Genomic and phenotypic insights from an atlas of genetic effects on DNA methylation

DNA methylation quantitative trait locus (mQTL) analyses on 32,851 participants identify genetic variants associated with DNA methylation at 420,509 sites in blood, resulting in a database of >270,000 independent mQTLs.Characterizing genetic influences on DNA methylation (DNAm) provides an opportunity to understand mechanisms underpinning gene regulation and disease. In the present study, we describe results of DNAm quantitative trait locus (mQTL) analyses on 32,851 participants, identifying genetic variants associated with DNAm at 420,509 DNAm sites in blood. We present a database of >270,000 independent mQTLs, of which 8.5% comprise long-range (trans) associations. Identified mQTL associations explain 15-17% of the additive genetic variance of DNAm. We show that the genetic architecture of DNAm levels is highly polygenic. Using shared genetic control between distal DNAm sites, we constructed networks, identifying 405 discrete genomic communities enriched for genomic annotations and complex traits. Shared genetic variants are associated with both DNAm levels and complex diseases, but only in a minority of cases do these associations reflect causal relationships from DNAm to trait or vice versa, indicating a more complex genotype-phenotype map than previously anticipated.Molecular Epidemiolog

Association of Forced Vital Capacity with the Developmental Gene NCOR2

Background Forced Vital Capacity (FVC) is an important predictor of all-cause mortality in the absence of chronic respiratory conditions. Epidemiological evidence highlights the role of early life factors on adult FVC, pointing to environmental exposures and genes affecting lung development as risk factors for low FVC later in life. Although highly heritable, a small number of genes have been found associated with FVC, and we aimed at identifying further genetic variants by focusing on lung development genes. Methods Per-allele effects of 24,728 SNPs in 403 genes involved in lung development were tested in 7,749 adults from three studies (NFBC1966, ECRHS, EGEA). The most significant SNP for the top 25 genes was followed-up in 46,103 adults (CHARGE and SpiroMeta consortia) and 5,062 children (ALSPAC). Associations were considered replicated if the replication p-value survived Bonferroni correction (p<0.002; 0.05/25), with a nominal p-value considered as suggestive evidence. For SNPs with evidence of replication, effects on the expression levels of nearby genes in lung tissue were tested in 1,111 lung samples (Lung eQTL consortium), with further functional investigation performed using public epigenomic profiling data (ENCODE). Results NCOR2-rs12708369 showed strong replication in children (p = 0.0002), with replication unavailable in adults due to low imputation quality. This intronic variant is in a strong transcriptional enhancer element in lung fibroblasts, but its eQTL effects could not be tested due to low imputation quality in the eQTL dataset. SERPINE2-rs6754561 replicated at nominal level in both adults (p = 0.036) and children (p = 0.045), while WNT16-rs2707469 replicated at nominal level only in adults (p = 0.026). The eQTL analyses showed association of WNT16-rs2707469 with expression levels of the nearby gene CPED1.We found no statistically significant eQTL effects for SERPINE2-rs6754561. Conclusions We have identified a new gene, NCOR2, in the retinoic acid signalling pathway pointing to a role of Vitamin A metabolism in the regulation of FVC. Our findings also support SERPINE2, a COPD gene with weak previous evidence of association with FVC, and suggest WNT16 as a further promising candidate

Hydraulic analog for simultaneous representation of pharmacokinetics and pharmacodynamics: application to vecuronium

