%, 1,41-1,74), 1,83 (IC95%, 1,50-2,23), 2,86 (IC95%, 2,48-3,29), 4,54 (IC95%, 3,93-5,24) y 5,33 (IC95%, 4,31-6,60). Conclusiones Los individuos de 60-84 anos con TFGe 30-59, de modo similar que la DM, presentaron un riesgo de ingreso por EC y ECV un 50% inferior que aquellos con EC previa. Una TFGe 30-59 no aparece como equivalente de riesgo coronario. Debe priorizarse un tratamiento mas intensivo del riesgo cardiovascular de los individuos con EC y DM o TFGe 30-59 mas DM.

Background: Studies have failed to establish a clear link between high-density lipoprotein (HDL) cholesterol and cardiovascular disease, leading to the hypothesis that the atheroprotective role of HDL lies in its biological activity rather than in its cholesterol content. However, to date, the association between HDL functional characteristics and acute coronary syndrome has not been investigated comprehensively. Methods: We conducted a case-control study nested within the PREDIMED (Prevención con Dieta Mediterránea) cohort, originally a randomized trial in which participants followed a Mediterranean or low-fat diet. Incident acute coronary syndrome cases (N=167) were individually matched (1:2) to control patients by sex, age, intervention group, body mass index, and follow-up time. We investigated 2 individual manifestations (myocardial infarction, unstable angina) as secondary outcomes. We measured the following functional characteristics: HDL cholesterol concentration (in plasma); cholesterol efflux capacity; antioxidant ability, measured by the HDL oxidative-inflammatory index; phospholipase A2 activity; and sphingosine-1-phosphate, apolipoproteins A-I and A-IV, serum amyloid A, and complement 3 protein (in apolipoprotein B–depleted plasma). We used conditional logistic regression models adjusted for HDL cholesterol levels and cardiovascular risk factors to estimate odds ratios (ORs) between 1-SD increments in HDL functional characteristics and clinical outcomes. Results: Low values of cholesterol efflux capacity (OR 1SD , 0.58; 95% CI, 0.40–0.83) and low levels of sphingosine-1-phosphate (OR 1SD , 0.70; 95% CI, 0.52–0.92) and apolipoprotein A-I (OR 1SD , 0.58; 95% CI, 0.42–0.79) were associated with higher odds of acute coronary syndrome. Higher HDL oxidative inflammatory index values were marginally linked to acute coronary syndrome risk (OR 1SD , 1.27; 95% CI, 0.99–1.63). Low values of cholesterol efflux capacity (OR 1SD , 0.33; 95% CI, 0.18–0.61), sphingosine-1-phosphate (OR 1SD : 0.60; 95% CI: 0.40–0.89), and apolipoprotein A-I (OR 1SD , 0.59; 95% CI, 0.37–0.93) were particularly linked to myocardial infarction, whereas high HDL oxidative-inflammatory index values (OR 1SD , 1.53; 95% CI, 1.01–2.33) and low apolipoprotein A-I levels (OR 1SD , 0.52; 95% CI, 0.31–0.88) were associated with unstable angina. Conclusions: Low cholesterol efflux capacity values, pro-oxidant/proinflammatory HDL particles, and low HDL levels of sphingosine-1-phosphate and apolipoprotein A-I were associated with increased odds of acute coronary syndrome and its manifestations in individuals at high cardiovascular risk. Clinical Trial Registration: URL: https://www.controlled-trials.com/ISRCTN35739639 . Unique identifier: ISRCTN35739639.

Assessment of individual cardiovascular risk, distinguishing primary and secondary prevention, would improve the clinical management of the population with familial hypercholesterolemia. We aimed to develop and validate two risk functions to predict incident and recurrent atherosclerotic cardiovascular disease (ASCVD) in a primary care-based population with familial hypercholesterolemia phenotype (FHP), and to compare their predictive capacity with that of the SpAnish Familial hypErcHolEsterolemiA cohoRT (SAFEHEART) risk equation (SAFEHEART-RE).Data from the Catalan primary care system database (SIDIAP) of patients ≥18 years old with FHP in 2006-2013 were used to develop and validate two risk functions to predict incident and recurrent ASCVD. A validation dataset was also used to compare the model predictive capacity to that of SAFEHEART-RE.The new model (SIDIAP-FHP) included age, diabetes, smoking, sex (male), hypertension, and baseline low-density lipoprotein cholesterol in the primary prevention cohort and age, diabetes, smoking, and disease characteristics (progressive, recent, polyvascular, or included myocardial infarction) in the secondary prevention cohort. The models demonstrated a fair fit: C-Statistic: 0.71 (95%CI:0.68-0.75) in primary prevention and 0.65 (95%CI:0.60-0.70) in secondary prevention (higher than that of SAFEHEART-RE: 0.64 [95%CI:0.60-0.68] and 0.55 [95%CI:0.51-0.59], respectively; both p 0.01). The Brier scores obtained with the SIDIAP-FHP score were significantly lower than that obtained with SAFEHEART-RE in both the primary and secondary prevention cohorts.The SIDIAP-FHP score provides accurate ASCVD risk estimates for primary and secondary prevention in the FHP population, with better predictive capacity than that of SAFEHEART-RE in this general population, especially in persons with previous ASCVD.

We assessed the correlation between the biomarkers of lower limb atherosclerosis (eg, ankle-brachial index [ABI]) and of carotid atherosclerosis (eg, common carotid intima-media thickness (IMT) and presence of atherosclerotic plaque) in a population-based cohort from Girona (Northwest Spain) recruited in 2010. Ankle-brachial index and carotid ultrasound were performed in all participants. Generalized additive multivariable models were used to adjust a regression model of common carotid IMT on ABI. Logistic regression multivariable models were adjusted to assess the probability of carotid plaque in individuals with peripheral artery disease. We included 3307 individuals (54.2% women), mean age 60 years (standard deviation 11). Two patterns of association were observed between subclinical biomarkers of atherosclerosis at the lower limb and carotid artery. Ankle-brachial index and common carotid IMT showed a linear trend in men [beta coefficient (95% confidence interval) =-.068 (−.123; −.012); P = .016]. Women with peripheral artery disease presented with high risk of atherosclerotic plaque at the carotid artery [Odds ratio (95% confidence interval) = 2.61, (1.46; 4.69); P = .001]. Men showed a significant linear association between ABI levels and common carotid IMT values. Women with peripheral artery disease presented with high risk of atherosclerotic plaque at the carotid artery.

