Electrocardiographic parameters and the risk of new-onset atrial fibrillation in the general population: the Rotterdam Study.

AIMS: We aimed to assess the (shape of the) association and sex differences in the link between electrocardiographic parameters and new-onset atrial fibrillation (AF). METHODS AND RESULTS: A total of 12 212 participants free of AF at baseline from the population-based Rotterdam Study were included. Up to five repeated measurements of electrocardiographic parameters including PR, QRS, QT, QT corrected for heart rate (QTc), JT, RR interval, and heart rate were assessed at baseline and follow-up examinations. Cox proportional hazards- and joint models, adjusted for cardiovascular risk factors, were used to determine the (shape of the) association between baseline and longitudinal electrocardiographic parameters with new-onset AF. Additionally, we evaluated potential sex differences. During a median follow-up of 9.3 years, 1282 incident AF cases occurred among 12 212 participants (mean age 64.9 years, 58.2% women). Penalized cubic splines revealed that associations between baseline electrocardiographic measures and risk of new-onset AF were generally U- and N-shaped. Sex differences in terms of the shape of the various associations were most apparent for baseline PR, QT, QTc, RR interval, and heart rate in relation to new-onset AF. Longitudinal measures of higher PR interval [fully adjusted hazard ratio (HR), 95% confidence interval (CI), 1.43, 1.02-2.04, P = 0.0393] and higher QTc interval (fully adjusted HR, 95% CI, 5.23, 2.18-12.45, P = 0.0002) were significantly associated with new-onset AF, in particular in men. CONCLUSION: Associations of baseline electrocardiographic measures and risk of new-onset AF were mostly U- and N-shaped. Longitudinal electrocardiographic measures of PR and QTc interval were significantly associated with new-onset AF, in particular among men.

The association of innate and adaptive immunity, subclinical atherosclerosis, and cardiovascular disease in the Rotterdam Study: A prospective cohort study.

BACKGROUND: Atherosclerotic cardiovascular disease (ASCVD) is driven by multifaceted contributions of the immune system. However, the dysregulation of immune cells that leads to ASCVD is poorly understood. We determined the association of components of innate and adaptive immunity longitudinally with ASCVD, and assessed whether arterial calcifications play a role in this association. METHODS AND FINDINGS: Granulocyte (innate immunity) and lymphocyte (adaptive immunity) counts were determined 3 times (2002-2008, mean age 65.2 years; 2009-2013, mean age 69.0 years; and 2014-2015, mean age 78.5 years) in participants of the population-based Rotterdam Study without ASCVD at baseline. Participants were followed-up for ASCVD or death until 1 January 2015. A random sample of 2,366 underwent computed tomography at baseline to quantify arterial calcification volume in 4 vessel beds. We studied the association between immunity components with risk of ASCVD and assessed whether immunity components were related to arterial calcifications at baseline. Of 7,730 participants (59.4% women), 801 developed ASCVD during a median follow-up of 8.1 years. Having an increased granulocyte count increased ASCVD risk (adjusted hazard ratio for doubled granulocyte count [95% CI] = 1.78 [1.34-2.37], P < 0.001). Higher granulocyte counts were related to larger calcification volumes in all vessels, most prominently in the coronary arteries (mean difference in calcium volume [mm3] per SD increase in granulocyte count [95% CI] = 32.3 [9.9-54.7], P < 0.001). Respectively, the association between granulocyte count and incident coronary heart disease and stroke was partly mediated by coronary artery calcification (overall proportion mediated [95% CI] = 19.0% [-10% to 32.3%], P = 0.08) and intracranial artery calcification (14.9% [-10.9% to 19.1%], P = 0.05). A limitation of our study is that studying the etiology of ASCVD remains difficult within an epidemiological setting due to the limited availability of surrogates for innate and especially adaptive immunity. CONCLUSIONS: In this study, we found that an increased granulocyte count was associated with a higher risk of ASCVD in the general population. Moreover, higher levels of granulocytes were associated with larger volumes of arterial calcification. Arterial calcifications may explain a proportion of the link between granulocytes and ASCVD.

COPD GWAS variant at 19q13.2 in relation with DNA methylation and gene expression.