Objective. To facilitate teaching the pharmacologic determinants of clinically observed drug effect, we expand on the hydraulic representation of the pharmacokinetics and pharmacodynamics of intravenous drugs. Introduction. There are two significant barriers to understanding the pharmacological determinants underlying clinically observed drug responses. The first obstacle is the mathematical nature of traditional descriptions of these phenomena; the second barrier to understanding is that most educational texts focus solely on pharmacokinetics. However, pharmacokinetics alone do not explain the action at the effect site. The scientific and educational literature has used analogs of pharmacokinetic phenomena to make the concepts more intuitive. This manuscript extends the use of a hydraulic analog to include the effect site, allowing a simultaneous representation of pharmacokinetics and pharmacodynamics. Methods. In the described hydraulic analog, fluid delivered into a central reservoir is representative of drug infusion, and the heights of the fluid columns in the central and peripheral reservoirs are representative of the drug concentrations in the corresponding pharmacologic compartments. The height of the fluid column in an ‘effect reservoir’ is representative of the apparent effect site concentration in a simultaneous pharmacokinetic-pharmacodynamic model. A non-linear scale on the effect reservoir represents the relationship between the effect site concentration and the clinical effect. Reservoir surface areas are equivalent to volumes of distribution and hydraulic resistances are inversely proportional to drug clearances. The proof of mathematical equivalency of the presented analog to simultaneous pharmacokinetic-pharmacodynamic models is given in an appendix. Illustration of the educational application. The effect window can represent monitored twitch response following the administration of a neuromuscular blocking agent. Using pharmacokinetic-pharmacodynamic parameter values for vecuronium, we demonstrate how the hydraulic analog can be used to explain the priming principle and the clinically observed time-course disparity of two effect sites: the larynx and the adductor pollicis

Mathematically equivalent hydraulic analogue for teaching the pharmcokinetics and pharmacodynamics of atracurium

We evaluated the mathematical equivalence between the two-compartment pharmacokinetic model of the neuromuscular blocking agent atracurium and a hydraulic analogue that includes harmacodynamic principles

Mathematically equivalent hydraulic analogue for teaching the pharmcokinetics and pharmacodynamics of atracurium

We evaluated the mathematical equivalence between the two-compartment pharmacokinetic model of the neuromuscular blocking agent atracurium and a hydraulic analogue that includes harmacodynamic principles

Pharmocokinetic-pharmacodynamic model for educational simulations

Pharmacokinetic-pharmacodynamic (PK-PD) models play an important role in educational simulations. The parameters of PK-PD models described in the scientific literature are obtained from studies in which the drug concentrations and the drug-effect data are measured simultaneously. Simultaneous PK-PD studies cannot be expected to incorporate all possible combinations of drugs and patient physiology that are desired for educational simulations. To solve this problem, the authors elaborate on the traditional simultaneous PK-PD model, creating a new model that accepts parameter data from different, more readily available, nonsimultaneous pharmacologic studies. These data are incorporated in the model using a novel estimation procedure for the parameters k/sub e0/ and EC/sub 50/. A sensitivity analysis of the parameter estimation procedure confirms that the time of peak effect following a bolus and the dose-response curve are accurately reflected by the new model. It also demonstrates how inconsistencies among the different parameter sets affect simulation of the recovery phase. The model is extended to incorporate any monotonic parametric or nonparametric dose-response curve. For the neuromuscular relaxant vecuronium, the authors demonstrate that data from different pharmacologic studies are available, and that the described estimation procedure leads to parameter estimates that are within the standard deviations of the parameters determined in a simultaneous PK-PD study

A simulator for training off-pump coronary bypass surgery

Background Coronary artery disease, due to stenosis in the coronary arteries, is the most common cause of death globally. A remedy is coronary artery bypass graft (CABG) surgery, executed over 10.000 times per year in the Netherlands. CABG can be done on a beating heart, without a cardiopulmonary bypass machine, and is then called off-pump CABG (OPCAB). An advantage of OPCAB is avoiding manipulation of the aorta, reducing the likelihood of stroke compared to on-pump CABG. Unfortunately, OPCAB is a complex surgical intervention. A large number of interventions is required to achieve proficiency and represents a steep learning curve. In the first interventions there is a high probability of conversion to on-pump CABG with associated complications such as myocardial infarction and kidney failure. Currently, only a few low-fidelity simulators for this procedure are available, meaning that most of the learning takes place on real patients. A shortcoming of available simulators is lack of realistic hemodynamic behaviour. Aim The aim of this study is to develop a realistic OPCAB simulator to shorten the learning curve of surgeons and limit the number of OPCAB to CABG conversions, unstable hemodynamics, and early mortality. Method Training needs of cardiothoracic surgeons will be identified via a questionnaire. Several critical case scenarios will be described. Then a simulation-based training program will be outlined, and simulator specifications will be set to improve our first prototype simulator (Figure 1). Surgeons will practice with this prototype, and give feedback to improve the prototype