To determine the dose-response association between current and past leisure-time physical activity (LTPA), total and at different intensities, and high-density lipoprotein (HDL) functionality parameters.Study participants (n=642) were randomly drawn from a large population-based survey. Mean age of the participants was 63.2 years and 51.1% were women. The analysis included data from a baseline and a follow-up visit (median follow-up, 4 years). LTPA was assessed using validated questionnaires at both visits. Two main HDL functions were assessed: cholesterol efflux capacity and HDL antioxidant capacity, at the follow-up visit. Linear regression and linear additive models were used to assess the linear and nonlinear association between LTPA and HDL functionality.Total LTPA at follow-up showed an inverse and linear relationship between 0 and 400 METs x min/d with HDL antioxidant capacity (regression coefficient [beta]: -0.022; 95%CI, -0.030, -0.013), with a plateau above this threshold. The results were similar for moderate (beta: -0.028; 95%CI, -0.049, -0.007) and vigorous (beta: -0.025; 95%CI, -0.043, -0.007), but not for light-intensity LTPA. LTPA at follow-up was not associated with cholesterol efflux capacity. Baseline LTPA was not associated with any of the HDL functionality parameters analyzed.Current moderate and vigorous LTPA showed a nonlinear association with higher HDL antioxidant capacity. Maximal benefit was observed with low-intermediate doses of total LTPA (up to 400 METs x min/d). Our results agree with current recommendations for moderate-vigorous LTPA practice and suggest an association between PA and HDL functionality in the general population.

Atherosclerosis is the main pathogenic process causing most Cardiovascular Diseases (CVDs). The Carotid Artery (CA) Ultrasound image is currently being used to detect the presence of subclinical atherosclerosis since it provides a measurement of the Intima Media Thickness (IMT) of the artery and can be used to identify the presence of atherosclerotic plaques. Moreover, it is well known that disruption of an atherosclerotic plaque plays a crucial role in the pathogenesis of CVD events. Thus, the characterization of plaque morphology based on B-mode Ultrasound images is useful to assess the vulnerability of atherosclerotic lesions and for the CV risk assessment. Many image analysis techniques have been developed for the automatic segmentation of intima-media in CA, as well as for plaque characterization. Recently, Deep Learning has appeared to be a popular representation-based machine learning technique based on artificial neural networks, which are breaking records in many computer vision applications. In this chapter, we review the state-of-the-art of CA segmentation, plaque classification, and risk assessment in B-mode Ultrasound images with a focus on the last proposals based on Deep Learning. We summarize the most recent works in comprehensive tables to easily compare them and emphasize their strengths and weaknesses. Finally, we try to help to lay the foundation for the next steps taking advantage of the power of Deep Learning, also considering the challenges that this entails (Part of the content of this chapter was previously published in Artificial Intelligence In Medicine (https://doi.org/10.1016/j.artmed.2019.101784)).

Cardiovascular diseases are the leading causes of morbidity and mortality. Overweight, obesity, and accelerated growth during early childhood have been associated with adverse cardiovascular outcomes in later life. Few studies have assessed whether trajectories of accelerated growth in early childhood are associated with preclinical cardiovascular measurements. We aimed to evaluate the associations between childhood body mass index (BMI) growth trajectories and measures of macro- and microvascular function in early adolescence. Measurements of macrovascular function (systolic and diastolic blood pressure (SBP and DBP), pulse wave velocity (PWV), and microvascular function (central retinal arteriolar/veinular equivalent) were assessed at 11 years old in a Spanish birth cohort study (n = 489). BMI trajectories from birth to 9 years were identified using latent class growth analysis. Multiple linear regression assessed the associations between the BMI trajectories and macro- and microvascular function. Compared to children with average birth size and slower BMI gain (reference), children with a lower birth size and accelerated BMI gain had increased SBP [β = 6.57; (95% CI 4.00, 9.15)], DBP [β = 3.65; (95% CI 1.45, 5.86)], and PWV [β = 0.14; (95% CI 0.01, 0.27)]. Children with higher birth size and accelerated BMI gain had increased SBP [β = 4.75; (95% CI 1.79, 7.71) compared to the reference. No significant associations between BMI trajectories and the microvascular measurements were observed. In conclusion, we found that childhood BMI trajectories characterized by accelerated growth are associated with preclinical macrovascular measurements in young adolescents.

South Asian (SA) individuals represent a large, growing population in a number of European countries. These individuals, particularly first-generation SA immigrants, are at higher risk of developing type 2 diabetes, atherogenic dyslipidaemia, and coronary heart disease than most other racial/ethnic groups living in Europe. SAs also have an increased risk of stroke compared to European-born individuals. Despite a large body of conclusive evidence, SA-specific cardiovascular health promotion and preventive interventions are currently scarce in most European countries, as well as at the European Union level. In this narrative review, we aim to increase awareness among clinicians and healthcare authorities of the public health importance of cardiovascular disease among SAs living in Europe, as well as the need for tailored interventions targeting this group - particularly, in countries where SA immigration is a recent phenomenon. To this purpose, we review key studies on the epidemiology and risk factors of cardiovascular disease in SAs living in the United Kingdom, Italy, Spain, Denmark, Norway, Sweden, and other European countries. Building on these, we discuss potential opportunities for multi-level, targeted, tailored cardiovascular prevention strategies. Because lifestyle interventions often face important cultural barriers in SAs, particularly for first-generation immigrants; we also discuss features that may help maximise the effectiveness of those interventions. Finally, we evaluate knowledge gaps, currently available risk stratification tools such as QRISK-3, and future directions in this important field.

Early smoking onset age (SOA) is a public health concern with scant empirical evidence of its role in health outcomes. The study had two aims: i) to assess whether an early SOA was associated with the risk of fatal and non-fatal CVD and all-cause and CVD mortality and ii) to explore the linear and non-linear association between SOA and the outcomes of interest. Data from 4499 current or former smokers, recruited from 1995 to 2005, aged 25 to 79 years, and with a median 7.02 years of follow-up, were obtained from the REGICOR population-based cohort. In the present analysis, performed in 2018, the independent variable was SOA and the dependent variables were CVD events, CVD mortality, and all-cause mortality. Penalized smoothing spline methods were used to assess the linear and non-linear association. During follow-up, 361 deaths and 210 CVD events were recorded. A significant non-linear component was identified in the association between SOA and CVD outcomes with a cut-off point at 12 years: In the group aged ≤12 years, each year of delay in SOA was inversely associated with CVD risk (HR = 0.71; 95%CI = 0.53 – 0.96) and CVD mortality (HR = 0.58; 95%CI = 0.37 – 0.90). No association was observed in the older SOA group. A linear association was observed between SOA and all-cause mortality, and each year of delay was associated with 4% lower risk of mortality (HR = 0.96; 95%CI = 0.93 – 0.98). The associations were adjusted for lifelong exposure to tobacco and cardiovascular risk factors. These results reinforce the value of preventing tobacco use among teenagers and adolescents.