Chronic obstructive pulmonary disease (COPD) is among the major health burdens in adults. While cigarette smoking is the leading risk factor, a growing number of genetic variations have been discovered to influence disease susceptibility. Epigenetic modifications may mediate the response of the genome to smoking and regulate gene expression. Chromosome 19q13.2 region is associated with both smoking and COPD, yet its functional role is unclear. Our study aimed to determine whether rs7937 (RAB4B, EGLN2), a top genetic variant in 19q13.2 region identified in genome-wide association studies of COPD, is associated with differential DNA methylation in blood (N = 1490) and gene expression in blood (N = 721) and lungs (N = 1087). We combined genetic and epigenetic data from the Rotterdam Study (RS) to perform the epigenome-wide association analysis of rs7937. Further, we used genetic and transcriptomic data from blood (RS) and from lung tissue (Lung expression quantitative trait loci mapping study), to perform the transcriptome-wide association study of rs7937. Rs7937 was significantly (FDR < 0.05) and consistently associated with differential DNA methylation in blood at 4 CpG sites in cis, independent of smoking. One methylation site (cg11298343-EGLN2) was also associated with COPD (P = 0.001). Additionally, rs7937 was associated with gene expression levels in blood in cis (EGLN2), 42% mediated through cg11298343, and in lung tissue, in cis and trans (NUMBL, EGLN2, DNMT3A, LOC101929709 and PAK2). Our results suggest that changes of DNA methylation and gene expression may be intermediate steps between genetic variants and COPD, but further causal studies in lung tissue should confirm this hypothesis.

A cross-omics integrative study of metabolic signatures of chronic obstructive pulmonary disease.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a common lung disorder characterized by persistent and progressive airflow limitation as well as systemic changes. Metabolic changes in blood may help detect COPD in an earlier stage and predict prognosis. METHODS: We conducted a comprehensive study of circulating metabolites, measured by proton Nuclear Magnetic Resonance Spectroscopy, in relation with COPD and lung function. The discovery sample consisted of 5557 individuals from two large population-based studies in the Netherlands, the Rotterdam Study and the Erasmus Rucphen Family study. Significant findings were replicated in 12,205 individuals from the Lifelines-DEEP study, FINRISK and the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) studies. For replicated metabolites further investigation of causality was performed, utilizing genetics in the Mendelian randomization approach. RESULTS: There were 602 cases of COPD and 4955 controls used in the discovery meta-analysis. Our logistic regression results showed that higher levels of plasma Glycoprotein acetyls (GlycA) are significantly associated with COPD (OR = 1.16, P = 5.6 × 10- 4 in the discovery and OR = 1.30, P = 1.8 × 10- 6 in the replication sample). A bi-directional two-sample Mendelian randomization analysis suggested that circulating blood GlycA is not causally related to COPD, but that COPD causally increases GlycA levels. Using the prospective data of the same sample of Rotterdam Study in Cox-regression, we show that the circulating GlycA level is a predictive biomarker of COPD incidence (HR = 1.99, 95%CI 1.52-2.60, comparing those in the highest and lowest quartile of GlycA) but is not significantly associated with mortality in COPD patients (HR = 1.07, 95%CI 0.94-1.20). CONCLUSIONS: Our study shows that circulating blood GlycA is a biomarker of early COPD pathology.

A comprehensive evaluation of the genetic architecture of sudden cardiac arrest.

Aims: Sudden cardiac arrest (SCA) accounts for 10% of adult mortality in Western populations. We aim to identify potential loci associated with SCA and to identify risk factors causally associated with SCA. Methods and results: We carried out a large genome-wide association study (GWAS) for SCA (n = 3939 cases, 25 989 non-cases) to examine common variation genome-wide and in candidate arrhythmia genes. We also exploited Mendelian randomization (MR) methods using cross-trait multi-variant genetic risk score associations (GRSA) to assess causal relationships of 18 risk factors with SCA. No variants were associated with SCA at genome-wide significance, nor were common variants in candidate arrhythmia genes associated with SCA at nominal significance. Using cross-trait GRSA, we established genetic correlation between SCA and (i) coronary artery disease (CAD) and traditional CAD risk factors (blood pressure, lipids, and diabetes), (ii) height and BMI, and (iii) electrical instability traits (QT and atrial fibrillation), suggesting aetiologic roles for these traits in SCA risk. Conclusions: Our findings show that a comprehensive approach to the genetic architecture of SCA can shed light on the determinants of a complex life-threatening condition with multiple influencing factors in the general population. The results of this genetic analysis, both positive and negative findings, have implications for evaluating the genetic architecture of patients with a family history of SCA, and for efforts to prevent SCA in high-risk populations and the general community.

