Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction

The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N=293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5% to 62.6%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease. On the electrocardiogram, the PR interval reflects conduction from the atria to ventricles and also serves as risk indicator of cardiovascular morbidity and mortality. Here, the authors perform genome-wide meta-analyses for PR interval in multiple ancestries and identify 141 previously unreported genetic loci.Peer reviewe

Erratum to: 36th International Symposium on Intensive Care and Emergency Medicine

[This corrects the article DOI: 10.1186/s13054-016-1208-6.]

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

From genome to genotype : regulation of the genome in glioblastoma multiforme and atrial fibrillation

The modern era of genomics has made sequencing a genome nearly routine. Genomics has amassed huge amounts of somatic and disease mutation data, as a result, the character sequence of the human genome has been extensively studied. This information is having an impact on the standard of care in the clinical sphere, with an increasing number of patients and clinicians turning to sequencing data as a determinant of treatment regimen. Knowledge of human protein coding genes and gene expression patterns is extensive, though not absolute. Venturing outside the relatively well-defined protein-coding regions of the genome, much is undetermined. Genome wide association studies (GWAS) have identified many genetic polymorphisms in non-coding regions on the genome that contribute to disease risk. Understanding the mechanisms by which a non-coding polymorphism can cause a phenotype demands an understanding of the physical organization and structure of chromatin in the eukaryotic nucleus. Gene expression data from primary gliolbastoma multiforme tumors (GBM) has uncovered the existence of four molecular subtypes, which affects prognosis and response to treatment. With the goal of gaining an understanding of transcriptional regulation in brain cancer, we profiled post-translational modifications of histone H3 in primary GBM tumors using ChIP-seq, and profiled gene expression in these tumors as well. We used a hidden Markov Model approach to abstract common co-occurrences of histone modifications into chromatin states. We were able to identify signatures consistent with known chromatin regulatory motifs, such as enhancers, and a bivalent state, marked by an active and repressive histone modification. These states regulated expression in a subtype-specific manner, with the proneural subtype showing a protective signature, and the mesenchymal and classical subtypes presenting a signature of invasive cellular migration and angiogenesis. The bivalent and enhancer states controlled a gene expression signature strongly suggestive of glioma stem cells (GSCs), the cells thought to be self-renewing in GBM. As part of profiling gene expression in primary GBMs, we performed RNA-sequencing in primary normal human astrocytes and six GBM-derived commercially available cell lines. We identified widespread differences in expression between tumors and cell lines, as well as a gene interaction network that is common to tumors and cell lines, dominated by chromatin remodelers and Rho guanine exchange factors. Finally, in a pilot study of 400 patients with atrial fibrillation (AF), we identified several SNPs associated with probability of success of cardiac ablation, a surgical therapy for AF. We propose that examining the local topology between a SNP of interest and any long-range contacts will help identify regulatory regions that allow a non-coding SNP to have an effect on gene expression, and thus phenotypePharmaceutical Science

The Willard-Perkins Plot: Men of Renown, Woman of Power

Report prepared as part of the coursework required for REL 167, Speaking Stones.Description and interpretation of the monument to Marie L. Atkinson Willard (1864-1940), her first husband Henry Hubble Perkins (1861-1894), and her second husband, Ernest Russell Willard (1854-1937). Includes information on their lives and philanthropic works

Chromatin state model for epigenetic marks in GBM tumors

Chromatin state model based on CTCF transcription factor marks and H3K27Ac, H3K27Me3, H3K4Me1, H3K4Me3, H3K9Ac, and H3K9Me3 histone modifications in 11 primary GBM tumors, produced by ChromHMM from binarized significant ChIP-seq peaks. See Methods section of doi:10.1158/0008-5472.CAN-17-1724 for more information