Resumen Introduccion y objetivos El adecuado control lipidico tras un sindrome coronario agudo (SCA) es una estrategia de prevencion secundaria crucial para disminuir el riesgo de reinfarto y muerte cardiovascular. Existen tablas que predicen la dosificacion necesaria del tratamiento hipolipidemiante segun el colesterol LDL (cLDL) inicial pero no han sido probadas en el SCA. Analizamos los factores asociados al control del cLDL tras un SCA y la utilidad de las tablas de Masana y Plana en este contexto. Metodos Entre enero de 2015 y mayo de 2016 se incluyeron 326 pacientes con SCA. Se registraron las concentraciones basales de cLDL y el tratamiento hipolipidemiante al alta. Se analizaron las variables asociadas a un adecuado control del cLDL ( Resultados La edad media fue 66 ± 13 anos, el 72% varones. El tratamiento hipolipidemiante al alta se ajusto a las recomendaciones de Masana en 196 (60%) pacientes. Tras 122 [66-184] dias, en 148 (45%) se alcanzo el objetivo de cLDL, siendo este porcentaje mayor (109/196 –56%– vs. 39/130 –30%– pacientes) cuando el tratamiento fue planificado segun las tablas de Masana y Plana (p Conclusiones El control lipidico adecuado tras un SCA se alcanza en menos de la mitad de casos. La dosificacion de la terapia hipolipidemiante segun las tablas de Masana y Plana mejora la consecucion de este crucial objetivo terapeutico.

Adequate LDL cholesterol (LDLc) control after an acute coronary syndrome (ACS) is a crucial secondary prevention strategy to minimize the incidence of recurrent myocardial infarction and cardiovascular death. There are tables that predict the necessary dosage of lipid-lowering treatment from the initial LDLc but have not been tested in ACS. Variables associated with optimal LDLc after an ACS were analyzed and the therapeutic yield of the use of Masana's recommendations in this setting.A total number of 326 ACS-patients were included between January-2015 and May-2016. Baseline LDLc concentration and prescribed hypolipemiant treatment at hospital discharge were registered. We analyzed the variables associated with optimal LDLc levels (70mg/dL) control during follow-up.Among our patient population (72% male, age 66±13 years), the hypolipemiant treatment at hospital discharge fulfilled the Masana's recommendations in 196 (60%) patients. After a follow-up period of 122 [66-184] days the targeted LDLc levels were achieved in 148 (45%) patients, being this percentage greater among those in whom the Masana's recommendations were fulfilled (109/196, 56%), as compared with the remaining (39/130, 30%; P.001). The male gender (P.001), the absence of prior history of dyslipemia (P.001) and the adherence to Masana's recommendations (P=.007) were independent predictors for the achievement of targeted LDLc levels during follow-up.In less than half of ACS-patients adequate mid-term LDLc control is obtained. The dosage of the lipid-lowering therapy according to Masana's recommendations helps to achieve this important therapeutic goal.

Background: \ud Spontaneous coronary artery dissection (SCAD) is an increasingly recognized cause of acute coronary syndromes (ACS) afflicting predominantly younger to middle-aged women. Observational studies have reported a high prevalence of extracoronary vascular anomalies, especially fibromuscular dysplasia (FMD) and a low prevalence of coincidental cases of atherosclerosis. PHACTR1/EDN1 is a genetic risk locus for several vascular diseases, including FMD and coronary artery disease, with the putative causal noncoding variant at the rs9349379 locus acting as a potential enhancer for the endothelin-1 (EDN1) gene.\ud \ud Objectives: \ud This study sought to test the association between the rs9349379 genotype and SCAD.\ud \ud Methods: \ud Results from case control studies from France, United Kingdom, United States, and Australia were analyzed to test the association with SCAD risk, including age at first event, pregnancy-associated SCAD (P-SCAD), and recurrent SCAD.\ud \ud Results: \ud The previously reported risk allele for FMD (rs9349379-A) was associated with a higher risk of SCAD in all studies. In a meta-analysis of 1,055 SCAD patients and 7,190 controls, the odds ratio (OR) was 1.67 (95% confidence interval [CI]: 1.50 to 1.86) per copy of rs9349379-A. In a subset of 491 SCAD patients, the OR estimate was found to be higher for the association with SCAD in patients without FMD (OR: 1.89; 95% CI: 1.53 to 2.33) than in SCAD cases with FMD (OR: 1.60; 95% CI: 1.28 to 1.99). There was no effect of genotype on age at first event, P-SCAD, or recurrence.\ud \ud Conclusions: \ud The first genetic risk factor for SCAD was identified in the largest study conducted to date for this condition. This genetic link may contribute to the clinical overlap between SCAD and FMD.

Introduction and objectives PCSK9 inhibitors (PCSK9i) are safe and effective lipid-lowering drugs . Their main limitation is their high cost. The aim of this study was to estimate the number of patients eligible for treatment with PCSK9i according to distinct published criteria. Methods Data were obtained from the Information System for the Development of Research in Primary Care. Included patients were equal to or older than 18 years and had at least 1 low-density lipoprotein cholesterol measurement recorded between 2006 and 2014 (n = 2 500 907). An indication for treatment with PCSK9i was assigned according to the following guidelines: National Health System, Spanish Society of Arteriosclerosis , Spanish Society of Cardiology, National Institute for Health and Care Excellence, and the European Society of Cardiology/European Atherosclerosis Society Task Force. Lipid-lowering treatment was defined as optimized if it reduced low-density lipoprotein levels by ≥ 50% and adherence was > 80%. Results Among the Spanish population aged 18 years or older, the number of possible candidates to receive PCSK9i in an optimal lipid-lowering treatment scenario ranged from 0.1% to 1.7%, depending on the guideline considered. The subgroup of patients with the highest proportion of potential candidates consisted of patients with familial hypercholesterolemia , and the subgroup with the highest absolute number consisted of patients in secondary cardiovascular prevention. Conclusions The number of candidates to receive PCSK9i in conditions of real-world clinical practice is high and varies widely depending on the recommendations of distinct scientific societies.

Resumen Introduccion y objetivos Los inhibidores de la PCSK9 (iPCSK9) son farmacos hipolipemiantes eficaces y seguros pero con un elevado coste. El objetivo del estudio es estimar el numero de pacientes candidatos a recibir iPCSK9 segun los diferentes criterios publicados. Metodos Los datos provienen del Sistema de Informacion para la Investigacion en Atencion Primaria. Se incluyo a pacientes de edad ≥ 18 anos con al menos una determinacion de colesterol unido a lipoproteinas de baja densidad entre 2006 y 2014 (n = 2.500.907). Los criterios de indicacion terapeutica de iPCSK9 analizados fueron: Sistema Nacional de Salud, Sociedad Espanola de Arteriosclerosis, Sociedad Espanola de Cardiologia, National Institute for Health and Care Excellence y Sociedad Europea de Cardiologia/European Atherosclerosis Society Task Force. Se definio como tratamiento lipidico optimizado el que alcanzara una reduccion del colesterol unido a lipoproteinas de baja densidad ≥ 50% y un cumplimiento > 80%. Resultados En la poblacion espanola de 18 o mas anos el numero de posibles candidatos a recibir iPCSK9 en un escenario de tratamiento hipolipemiante optimo oscila entre el 0,1 y el 1,7% segun los diferentes criterios. El subgrupo con mayor porcentaje de candidatos seria el de los pacientes con hipercolesterolemia familiar, y el mayor numero absoluto vendria de los pacientes en prevencion secundaria. Conclusiones El numero de posibles candidatos a recibir iPCSK9 en condiciones de practica clinica es muy alto y varia mucho segun las recomendaciones de las diferentes sociedades cientificas.

Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): CIBERCV of cardiovascular diseases; CIBERESP. OnBehalf REGICOR investigators Background Although myocardial infarction (MI) severity trends are systematically measured with mortality rates, MI incidence trends and the precision of its estimation by linkage of anonymized electronic databases are relatively untested. We validated a linked-data method (LDM) to estimate a population MI incidence and case-fatality, and to analyse the 1990-2016 trends in North-Eastern Spain. Methods LDM consisted of linking MI hospital discharges (n = 4,533,981) and mortality registry data (n = 40,676) for 2008-2016, selecting key MI diagnostic codes. The prospective REGICOR study, including all MI cases in Girona, 1990-2009, was used as the gold standard for validation purposes. Standardized MI cumulated incidence and 28-day case fatality for population aged 35-74 years was calculated, 1990-2016 trends were analysed by linear and joinpoint regression and annual percentage change (APC). Results LDM and REGICOR MI incidence and case-fatality estimates were similar for 2008-09 (Table). LDM MI incidence and case-fatality significantly decreased: APC 1990-2016 [95% CI]) was -1.8 [-2.6;-0.9] in women, and APC 2002-2016 -2.8 [-3.8;-1.8] in men; case-fatality APC 1990-2016 was -4.7% [-5.7;-3.8] in women and APC 1995-2005 -6.5%[-8.5;-4.5] in men. Conclusions LDM in population aged 35-74 reliably estimated MI incidence and case-fatality. MI incidence and case-fatality significantly decreased after 1990. Comparative analysis of REGICOR vs LDM REGICOR 2008-2009 LDM 2008-2009 Estimate 95% CI Estimate 95% CI P-Value Cumulated incidence Men 245.4 228.3; 262.5 239.7 222.5; 256.3 0.626 Women 61.1 52.6; 69.6 58.2 49.9; 66.4 0.626 Overall 28-day case-fatality Men 23.5% 19.7; 27.2 21.3% 17.8; 24.9 0.422 Women 19.3% 6.7; 31.9 17.7% 6.3; 29.1 0.855 In-hospital case-fatality Men 6.9% 4.8; 9.0 5.7% 3.8; 7.6 0.394 Women 5.0% 1.9; 8.2 3.7% 1.0; 6.5 0.540 Pre-hospital case-fatality Men 16.5% 11.8; 21.3 15.6% 11.2; 20.1 0.791 Women 14.2 % 6.6; 21.9 14.0% 6.3; 21.7 0.961 CI Confidence Interval

Funding Acknowledgements Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Spanish Society of Cardiology OnBehalf REGICOR Study Background Cardiovascular risk assessment is the cornerstone of cardiovascular primary prevention. However, most of the recommended or regionally validated risk assessment tools are not updated. Purpose To analyze the effect of including longitudinal information of risk factors as well as competing risks for cardiovascular risk prediction. Methods Data from 10,152 general population individuals from North-Eastern Spain was included. Individuals were recruited in 1995-2000-2005 in three different cohorts of the REGICOR Study. Risk factor data was obtained at baseline and in 2 follow-up visits. Risk factor data included age, sex, education, lipid profile, blood pressure, glucose, smoking, body mass index, and treatment for hypercholesterolemia, hypertension and diabetes. Event data was obtained by cross linkage with healthcare and mortality databases. Cardiovascular events included myocardial infarction, angina and stroke. Cancer mortality and other mortality were included as competing risks. Four cox proportional hazards models developed to model time to coronary/cerebrovascular events with longitudinal or competing risk data. Interactions between age and risk factors were included. Discrimination was assessed with the area under the ROC curve (AUC) and Sommer’s D statistic, and compared with discrimination of Framingham-REGICOR function. Results The variable with the largest effect on coronary/cerebrovascular event incidence was diabetes treatment in the longitudinal models [Hazard ratio -HR- (95% confidence interval -CI-): 3.02 (2.00, 4.58)/2.58 (1.33, 5.00)] as well as in the competing risk models [HR (95% CI): 3.08 (2.09, 4.55)/2.77 (1.48, 5.18)]. In addition to currently used variables, medication for hypertension and diabetes, and interaction between age and diabetes medication were included in all models. Compared to the Framingham-REGICOR function, discrimination improved with the inclusion of longitudinal or competing risk data as shown in the Table. Conclusion Including longitudinal information of cardiovascular risk factors or competing risks improved discrimination of a regionally validated cardiovascular risk function. The availability of these data in healthcare databases would allow its use in primary care cardiovascular risk assessment. Discrimination analysis Models AUC (95% CI) developed models AUC (95% CI) Framingham-REGICORfunction p-value Competing risks - coronary events 0.80 (0.77-0.82) 0.74 (0.71-0.77) < 0.001 Competing risks - cerebrovascular events 0.78 (0.74-0.82) 0.68 (0.63-0.72) < 0.001 Longitudinal data - coronary events 0.79 (0.78-0.81) 0.76 (0.74-0.78) < 0.001 Longitudinal data - cerebrovascular events 0.80 (0.78-0.83) 0.71 (0.69-0.74) < 0.001

To explore the role of chronic inflammation inherent to autoimmune diseases in the development of subclinical atherosclerosis and arterial stiffness, this study recruited two population-based samples of individuals with and without autoimmune disease (ratio 1:5) matched by age, sex, and education level and with a longstanding (≥6 years) diagnosis of autoimmune disease. Common carotid intima media thickness (IMT) and arterial distensibility and compliance were assessed with carotid ultrasound. Multivariable linear and logistic regression models were adjusted for 10-year cardiovascular risk. In total, 546 individuals with and without autoimmune diseases (91 and 455, respectively) were included. Mean age was 66 years (standard deviation 12), and 240 (43.9%) were women. Arterial stiffness did not differ according to presence of autoimmune diseases. In men, the diagnosis of autoimmune diseases significantly increased common carotid IMT [beta-coefficient (95% confidence interval): 0.058 (0.009; 0.108); p-value=0.022] and the percentage having IMT ≥ percentile 75 [1.012 (0.145; 1.880); p-value=0.022]. Women without autoimmune disease were more likely to have IMT ≥ percentile 75 [-2.181 (-4.214; -0.149); p-value=0.035] but analysis of IMT as a continuous variable did not yield significant results. In conclusion, subclinical carotid atherosclerosis, but not arterial stiffness, was higher in men with autoimmune diseases. Women did not show significant differences in any of these carotid features. Sex was an effect modifier in the association between common carotid IMT values and the diagnosis of autoimmune diseases.