Genetic Obesity and the Risk of Atrial Fibrillation: Causal Estimates from Mendelian Randomization.

BACKGROUND: Observational studies have identified an association between body mass index (BMI) and incident atrial fibrillation (AF). Inferring causality from observational studies, however, is subject to residual confounding, reverse causation, and bias. The primary objective of this study was to evaluate the causal association between BMI and AF by using genetic predictors of BMI. METHODS: We identified 51 646 individuals of European ancestry without AF at baseline from 7 prospective population-based cohorts initiated between 1987 and 2002 in the United States, Iceland, and the Netherlands with incident AF ascertained between 1987 and 2012. Cohort-specific mean follow-up ranged from 7.4 to 19.2 years, over which period there was a total of 4178 cases of incident AF. We performed a Mendelian randomization with instrumental variable analysis to estimate a cohort-specific causal hazard ratio for the association between BMI and AF. Two genetic instruments for BMI were used: FTO genotype (rs1558902) and a BMI gene score comprising 39 single-nucleotide polymorphisms identified by genome-wide association studies to be associated with BMI. Cohort-specific estimates were combined by random-effects, inverse variance-weighted meta-analysis. RESULTS: In age- and sex-adjusted meta-analysis, both genetic instruments were significantly associated with BMI (FTO: 0.43 [95% confidence interval, 0.32-0.54] kg/m2 per A-allele, P<0.001; BMI gene score: 1.05 [95% confidence interval, 0.90-1.20] kg/m2 per 1-U increase, P<0.001) and incident AF (FTO, hazard ratio, 1.07 [1.02-1.11] per A-allele, P=0.004; BMI gene score, hazard ratio, 1.11 [1.05-1.18] per 1-U increase, P<0.001). Age- and sex-adjusted instrumental variable estimates for the causal association between BMI and incident AF were hazard ratio, 1.15 (1.04-1.26) per kg/m2, P=0.005 (FTO) and 1.11 (1.05-1.17) per kg/m2, P<0.001 (BMI gene score). Both of these estimates were consistent with the meta-analyzed estimate between observed BMI and AF (age- and sex-adjusted hazard ratio 1.05 [1.04-1.06] per kg/m2, P<0.001). Multivariable adjustment did not significantly change findings. CONCLUSIONS: Our data are consistent with a causal relationship between BMI and incident AF. These data support the possibility that public health initiatives targeting primordial prevention of obesity may reduce the incidence of AF.

Heritability and genome-wide association study of diffusing capacity of the lung.

Although several genome-wide association studies (GWAS) have investigated the genetics of pulmonary ventilatory function, little is known about the genetic factors that influence gas exchange. The aim of the study was to investigate the heritability of, and genetic variants associated with the diffusing capacity of the lung.GWAS was performed on diffusing capacity of the lung measured by carbon monoxide uptake (DLCO) and per alveolar volume (VA) using the single-breath technique, in 8372 individuals from two population-based cohort studies, the Rotterdam Study and the Framingham Heart Study. Heritability was estimated in related (n=6246) and unrelated (n=3286) individuals.Heritability of DLCO and DLCO/VA ranged between 23% and 28% in unrelated individuals and between 45% and 49% in related individuals. Meta-analysis identified a genetic variant in ADGRG6 that is significantly associated with DLCO/VA Gene expression analysis of ADGRG6 in human lung tissue revealed a decreased expression in patients with chronic obstructive pulmonary disease (COPD) and subjects with decreased DLCO/VADLCO and DLCO/VA are heritable traits, with a considerable proportion of variance explained by genetics. A functional variant in ADGRG6 gene region was significantly associated with DLCO/VA Pulmonary ADGRG6 expression was decreased in patients with COPD.

