Lifestyle, heart rate and cardiovascular disease:novel insights from genomics and big data

Cardiovascular disease (CVD) remains the leading cause of mortality worldwide, despite declining mortality rates due to improved treatment. Preventive strategies could be essential to reduce CVD burden, but will require a better understanding of the pathophysiological mechanisms underlying CVD development. Studying the genetic architecture of CVD and its risk factors might aid in this endeavor. Genome-wide association studies can increase our understanding of the underlying biological architecture of CVD and its risk factors by identifying associated genetic variants. These genetic variants can then be used to obtain generally unconfounded genetic associations between a risk factor and CVD. This thesis identifies novel genetic variants associated with prevalent lifestyle behaviors and several heart rate traits. We provide evidence that television watching might causally increase risk of coronary artery disease development. A genetic association between caffeine intake and CVD was not established. We find that heart rate at rest, its variability, its increase during exercise, and its recovery after exercise, are not likely on the causal pathway to mortality. We do find that higher genetically predicted resting heart rate decreases risk of atrial fibrillation, ischemic stroke and cardio-embolic stroke. The genetic association of resting heart rate with ischemic and cardio-embolic stroke is unlikely caused by resting heart rate itself, but is probably driven by the effect of resting heart rate associated variants on respectively pulse pressure and atrial fibrillation. The findings described in this thesis increase our insights in the pathophysiological mechanisms leading to CVD and may improve risk stratification and prevention strategies

Associations of Observational and Genetically Determined Caffeine Intake With Coronary Artery Disease and Diabetes Mellitus

Background Caffeine is the most widely consumed psychostimulant and is associated with lower risk of coronary artery disease (CAD) and type 2 diabetes mellitus (T2DM). However, whether these associations are causal remains unknown. This study aimed to identify genetic variants associated with caffeine intake, and to investigate evidence for causal links with CAD or T2DM. In addition, we aimed to replicate previous observational findings. Methods and Results Observational associations were tested within UK Biobank using Cox regression analyses. Moderate observational caffeine intakes from coffee or tea were associated with lower risks of CAD or T2DM, with the lowest risks at intakes of 121 to 180 mg/day from coffee for CAD (hazard ratio [HR], 0.77 [95% CI, 0.73-0.82; P<1×10-16]), and 301 to 360 mg/day for T2DM (HR, 0.76 [95% CI, 0.67-0.86]; P=1.57×10-5). Next, genome-wide association studies were performed on self-reported caffeine intake from coffee, tea, or both in 407 072 UK Biobank participants. These analyses identified 51 novel genetic variants associated with caffeine intake at P<1.67×10-8. These loci were enriched for central nervous system genes. However, in contrast to the observational analyses, 2-sample Mendelian randomization analyses using the identified loci in independent disease-specific cohorts yielded no evidence for causal links between genetically determined caffeine intake and the development of CAD or T2DM. Conclusions Mendelian randomization analyses indicate genetically determined higher caffeine intake might not protect against CAD or T2DM, despite protective associations in observational analyses

Genetic insights into resting heart rate and its role in cardiovascular disease

Resting heart rate is associated with cardiovascular diseases and mortality in observational and Mendelian randomization studies. The aims of this study are to extend the number of resting heart rate associated genetic variants and to obtain further insights in resting heart rate biology and its clinical consequences. A genome-wide meta-analysis of 100 studies in up to 835,465 individuals reveals 493 independent genetic variants in 352 loci, including 68 genetic variants outside previously identified resting heart rate associated loci. We prioritize 670 genes and in silico annotations point to their enrichment in cardiomyocytes and provide insights in their ECG signature. Two-sample Mendelian randomization analyses indicate that higher genetically predicted resting heart rate increases risk of dilated cardiomyopathy, but decreases risk of developing atrial fibrillation, ischemic stroke, and cardio-embolic stroke. We do not find evidence for a linear or non-linear genetic association between resting heart rate and all-cause mortality in contrast to our previous Mendelian randomization study. Systematic alteration of key differences between the current and previous Mendelian randomization study indicates that the most likely cause of the discrepancy between these studies arises from false positive findings in previous one-sample MR analyses caused by weak-instrument bias at lower P-value thresholds. The results extend our understanding of resting heart rate biology and give additional insights in its role in cardiovascular disease development