Background DNA methylation is associated with atherosclerosis and cardiovascular risk factors. However, little evidence regarding its association with cardiovascular diseases in large studies is currently available. We aimed to assess the association between DNA methylation and cardiovascular events, and to determine both the predictive capacity of the identified loci and the causality of those associations. Methods We defined two strategies: epigenome-wide (EWAS) and candidate-gene association studies. In both strategies, we designed one approach with prevalent cases of coronary heart disease (CHD) and another with incident cases of CHD and cardiovascular disease. We used data from three independent cohorts: the REgistre GIroní del COR (REGICOR) study, the Framingham Offspring Study and the Women’s Health Initiative. We also assessed the association between the identified CpGs and cardiovascular risk factors in the three populations. Then, we developed methylation risk scores to evaluate whether their inclusion in the Framingham risk function improved its predictive capacity. Finally, we performed a Mendelian randomization study to determine the causality of the identified associations. Results We found 17 CpGs related to prevalent CHD and/or incident cardiovascular events, two of them observed using both approaches ( p

Background The integration of different layers of omics information is an opportunity to tackle the complexity of cardiovascular diseases (CVD) and to identify new predictive biomarkers and potential therapeutic targets. Our aim was to integrate DNA methylation and gene expression data in an effort to identify biomarkers related to cardiovascular disease risk in a community-based population. We accessed data from the Framingham Offspring Study, a cohort study with data on DNA methylation (Infinium HumanMethylation450 BeadChip; Illumina) and gene expression (Human Exon 1.0 ST Array; Affymetrix). Using the MOFA2 R package, we integrated these data to identify biomarkers related to the risk of presenting a cardiovascular event. Results Four independent latent factors (9, 19, 21—only in women—and 27), driven by DNA methylation, were associated with cardiovascular disease independently of classical risk factors and cell-type counts. In a sensitivity analysis, we also identified factor 21 as associated with CVD in women. Factors 9, 21 and 27 were also associated with coronary heart disease risk. Moreover, in a replication effort in an independent study three of the genes included in factor 27 were also present in a factor identified to be associated with myocardial infarction (CDC42BPB, MAN2A2 and RPTOR). Factor 9 was related to age and cell-type proportions; factor 19 was related to age and B cells count; factor 21 pointed to human immunodeficiency virus infection-related pathways and inflammation; and factor 27 was related to lifestyle factors such as alcohol consumption, smoking and body mass index. Inclusion of factor 21 (only in women) improved the discriminative and reclassification capacity of the Framingham classical risk function and factor 27 improved its discrimination. Conclusions Unsupervised multi-omics data integration methods have the potential to provide insights into the pathogenesis of cardiovascular diseases. We identified four independent factors (one only in women) pointing to inflammation, endothelium homeostasis, visceral fat, cardiac remodeling and lifestyles as key players in the determination of cardiovascular risk. Moreover, two of these factors improved the predictive capacity of a classical risk function.

El síndrome de Bayés es una entidad clínica que se define como la asociación entre la presencia de bloqueo interauricular avanzado (BIA-A), y el desarrollo de taquiarritmias supraventriculares (TSV), siendo la fibrilación auricular (FA) la más frecuente. Esta asociación salió a la luz con los estudios del Prof. Antoni Bayés de Luna en los años 80. Estudios realizados posteriormente por otros grupos encontraron una fuerte asociación entre este síndrome y la ocurrencia de fenómenos tromboembólicos, siendo el accidente cerebrovascular (ACV) el más grave. Del mismo modo, se documentó una asociación con deterioro cognitivo y demencia. Esto generó la pregunta acerca de si la terapia de anticoagulación previa a la documentación de FA podría prevenir la ocurrencia de tromboembolismos asociados al BIA-A y, de esta manera, preservar el estado cognitivo. Esta pregunta permanece, aún hoy, sin respuesta definitiva. Existen estudios en diferentes estadios de su desarrollo cuyo objetivo es comparar la efectividad de la anticoagulación en pacientes con BIA-A y sin FA documentada. Los resultados permitirán establecer la efectividad de esta opción terapéutica temprana y, de manera conclusiva, definir si, para decidir anticoagular un paciente, la FA tiene que ser previamente documentada o no. Sin financiación No data 2020 UEM

Background Coronary care units were established in the 1960s to reduce acute-phase mortality in acute coronary syndrome. In the 21st century, the original coronary care unit concept has evolved into an intensive cardiovascular care unit. The aim of this study was to analyse trend changes in characteristics and mortality of patients admitted to a coronary care unit over the past three decades. Method Between February 1989 and December 2017, a total of 18,334 patients was consecutively admitted to the coronary care unit of a university hospital in Barcelona. Data were analysed in five time frames: 1989–1994, 1995–1999, 2000–2004, 2005–2009 and 2010–2017. We analysed demographic profile, diagnoses at admission and trend changes in mortality across periods. Results During the periods, the patients’ ages and comorbidities increased. Diagnoses at admission have evolved. Acute coronary syndrome cases declined from the first to the last period (72.6% vs. 62.8%) while heart failure (6.0% vs. 8.6%) and malignant arrhythmias (0.8% vs. 4.0%) increased significantly. Overall, coronary care unit mortality decreased 34% from the first to the last period (6.8% vs. 4.5%, P Conclusions Although acute coronary syndrome remained the main diagnosis, heart failure and arrhythmias have increased. Despite the aging and comorbidities, overall mortality in the coronary care unit decreased by 34% in the past three decades. Deaths due to acute coronary syndrome have declined, whereas those due to malignant arrhythmias have increased.

To explore the role of chronic inflammation inherent to autoimmune diseases in the development of subclinical atherosclerosis and arterial stiffness, this study recruited two population-based samples of individuals with and without autoimmune disease (ratio 1:5) matched by age, sex, and education level and with a longstanding (≥6 years) diagnosis of autoimmune disease. Common carotid intima-media thickness (IMT) and arterial distensibility and compliance were assessed with carotid ultrasound. Multivariable linear and logistic regression models were adjusted for 10-year cardiovascular risk. In total, 546 individuals with and without autoimmune diseases (91 and 455, respectively) were included. The mean age was 66 years (standard deviation 12), and 240 (43.9%) were women. Arterial stiffness did not differ according to the presence of autoimmune diseases. In men, the diagnosis of autoimmune diseases significantly increased common carotid IMT [beta-coefficient (95% confidence interval): 0.058 (0.009; 0.108); p value = 0.022] and the percentage with IMT ≥ 75th percentile [1.012 (0.145; 1.880); p value = 0.022]. Women without autoimmune disease were more likely to have IMT ≥ the 75th percentile [-2.181 (-4.214; -0.149); p value = 0.035], but the analysis of IMT as a continuous variable did not yield significant results. In conclusion, subclinical carotid atherosclerosis, but not arterial stiffness, was more common in men with autoimmune diseases. Women did not show significant differences in any of these carotid features. Sex was an effect modifier in the association between common carotid IMT values and the diagnosis of autoimmune diseases.