Thyroid Function and Sudden Cardiac Death: A Prospective Population-Based Cohort Study.

BACKGROUND: The association between thyroid function and cardiovascular disease is well established, but no study to date has assessed whether it is a risk factor for sudden cardiac death (SCD). Therefore, we studied the association of thyroid function with SCD in a prospective population-based cohort. METHODS: Participants from the Rotterdam Study ≥45 years with thyroid-stimulating hormone or free thyroxine (FT4) measurements and clinical follow-up were eligible. We assessed the association of thyroid-stimulating hormone and FT4 with the risk of SCD by using an age- and sex-adjusted Cox proportional-hazards model, in all participants and also after restricting the analysis to euthyroid participants (defined by thyroid-stimulating hormone 0.4-4.0 mIU/L). Additional adjustment included cardiovascular risk factors, notably hypertension, serum cholesterol, and smoking. We stratified by age and sex and performed sensitivity analyses by excluding participants with abnormal FT4 values (reference range of 0.85-1.95 ng/dL) and including only witnessed SCDs as outcome. Absolute risks were calculated in a competing risk model by taking death by other causes into account. RESULTS: We included 10 318 participants with 261 incident SCDs (median follow-up, 9.1 years). Higher levels of FT4 were associated with an increased SCD risk, even in the normal range of thyroid function (hazard ratio, 2.28 per 1 ng/dL FT4; 95% confidence interval, 1.31-3.97). Stratification by age or sex and sensitivity analyses did not change the risk estimates substantially. The absolute 10-year risk of SCD increased in euthyroid participants from 1% to 4% with increasing FT4 levels. CONCLUSIONS: Higher FT4 levels are associated with an increased risk of SCD, even in euthyroid participants.

Gait patterns in COPD: the Rotterdam Study.

Gait disturbances in patients with chronic obstructive pulmonary disease (COPD) may lead to disability and falls. As studies assessing gait kinematics in COPD are sparse, we investigated associations of COPD with various gait domains and explored a potential link with falling. Gait was measured within the prospective, population-based Rotterdam Study (age ≥55 years) using an electronic walkway and summarised into seven gait domains: Rhythm, Variability, Phases, Pace, Tandem, Turning and Base of Support. Rhythm is a temporal gait aspect that includes cadence and reflects how quickly steps are taken. Persons with COPD (n=196) exhibited worse Rhythm (-0.21 SD, 95% CI -0.36- -0.06 SD) compared with persons with normal lung function (n=898), independent of age, sex, height, education, smoking or analgesic use, especially when dyspnoea and severe airflow limitation or frequent exacerbations (Global Initiative for Chronic Obstructive Lung Disease group D: -0.83 SD, 95% CI -1.25- -0.41 SD) were present. A lower forced expiratory volume in 1 s was associated with worse Rhythm and Pace, including lower cadence and gait velocity, respectively. Importantly, fallers with COPD had significantly worse Rhythm than nonfallers with COPD. This study demonstrates that persons with COPD exhibit worse Rhythm, especially fallers with COPD. The degree of Rhythm deterioration was associated with the degree of airflow limitation, symptoms and frequency of exacerbations.

Generalized estimating equations for genome-wide association studies using longitudinal phenotype data.

Many longitudinal cohort studies have both genome-wide measures of genetic variation and repeated measures of phenotypes and environmental exposures. Genome-wide association study analyses have typically used only cross-sectional data to evaluate quantitative phenotypes and binary traits. Incorporation of repeated measures may increase power to detect associations, but also requires specialized analysis methods. Here, we discuss one such method-generalized estimating equations (GEE)-in the contexts of analysis of main effects of rare genetic variants and analysis of gene-environment interactions. We illustrate the potential for increased power using GEE analyses instead of cross-sectional analyses. We also address challenges that arise, such as the need for small-sample corrections when the minor allele frequency of a genetic variant and/or the prevalence of an environmental exposure is low. To illustrate methods for detection of gene-drug interactions on a genome-wide scale, using repeated measures data, we conduct single-study analyses and meta-analyses across studies in three large cohort studies participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium-the Atherosclerosis Risk in Communities study, the Cardiovascular Health Study, and the Rotterdam Study.