Atrial fibrillation and left atrial size and function:a Mendelian randomization study

Atrial fibrillation (AF) patients have enlarged left atria (LA), but prior studies suggested enlarged atria as both cause and consequence of AF. The aim of this study is to investigate the causal association between AF and LA size and function. In the UK Biobank, all individuals with contoured cardiovascular magnetic resonance data were selected. LA maximal volume (LA max), LA minimal volume (LA min), LA stroke volume and LA ejection fraction were measured and indexed to body surface area (BSA). Two-sample Mendelian randomization analyses were performed using 84 of the known genetic variants associated with AF to assess the association with all LA size and function in individuals without prevalent AF. A total of 4274 individuals (mean age 62.0 ± 7.5 years, 53.2% women) were included. Mendelian randomization analyses estimated a causal effect between genetically determined AF and BSA-indexed LA max, LA min, and LA ejection fraction, but not between AF and LA stroke volume. Leave-one-out analyses showed that the causal associations were attenuated after exclusion of rs67249485, located near PITX2 gene. Our results suggest that AF causally increases LA size and decreases LA ejection fraction. The AF risk allele of rs67249485, located near the PITX2 gene, contributes strongly to these associations

Heart Rate Recovery 10 Seconds After Cessation of Exercise Predicts Death

BACKGROUND: Heart rate recovery (HRR) is commonly defined as the decrease of heart rate at 1 minute after cessation of exercise and is an important predictor of all-cause mortality and death associated with coronary artery disease. However, HRR at earlier time intervals after cessation has not been well evaluated and might better reflect PNS reactivation. We hypothesize that early HRR indices within the first minute is better associated with all-cause and coronary artery disease mortality compared with HRR at 1 minute. METHODS AND RESULTS: The prognostic value of HRR at 10, 20, 30, 40, and 50 seconds after cessation of exercise was investigated in 40 727 selected UK Biobank participants (mean age 56 years, 45% male) free from cardiovascular disease. During a median follow-up period of 6 years, 536 participants died (including 39 of coronary artery disease). In multivariable analyses, including adjustments for aerobic exercise capacity, cardiovascular risk factors, and factors associated with mortality in general, only HRR at 10 seconds remained predictive of both all-cause and coronary artery disease mortality. Effects of HRR were larger and more significant when measured early after exercise cessation. Moreover, the association of change in heart rate between 10 seconds and 1 minute after exercise cessation with mortality was dependent on HRR at 10 seconds. CONCLUSIONS: We provide evidence that decreased HRR at 10 seconds after cessation of exercise is a superior predictor of outcome compared with HRR at later time intervals. This observation might have important implications for the future reporting and interpretation of exercise tests

Genome-wide association studies and Mendelian randomization analyses for leisure sedentary behaviours

Leisure sedentary behaviours are associated with increased risk of cardiovascular disease, but whether this relationship is causal is unknown. The aim of this study is to identify genetic determinants associated with leisure sedentary behaviours and to estimate the potential causal effect on coronary artery disease (CAD). Genome wide association analyses of leisure television watching, leisure computer use and driving behaviour in the UK Biobank identify 145, 36 and 4 genetic loci (P < 1×10−8), respectively. High genetic correlations are observed between sedentary behaviours and neurological traits, including education and body mass index (BMI). Two-sample Mendelian randomization (MR) analysis estimates a causal effect between 1.5 hour increase in television watching and CAD (OR 1.44, 95%CI 1.25–1.66, P = 5.63 × 10−07), that is partially independent of education and BMI in multivariable MR analyses. This study finds independent observational and genetic support for the hypothesis that increased sedentary behaviour by leisure television watching is a risk factor for CAD