Background Advanced interatrial block (IAB), prolonged and bimodal P waves in surface ECG inferior leads, is an unrecognized surrogate of atrial dysfunction and a trigger of atrial dysrhythmias, mainly atrial fibrillation (AF). Our aim was to prospectively assess whether advanced IAB in sinus rhythm precedes AF and stroke in elderly outpatients with structural heart disease, a group not previously studied. Methods Prospective observational registry that included outpatients aged ≥70 years with structural heart disease and no previous diagnosis of AF. Patients were divided into three groups according to P-wave characteristics. Results Among 556 individuals, 223 had normal P-wave (40.1%), 196 partial IAB (35.3%), and 137 advanced IAB (24.6%). After a median follow-up of 694 days; 93 patients (16.7%) developed AF, 30 stroke (5.4%), and 34 died (6.1%). Advanced IAB was independently associated with AF (hazard ratio [HR] 2.9, 95% confidence interval [CI] 1.7–5.1, p Conclusions The presence of advanced IAB in sinus rhythm is a risk factor for AF and stroke in an elderly population with structural heart disease and no previous diagnosis of AF. P-wave duration was also associated with all-cause mortality. Figure. Age- and sex-adjusted linear and non-linear association between P-wave duration (msec) and atrial fibrillation (A), stroke (B), and atrial fibrillation or stroke (C) risk. Results of a generalized additive model with spline smoothing functions and 4 degrees of freedom. Figure 1. Kaplan-Meyer curves of survival free of atrial fibrillation (A), stroke (B) and atrial fibrillation or stroke (C) in patients with normal P-wave, partial interatrial block (IAB) and advanced IAB. Funding Acknowledgement Type of funding source: None

Background:Familial sitosterolemia is a rare Mendelian disorder characterized by hyperabsorption and decreased biliary excretion of dietary sterols. Affected individuals typically have complete genetic deficiency—homozygous loss-of-function (LoF) variants—in theABCG5orABCG8genes and have substantially elevated plasma sitosterol and LDL (low-density lipoprotein) cholesterol (LDL-C) levels. The impact of partial genetic deficiency ofABCG5orABCG8—as occurs in heterozygous carriers of LoF variants—on LDL-C and risk of coronary artery disease (CAD) has remained uncertain.Methods:We first recruited 9 sitosterolemia families, identified causative LoF variants inABCG5orABCG8, and evaluated the associations of theseABCG5orABCG8LoF variants with plasma phytosterols and lipid levels. We next assessed for LoF variants inABCG5orABCG8in CAD cases (n=29 321) versus controls (n=357 326). We tested the association of rare LoF variants inABCG5orABCG8with blood lipids and risk for CAD. Rare LoF variants were defined as protein-truncating variants with minor allele frequency ABCG5orABCG8.Results:In sitosterolemia families, 7 pedigrees harbored causative LoF variants inABCG5and 2 pedigrees inABCG8. Homozygous LoF variants in eitherABCG5orABCG8led to marked elevations in sitosterol and LDL-C. Of those sitosterolemia families, heterozygous carriers ofABCG5LoF variants exhibited increased sitosterol and LDL-C levels compared with noncarriers. Within large-scale CAD case-control cohorts, prevalence of rare LoF variants inABCG5and inABCG8was ≈0.1% each.ABCG5heterozygous LoF variant carriers had significantly elevated LDL-C levels (25 mg/dL [95% CI, 14–35];P=1.1×10−6) and were at 2-fold increased risk of CAD (odds ratio, 2.06 [95% CI, 1.27–3.35];P=0.004). By contrast,ABCG8heterozygous LoF carrier status was not associated with increased LDL-C or risk of CAD.Conclusions:Although familial sitosterolemia is traditionally considered as a recessive disorder, we observed that heterozygous carriers of an LoF variant inABCG5had significantly increased sitosterol and LDL-C levels and a 2-fold increase in risk of CAD.

Background: To assess whether genetically determined quantitative and qualitative HDL characteristics were independently associated with coronary artery disease (CAD). Methods: We designed a two-sample multivariate Mendelian randomization study with available genome-wide association summary data. We identified genetic variants associated with HDL cholesterol and apolipoprotein A-I levels, HDL size, particle levels, and lipid content to define our genetic instrumental variables in one sample (Kettunen et al. study, n = 24,925) and analyzed their association with CAD risk in a different study (CARDIoGRAMplusC4D, n = 184,305). We validated these results by defining our genetic variables in another database (METSIM, n = 8372) and studied their relationship with CAD in the CARDIoGRAMplusC4D dataset. To estimate the effect size of the associations of interest adjusted for other lipoprotein traits and minimize potential pleiotropy, we used the Multi-trait-based Conditional & Joint analysis. Results: Genetically determined HDL cholesterol and apolipoprotein A-I levels were not associated with CAD. HDL mean diameter (β = 0.27 [95%CI = 0.19; 0.35]), cholesterol levels in very large HDLs (β = 0.29 [95%CI = 0.17; 0.40]), and triglyceride content in very large HDLs (β = 0.14 [95%CI = 0.040; 0.25]) were directly associated with CAD risk, whereas the cholesterol content in medium-sized HDLs (β = -0.076 [95%CI = -0.10; -0.052]) was inversely related to this risk. These results were validated in the METSIM-CARDIoGRAMplusC4D data. Conclusions: Some qualitative HDL characteristics (related to size, particle distribution, and cholesterol and triglyceride content) are related to CAD risk while HDL cholesterol levels are not. This work was supported by the Instituto de Salud Carlos III– European Regional Development Fund [grant numbers CD17/00122, IFI14/00007, PI18/00017], the Medical Research Council [grant numbers MR/K501256/1, MR/N013468/1], the Spanish Ministry of Economy and Competitiveness [grant numbers BES-2014-069718, SAF2015-71653- R], the European Union's Horizon 2020 Research and Innovation Program [grant number 796216], and the Government of Catalonia through the Agency for Management of University and Research Grants [2017 SGR 222]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. CIBER Enfermedades Cardiovasculares (CIBERCV), Epidemiología y Salud Pública (CIBERESP), and Fisiopatología de la Obesidad y Nutrición (CIBEROBN) are initiatives of the Instituto de Salud Carlos III, Madrid, Spain, and financed by the European Regional Development Fund.