The role of electronic healthcare record databases in paediatric drug safety surveillance: a retrospective cohort study.

AIM: Electronic healthcare record (EHR)-based surveillance systems are increasingly being developed to support early detection of safety signals. It is unknown what the power of such a system is for surveillance among children and adolescents. In this paper we provide estimates of the number and classes of drugs, and incidence rates (IRs) of events, that can be monitored in children and adolescents (0-18 years). METHODS: Data were obtained from seven population-based EHR databases in Denmark, Italy, and the Netherlands during the period 1996-2010. We estimated the number of drugs for which specific adverse events can be monitored as a function of actual drug use, minimally detectable relative risk (RR) and IRs for 10 events. RESULTS: The population comprised 4 838 146 individuals (25 575 132 person years (PYs)), who were prescribed 2170 drugs (1 610 631 PYs drug-exposure). Half of the total drug-exposure in PYs was covered by only 18 drugs (0.8%). For a relatively frequent event like upper gastrointestinal bleeding there were 39 drugs for which an association with a RR ≥4, if present, could be investigated. The corresponding number of drugs was eight for a rare event like anaphylactic shock. CONCLUSION: Drug use in children is rare and shows little variation. The number of drugs with enough exposure to detect rare adverse events in children and adolescents within an EHR-based surveillance system such as EU-ADR is limited. Use of additional sources of paediatric drug exposure information and global collaboration are imperative in order to optimize EHR data for paediatric safety surveillance.

Incident cancer risk after the start of aspirin use: results from a Dutch population-based cohort study of low dose aspirin users.

Observational and intervention studies suggest that low dose aspirin use may prevent cancer. The objective of this study was to investigate the protective effect of long term low dose aspirin use (≤100 mg daily) on cancer in general and site-specific cancer among low dose aspirin users in the Dutch general population. We conducted a population-based cohort study with detailed information on aspirin exposure and cancer incidence. Only incident (new) low dose aspirin users, who were included in the linkage between PHARMO and the Eindhoven Cancer Registry (1998-2010) and free of cancer before the start of follow up were included. A Cox proportional hazard model with cumulative aspirin use as a time-varying determinant was used to obtain hazard ratios (HR). Duration of aspirin use amongst 109,276 incident low dose aspirin users was not associated with a decreased risk of any of the site-specific cancers or cancer in general (adjusted HR per year of aspirin use for all cancers: 1.02, 95% confidence interval [CI] 1.00-1.04, HR of >6 years aspirin use compared to <2 years: 1.17, 95% CI 1.02-1.34). After adjusting for current and past aspirin use, 2-6 years of low dose aspirin use was associated with a reduced colorectal cancer risk compared to <2 years of aspirin use (adjusted HR 0.75, 95% CI 0.59-0.96). However, a clear dose-response relationship was not observed (adjusted HR >6 years aspirin use 0.95, 95% CI 0.60-1.49). Our results do not support the primary prevention of cancer among long term aspirin users.

Prenatal exposure to selective serotonin reuptake inhibitors and social responsiveness symptoms of autism: population-based study of young children.

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) are considered safe and are frequently used during pregnancy. However, two case-control studies suggested an association between prenatal SSRI exposure with childhood autism. AIMS: To prospectively determine whether intra-uterine SSSRI exposure is associated with childhood autistic symptoms in a population-based study. METHOD: A total of 376 children prenatally exposed to maternal depressive symptoms (no SSRI exposure), 69 children prenatally exposed to SSRIs and 5531 unexposed children were included. Child pervasive developmental and affective problems were assessed by parental report with the Child Behavior Checklist at ages 1.5, 3 and 6. At age 6, we assessed autistic traits using the Social Responsiveness Scale (n = 4264). RESULTS: Prenatal exposure to maternal depressive symptoms without SSRIs was related to both pervasive developmental (odds ratio (OR) = 1.44, 95% CI 1.07-1.93) and affective problems (OR = 1.44, 95% CI 1.15-1.81). Compared with unexposed children, those prenatally exposed to SSRIs also were at higher risk for developing pervasive developmental problems (OR = 1.91, 95% CI 1.13-3.47), but not for affective problems. Children prenatally exposed to SSRIs also had more autistic traits (B = 0.15, 95% CI 0.08-0.22) compared with those exposed to depressive symptoms only. CONCLUSIONS: Our results suggest an association between prenatal SSRI exposure and autistic traits in children. Prenatal depressive symptoms without SSRI use were also associated with autistic traits, albeit this was weaker and less specific. Long-term drug safety trials are needed before evidence-based recommendations are possible.