The Groningen electrocardiographic criteria for left ventricular hypertrophy:a sex-specific analysis

The sensitivity of electrocardiogram (ECG) criteria to detect left ventricular hypertrophy (LVH) is low, especially in women. We determined sex-specific sensitivities of ECG-LVH criteria, and developed new criteria, using cardiovascular magnetic resonance imaging (CMR). Sensitivities of ECG-LVH criteria were determined in participants of the UK Biobank (N = 3632). LVH was defined when left ventricular mass was > 95% confidence interval (CI) according to age and sex. In a training cohort (75%, N = 2724), sex-specific ECG-LVH criteria were developed by investigating all possible sums of QRS-amplitudes in all 12 leads, and selecting the sum with the highest pseudo-R2 and area under the curve to detect LVH. Performance was assessed in a validation cohort (25%, N = 908), and association with blood pressure change was investigated in an independent cohort. Sensitivities of ECG-LVH criteria were low, especially in women. Newly developed Groningen-LVH criterion for women (QV2 + RI + RV5 + RV6 + SV2 + SV4 + SV5 + SV6) outperformed all ECG-LVH criteria with a sensitivity of 42% (95% CI 35-49%). In men, newly developed criterion ((RI + RV5 + SII + SV2 + SV6) × QRS duration) was equally sensitive as 12-lead sum with a sensitivity of 44% (95% CI 37-51%) and outperformed the other criteria. In an independent cohort, the Groningen-LVH criteria were strongest associated with change in systolic blood pressure. Our proposed CMR sex-specific Groningen-LVH criteria improve the sensitivity to detect LVH, especially in women. Further validation and its association with clinical outcomes is warranted

Human genetic determinants of the gut microbiome and their associations with health and disease:a phenome-wide association study

Small-scale studies have suggested a link between the human gut microbiome and highly prevalent diseases. However, the extent to which the human gut microbiome can be considered a determinant of disease and healthy aging remains unknown. We aimed to determine the spectrum of diseases that are linked to the human gut microbiome through the utilization of its genetic determinants as a proxy for its composition. 180 single nucleotide polymorphisms (SNPs) known to influence the human gut microbiome were used to assess the association with health and disease outcomes in 422,417 UK Biobank participants. Potential causal estimates were obtained using a Mendelian randomization (MR) approach. From the total sample analysed (mean age was 57 ± 8 years), 194,567 (46%) subjects were male. Median exposure was 66-person years (interquartile range 59–72). Eleven SNPs were significantly associated with 28 outcomes (Bonferroni corrected P value < 4.63·10−6) including food intake, hypertension, atopy, COPD, BMI, and lipids. Multiple SNP MR pointed to a possible causal link between Ruminococcus flavefaciens and hypertension, and Clostridium and platelet count. Microbiota and their metabolites might be of importance in the interplay between overlapping pathophysiological processes, although challenges remain in establishing causal relationships

Twenty-Five Novel Loci for Carotid Intima-Media Thickness:A Genome-Wide Association Study in &gt;45 000 Individuals and Meta-Analysis of &gt;100 000 Individuals

OBJECTIVE: Carotid artery intima-media thickness (cIMT) is a widely accepted marker of subclinical atherosclerosis. Twenty susceptibility loci for cIMT were previously identified and the identification of additional susceptibility loci furthers our knowledge on the genetic architecture underlying atherosclerosis. Approach and Results: We performed 3 genome-wide association studies in 45 185 participants from the UK Biobank study who underwent cIMT measurements and had data on minimum, mean, and maximum thickness. We replicated 15 known loci and identified 20 novel loci associated with cIMT at P100 000 individuals identified 25 novel loci associated with cIMT providing insights into genes and tissue-specific regulatory mechanisms of proatherosclerotic processes. We found evidence for shared biological mechanisms with cardiovascular diseases