We present the adaptation for Spain of the updated European Cardiovascular Prevention Guidelines. In this update, greater stress is laid on the population approach, and especially on the promotion of physical activity and healthy diet through dietary, leisure and active transport policies in Spain. To estimate vascular risk, note should be made of the importance of recalibrating the tables used, by adapting them to population shifts in the prevalence of risk factors and incidence of vascular diseases, with particular attention to the role of chronic kidney disease. At an individual level, the key element is personalised support for changes in behaviour, adherence to medication in high-risk individuals and patients with vascular disease, the fostering of physical activity, and cessation of smoking habit. Furthermore, recent clinical trials with PCSK9 inhibitors are reviewed, along with the need to simplify pharmacological treatment of arterial hypertension to improve control and adherence to treatment. In the case of patients with type 2 diabetes mellitus and vascular disease or high vascular disease risk, when lifestyle changes and metformin are inadequate, the use of drugs with proven vascular benefit should be prioritised. Lastly, guidelines on peripheral arterial disease and other specific diseases are included, as is a recommendation against prescribing antiaggregants in primary prevention.Presentamos la adaptación para España de la actualización de las Guías Europeas de Prevención Vascular. En esta actualización se hace mayor énfasis en el abordaje poblacional, especialmente en la promoción de la actividad física y de una dieta saludable mediante políticas alimentarias y de ocio y transporte activo en España. Para estimar el riesgo vascular, se destaca la importancia de recalibrar las tablas que se utilicen, adaptándolas a los cambios poblaciones en la prevalencia de los factores de riesgo y en la incidencia de enfermedades vasculares, con particular atención al papel de la enfermedad renal crónica. A nivel individual resulta clave el apoyo personalizado para el cambio de conducta, la adherencia a la medicación en los individuos de alto riesgo y pacientes con enfermedad vascular, la promoción de la actividad física y el abandono del hábito tabáquico. Además, se revisan los ensayos clínicos recientes con inhibidores de PCKS9, la necesidad de simplificar el tratamiento farmacológico de la hipertensión arterial para mejorar su control y la adherencia al tratamiento. En los pacientes con diabetes mellitus 2 y enfermedad vascular o riesgo vascular alto, cuando los cambios de estilo de vida y la metformina resultan insuficientes, deben priorizarse los fármacos con demostrado beneficio vascular. Por último, se incluyen pautas sobre enfermedad arterial periférica y otras enfermedades específicas, y se recomienda no prescribir antiagregantes en prevención primaria.

The aim of this study was to determine whether genetic variants in FADS1/FADS2 and ELOVL2 are associated with overweight–obesity and body mass index (BMI) and to assess the association between these genetic variants and lipid profile and fatty acid levels. A total of 259 overweight–obese patients were compared to 369 healthy controls. FADS1, FADS2, and ELOVL2 genes were associated with BMI and overweight–obesity ( P ≤ .001). In an additive model, the C allele in each of these variants was associated with a lower BMI: −1.18, −0.90, and −1.23 units, respectively. Higher amounts of total cholesterol, low-density lipoprotein cholesterol, total saturated fatty acids (lauric [12:0], myristic [C14:0], palmitic [C16:0], stearic [C18:0], arachidic [20:0], lignoceric [24:0]), monounsaturated fatty acids (myristoleic [C14:1], erucic [C22:1 n-9]), and polyunsaturated fatty acids (α-linolenic [ALA, 18:3 n-3], docosahexaenoic [DHA, C22:6 n-3], eicosapentaenoic acid [EPA, C20:5n-3], arachidonic acid [AA, 20:4n-6], and conjugated linolenic acids [CLA1 and CLA2]) were shown in patients. A significant increase in D6D activities presented by 20:4n-6/18:2n-6 and 18:3n-6/18:2n-6, Δ9 desaturase (D9D) activity, estimated by the ratio 18:1n-9/18:0 and elongase activities (AE), and estimated by the ratio of docosatetraenoic/AA and DPA/EPA in patients. The C minor allele of FADS1 had significantly lower DHA. A significant decrease in stearic acid, EPA, and AE activity (docosatetraenoic/AA) was revealed in patients with the minor allele carriers of FADS2. The C minor allele of ELOVL2 had significantly lower ALA, EPA, DPA, and D6D activity (C20:4 n-6/C18:2n-6). These data suggest that variations in FADS1, FADS2, and ELOVL2 affect the risk of overweight–obesity and the level of circulating fatty acids and could point to a key molecular pathway of metabolic syndrome and its related comorbidities.

DNA methylation is dynamic, varies throughout the life course, and its levels are influenced by lifestyle and environmental factors, as well as by genetic variation. The leading genetic variants at stroke risk loci identified to date explain roughly 1–2% of stroke heritability. Most of these single nucleotide polymorphisms are situated within a regulatory sequence marked by DNase I hypersensitivity sites, which would indicate involvement of an epigenetic mechanism. To detect epigenetic variants associated with stroke occurrence and stroke subtypes. A two-stage case–control epigenome-wide association study was designed. The discovery sample with 401 samples included 218 ischaemic stroke (IS) patients, assessed at Hospital del Mar (Barcelona, Spain) and 183 controls from the REGICOR cohort. In two independent samples (N = 226 and N = 166), we replicated 22 CpG sites differentially methylated in IS in 21 loci, including 2 CpGs in locus ZFHX3, which includes known genetic variants associated with stroke. The pathways associated with these loci are inflammation and angiogenesis. The meta-analysis identified 384 differentially methylated CpGs, including loci of known stroke and vascular risk genetic variants, enriched by loci involved in lipid metabolism, adipogenesis, circadian clock, and glycolysis pathways. We identified a set of 22 CpGs in 21 loci associated with IS. Our analysis suggests that DNA methylation changes may contribute to orchestrating gene expression that contributes to IS.

Aims Advanced interatrial block (IAB), is an unrecognized surrogate of atrial dysfunction and a trigger of atrial dysrhythmias, mainly atrial fibrillation (AF). Our aim was to prospectively assess whether advanced IAB in sinus rhythm is associated with AF and stroke in elderly outpatients with structural heart disease, a group not previously studied. Methods and results Prospective observational registry that included outpatients aged ≥70 years with structural heart disease and no previous diagnosis of AF. Patients were divided into three groups: normal P-wave duration ( Conclusions The presence of advanced IAB in sinus rhythm is independently associated with AF and stroke in an elderly population with structural heart disease and no previous diagnosis of AF. P-wave duration was also associated with all-cause mortality.