B-type natriuretic peptide and C-reactive protein in the prediction of atrial fibrillation risk: the CHARGE-AF Consortium of community-based cohort studies.

AIMS: B-type natriuretic peptide (BNP) and C-reactive protein (CRP) predict atrial fibrillation (AF) risk. However, their risk stratification abilities in the broad community remain uncertain. We sought to improve risk stratification for AF using biomarker information. METHODS AND RESULTS: We ascertained AF incidence in 18 556 Whites and African Americans from the Atherosclerosis Risk in Communities Study (ARIC, n=10 675), Cardiovascular Health Study (CHS, n = 5043), and Framingham Heart Study (FHS, n = 2838), followed for 5 years (prediction horizon). We added BNP (ARIC/CHS: N-terminal pro-B-type natriuretic peptide; FHS: BNP), CRP, or both to a previously reported AF risk score, and assessed model calibration and predictive ability [C-statistic, integrated discrimination improvement (IDI), and net reclassification improvement (NRI)]. We replicated models in two independent European cohorts: Age, Gene/Environment Susceptibility Reykjavik Study (AGES), n = 4467; Rotterdam Study (RS), n = 3203. B-type natriuretic peptide and CRP were significantly associated with AF incidence (n = 1186): hazard ratio per 1-SD ln-transformed biomarker 1.66 [95% confidence interval (CI), 1.56-1.76], P < 0.0001 and 1.18 (95% CI, 1.11-1.25), P < 0.0001, respectively. Model calibration was sufficient (BNP, χ(2) = 17.0; CRP, χ(2) = 10.5; BNP and CRP, χ(2) = 13.1). B-type natriuretic peptide improved the C-statistic from 0.765 to 0.790, yielded an IDI of 0.027 (95% CI, 0.022-0.032), a relative IDI of 41.5%, and a continuous NRI of 0.389 (95% CI, 0.322-0.455). The predictive ability of CRP was limited (C-statistic increment 0.003). B-type natriuretic peptide consistently improved prediction in AGES and RS. CONCLUSION: B-type natriuretic peptide, not CRP, substantially improved AF risk prediction beyond clinical factors in an independently replicated, heterogeneous population. B-type natriuretic peptide may serve as a benchmark to evaluate novel putative AF risk biomarkers.

Early pregnancy exposure to antihistamines and risk of congenital heart defects: results of two case-control studies.

UNLABELLED: We aimed to study the association between use of antihistamines in early pregnancy and congenital heart defects (CHD) in the offspring. DESIGN: Two case-control studies. SETTING: HAVEN study, Erasmus MC, University Medical Centre, Rotterdam, and Eurocat Northern Netherlands (NNL), University Medical Center Groningen, Groningen, the Netherlands. We studied 361 children with CHD and 410 controls without congenital malformations from the HAVEN study and replicated the analyses in 445 children with CHD and 530 controls from the Eurocat NNL registry. Information about antihistamine use in early pregnancy and potential confounders was obtained from questionnaires postpartum. We calculated the association between antihistamines and CHD risk by multivariable logistic regression analysis. MAIN OUTCOME MEASURES: Odds ratios (OR) with 95% confidence intervals (CI). In the HAVEN study, 25 of 771 mothers used antihistamines that were associated with an increased CHD risk (OR 3.0, 95% CI 1.2-7.3), particularly atrioventricular septal defects (AVSD) (OR 5.1, 95 % CI 1.3-20.5) and perimembranous ventricular septal defects (pVSD) (OR 5.1, 95% CI 1.8-14.4). Mothers with severe nausea who did not use antihistamines had a reduced risk (OR 0.7, 95% CI 0.5-0.98), whereas nauseous mothers using antihistamines showed an almost fivefold increased risk of pVSD (OR 4.8, 95% CI 1.1-21.8). The association between antihistamines and AVSD was confirmed in the Eurocat cohort (OR 3.5, 95% CI 1.4-8.7), but we could not replicate the association with overall CHD risk. We found a positive association between antihistamine use in early pregnancy and CHD risk, particularly AVSD, which seemed to be independent of nausea/vomiting.