Analyzing 12,361 all-cause cirrhosis cases and 790,095 controls from eight cohorts, we identify a common missense variant in the Mitochondrial Amidoxime Reducing Component 1 gene (MARC1 p.A165T) that associates with protection from all-cause cirrhosis (OR 0.91, p = 2.3*10−11). This same variant also associates with lower levels of hepatic fat on computed tomographic imaging and lower odds of physician-diagnosed fatty liver as well as lower blood levels of alanine transaminase (-0.025 SD, 3.7*10−43), alkaline phosphatase (-0.025 SD, 1.2*10−37), total cholesterol (-0.030 SD, p = 1.9*10−36) and LDL cholesterol (-0.027 SD, p = 5.1*10−30) levels. We identified a series of additional MARC1 alleles (low-frequency missense p.M187K and rare protein-truncating p.R200Ter) that also associated with lower cholesterol levels, liver enzyme levels and reduced risk of cirrhosis (0 cirrhosis cases for 238 R200Ter carriers versus 17,046 cases of cirrhosis among 759,027 non-carriers, p = 0.04) suggesting that deficiency of the MARC1 enzyme may lower blood cholesterol levels and protect against cirrhosis., Author summary Cirrhosis is a leading cause of death worldwide. However, the genetic underpinnings of cirrhosis remain poorly understood. In this study, we analyze twelve thousand individuals with cirrhosis and identify a common missense variant in a gene called MARC1 that protects against cirrhosis. Carriers of this missense variant also have lower blood cholesterol levels, lower liver enzyme levels and reduced liver fat. We identify an additional two low-frequency coding variants in MARC1 that are also associated with lower cholesterol levels, lower liver enzyme levels and protection from cirrhosis. Finally, we identify an individual homozygous for a predicted loss-of-function variant in MARC1 who exhibits very low blood LDL cholesterol levels. These genetic findings suggest that MARC1 deficiency may lower blood cholesterol levels and protect against cirrhosis, pointing to MARC1 as a potential therapeutic target for liver disease.

Background Epigenome-wide association studies for cardiometabolic risk factors have discovered multiple loci associated with incident cardiovascular disease (CVD). However, few studies have sought to directly optimize a predictor of CVD risk. Furthermore, it is challenging to train multivariate models across multiple studies in the presence of study- or batch effects. Methods and Results Here, we analyzed existing DNA methylation data collected using the Illumina HumanMethylation450 microarray to create a predictor of CVD risk across 3 cohorts: Women's Health Initiative, Framingham Heart Study Offspring Cohort, and Lothian Birth Cohorts. We trained Cox proportional hazards-based elastic net regressions for incident CVD separately in each cohort and used a recently introduced cross-study learning approach to integrate these individual scores into an ensemble predictor. The methylation-based risk score was associated with CVD time-to-event in a held-out fraction of the Framingham data set (hazard ratio per SD=1.28, 95% CI, 1.10-1.50) and predicted myocardial infarction status in the independent REGICOR (Girona Heart Registry) data set (odds ratio per SD=2.14, 95% CI, 1.58-2.89). These associations remained after adjustment for traditional cardiovascular risk factors and were similar to those from elastic net models trained on a directly merged data set. Additionally, we investigated interactions between the methylation-based risk score and both genetic and biochemical CVD risk, showing preliminary evidence of an enhanced performance in those with less traditional risk factor elevation. Conclusions This investigation provides proof-of-concept for a genome-wide, CVD-specific epigenomic risk score and suggests that DNA methylation data may enable the discovery of high-risk individuals who would be missed by alternative risk metrics. This work was supported by the US Department of Agriculture, Agriculture Research Service (8050–51000-098-00D). Dr. Westerman was additionally supported by National Institutes of Health predoctoral training grant 5T32HL069772-14. The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services through contracts HHSN268201600018C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C, and HHSN268201600004C. This article was prepared in collaboration with investigators of the WHI but has not been reviewed by the WHI and does not necessarily reflect the opinions of the WHI investigators or the National Heart, Lung, and Blood Institute. The Framingham Heart Study is conducted and supported by the National Heart, Lung, and Blood Institute in collaboration with Boston University (Contract No. N01-HC-25195 and HHSN268201500001I). This article was not prepared in collaboration with investigators of the Framingham Heart Study and does not necessarily reflect the opinions or views of the Framingham Heart Study, Boston University, or National Heart, Lung, and Blood Institute. The LBC 1936 is supported by Age UK (Disconnected Mind program) and the Medical Research Council (MR/M01311/1). Methylation typing in LBC 1936 was supported by Centre for Cognitive Ageing and Cognitive Epidemiology (Pilot Fund award), Age UK, The Wellcome Trust Institutional Strategic Support Fund, The University of Edinburgh, and The University of Queensland. LBC 1936 work was conducted in the Centre for Cognitive Ageing and Cognitive Epidemiology, which supported Dr. Deary and is supported by the medical Research Council and Biotechnology and Biological Sciences Research Council (MR/K026992/1). Sí

Producción Científica, Risk prediction tools cannot identify most individuals at high coronary artery disease (CAD) risk. Oxidized low-density lipoproteins (oxLDLs) and microRNAs are actively involved in atherosclerosis. Our aim was to examine the association of CAD and oxLDLs-induced microRNAs, and to assess the microRNAs predictive capacity of future CAD events. Human endothelial and vascular smooth muscle cells were treated with oxidized/native low-density lipoproteins, and microRNA expression was analyzed. Differentially expressed and CAD-related miRNAs were examined in serum samples from (1) a case-control study with 476 myocardial infarction (MI) patients and 487 controls, and (2) a case-cohort study with 105 incident CAD cases and 455 randomly-selected cohort participants. MicroRNA expression was analyzed with custom OpenArray plates, log rank tests and Cox regression models. Twenty-one microRNAs, two previously undescribed (hsa-miR-193b-5p and hsa-miR-1229-5p), were up- or down-regulated upon cell treatment with oxLDLs. One of the 21, hsa-miR-122-5p, was also upregulated in MI cases (fold change = 4.85). Of the 28 CAD-related microRNAs tested, 11 were upregulated in MI cases-1 previously undescribed (hsa-miR-16-5p)-, and 1/11 was also associated with CAD incidence (adjusted hazard ratio = 0.55 (0.35–0.88)) and improved CAD risk reclassification, hsa-miR-143-3p. We identified 2 novel microRNAs modulated by oxLDLs in endothelial cells, 1 novel microRNA upregulated in AMI cases compared to controls, and one circulating microRNA that improved CAD risk classification., Fondo Europeo de Desarrollo Regional (projects FIS-CP12/03287, FIS-14/00449, FIS-PI081327, INTRASALUD PI11/01801, PI15/00064, IJCI-2016-29393 to DdG-C, CIBERCV (CB16/11/00229, 00246, 00403), CIBERESP CB06/02/0029 and CIBEROBN CB06/03/0028), Ministerio de Economía, Industria y Competitividad (project BFU2016-75360-R), Fundación BBVA (project PR-16-BIO-CAR-0041), Departament de Salut de la Generalitat de Catalunya - Agència de Gestió d’Ajuts Universitaris de Recerca de Catalunya (project 2017SGR222), Pla estratègic de recerca i innovació en salut (project SLT006/17/00234, SLT002/16/00145 and SLT006/17/00029), Junta de Castilla y León (project VA114P17)