Antihypertensive Drugs for the Prevention of Atrial Fibrillation: A Drug Target Mendelian Randomization Study.

BACKGROUND: We investigated the potential impact of antihypertensive drugs for atrial fibrillation (AF) prevention through a drug target Mendelian randomization study to avoid the potential limitations of clinical studies. METHODS: Validated published single-nucleotide polymorphisms (SNPs) that mimic the action of 12 antihypertensive drug classes, including alpha-adrenoceptor blockers, adrenergic neuron blockers, angiotensin-converting enzyme inhibitors, angiotensin-II receptor blockers, beta-adrenoceptor blockers, centrally acting antihypertensive drugs, calcium channel blockers, loop diuretics, potassium-sparing diuretics and mineralocorticoid receptor antagonists, renin inhibitors, thiazides and related diuretic agents, and vasodilators were used. We estimated, via their corresponding gene and protein targets, the downstream effect of these drug classes to prevent AF via systolic blood pressure using 2-sample Mendelian randomization analyses. The SNPs were extracted from 2 European genome-wide association studies for the drug classes (n=317 754; n=757 601) and 1 European genome-wide association study for AF (n=1 030 836). RESULTS: Drug target Mendelian randomization analyses supported the significant preventive causal effects of lowering systolic blood pressure per 10 mm Hg via alpha-adrenoceptor blockers (n=11 SNPs; odds ratio [OR], 0.34 [95% CI, 0.21-0.56]; P=2.74×10-05), beta-adrenoceptor blockers (n=17 SNPs; OR, 0.52 [95% CI, 0.35-0.78]; P=1.62×10-03), calcium channel blockers (n=49 SNPs; OR, 0.50 [95% CI, 0.36-0.70]; P=4.51×10-05), vasodilators (n=19 SNPs; OR, 0.53 [95% CI, 0.34-0.84]; P=7.03×10-03), and all 12 antihypertensive drug classes combined (n=158 SNPs; OR, 0.64 [95% CI, 0.54-0.77]; P=8.50×10-07) on AF risk. CONCLUSIONS: Our results indicated that lowering systolic blood pressure via protein targets of various antihypertensive drugs seems promising for AF prevention. Our findings inform future clinical trials and have implications for repurposing antihypertensive drugs for AF prevention.

Heart rate variability and atrial fibrillation in the general population: a longitudinal and Mendelian randomization study.

BACKGROUND: Sex differences and causality of the association between heart rate variability (HRV) and atrial fibrillation (AF) in the general population remain unclear. METHODS: 12,334 participants free of AF from the population-based Rotterdam Study were included. Measures of HRV including the standard deviation of normal RR intervals (SDNN), SDNN corrected for heart rate (SDNNc), RR interval differences (RMSSD), RMSSD corrected for heart rate (RMSSDc), and heart rate were assessed at baseline and follow-up examinations. Joint models, adjusted for cardiovascular risk factors, were used to determine the association between longitudinal measures of HRV with new-onset AF. Genetic variants for HRV were used as instrumental variables in a Mendelian randomization (MR) analysis using genome-wide association studies (GWAS) summary-level data. RESULTS: During a median follow-up of 9.4 years, 1302 incident AF cases occurred among 12,334 participants (mean age 64.8 years, 58.3% women). In joint models, higher SDNN (fully-adjusted hazard ratio (HR), 95% confidence interval (CI) 1.24, 1.04-1.47, p = 0.0213), and higher RMSSD (fully-adjusted HR, 95% CI 1.33, 1.13-1.54, p = 0.0010) were significantly associated with new-onset AF. Sex-stratified analyses showed that the associations were mostly prominent among women. In MR analyses, a genetically determined increase in SDNN (odds ratio (OR), 95% CI 1.60, 1.27-2.02, p = 8.36 × 10-05), and RMSSD (OR, 95% CI 1.56, 1.31-1.86, p = 6.32 × 10-07) were significantly associated with an increased odds of AF. CONCLUSION: Longitudinal measures of uncorrected HRV were significantly associated with new-onset AF, especially among women. MR analyses supported the causal relationship between uncorrected measures of HRV with AF. Our findings indicate that measures to modulate HRV might prevent AF in the general population, in particular in women. AF; atrial fibrillation, GWAS; genome-wide association study, IVW; inverse variance weighted, MR; Mendelian randomization, MR-PRESSO; MR-egger and mendelian randomization pleiotropy residual sum and outlier, RMSSD; root mean square of successive RR interval differences, RMSSDc; root mean square of successive RR interval differences corrected for heart rate, SDNN; standard deviation of normal to normal RR intervals, SDNNc; standard deviation of normal to normal RR intervals corrected for heart rate, WME; weighted median estimator. aRotterdam Study n=12,334 bHRV GWAS n=53,174 cAF GWAS n=1,030,836.

Clinical Impact and Mechanisms of Nonatherosclerotic Vascular Aging: The New Kid to Be Blocked.

Ischemic cardiovascular disease and stroke remain the leading cause of global morbidity and mortality. During aging, protective mechanisms in the body gradually deteriorate, resulting in functional, structural, and morphologic changes that affect the vascular system. Because atherosclerotic plaques are not always present along with these alterations, we refer to this kind of vascular aging as nonatherosclerotic vascular aging (NAVA). To maintain proper vascular function during NAVA, it is important to preserve intracellular signalling, prevent inflammation, and block the development of senescent cells. Pharmacologic interventions targeting these components are potential therapeutic approaches for NAVA, with a particular emphasis on inflammation and senescence. This review provides an overview of the pathophysiology of vascular aging and explores potential pharmacotherapies that can improve the function of aged vasculature, focusing on NAVA.

Susceptibility to amoxicillin-clavulanate-induced liver injury is influenced by multiple HLA class I and II alleles.

BACKGROUND & AIMS: Drug-induced liver injury (DILI), especially from antimicrobial agents, is an important cause of serious liver disease. Amoxicillin-clavulanate (AC) is a leading cause of idiosyncratic DILI, but little is understood about genetic susceptibility to this adverse reaction. METHODS: We performed a genome-wide association study using 822,927 single nucleotide polymorphism (SNP) markers from 201 White European and US cases of DILI following AC administration (AC-DILI) and 532 population controls, matched for genetic background. RESULTS: AC-DILI was associated with many loci in the major histocompatibility complex. The strongest effect was with an HLA class II SNP (rs9274407, P=4.8×10(-14)), which correlated with rs3135388, a tag SNP of HLA-DRB1*1501-DQB1*0602 that was previously associated with AC-DILI. Conditioned on rs3135388, rs9274407 is still significant (P=1.1×10(-4)). An independent association was observed in the class I region (rs2523822, P=1.8×10(-10)), related to HLA-A*0201. The most significant class I and II SNPs showed statistical interaction (P=.0015). High-resolution HLA genotyping (177 cases and 219 controls) confirmed associations of HLA-A*0201 (P=2×10(-6)) and HLA-DQB1*0602 (P=5×10(-10)) and their interaction (P=.005). Additional, population-dependent effects were observed in HLA alleles with nominal significance. In an analysis of autoimmune-related genes, rs2476601 in the gene PTPN22 was associated (P=1.3×10(-4)). CONCLUSIONS: Class I and II HLA genotypes affect susceptibility to AC-DILI, indicating the importance of the adaptive immune response in pathogenesis. The HLA genotypes identified will be useful in studies of the pathogenesis of AC-DILI but have limited utility as predictive or diagnostic biomarkers because of the low positive predictive values.