Showing papers by "Christopher J. O'Donnell published in 2021"

Actionable druggable genome-wide Mendelian randomization identifies repurposing opportunities for COVID-19.

Abstract: Drug repurposing provides a rapid approach to meet the urgent need for therapeutics to address COVID-19. To identify therapeutic targets relevant to COVID-19, we conducted Mendelian randomization analyses, deriving genetic instruments based on transcriptomic and proteomic data for 1,263 actionable proteins that are targeted by approved drugs or in clinical phase of drug development. Using summary statistics from the Host Genetics Initiative and the Million Veteran Program, we studied 7,554 patients hospitalized with COVID-19 and >1 million controls. We found significant Mendelian randomization results for three proteins (ACE2, P = 1.6 × 10-6; IFNAR2, P = 9.8 × 10-11 and IL-10RB, P = 2.3 × 10-14) using cis-expression quantitative trait loci genetic instruments that also had strong evidence for colocalization with COVID-19 hospitalization. To disentangle the shared expression quantitative trait loci signal for IL10RB and IFNAR2, we conducted phenome-wide association scans and pathway enrichment analysis, which suggested that IFNAR2 is more likely to play a role in COVID-19 hospitalization. Our findings prioritize trials of drugs targeting IFNAR2 and ACE2 for early management of COVID-19.

Discovery and prioritization of variants and genes for kidney function in >1.2 million individuals.

Abstract: Genes underneath signals from genome-wide association studies (GWAS) for kidney function are promising targets for functional studies, but prioritizing variants and genes is challenging. By GWAS meta-analysis for creatinine-based estimated glomerular filtration rate (eGFR) from the Chronic Kidney Disease Genetics Consortium and UK Biobank (n = 1,201,909), we expand the number of eGFRcrea loci (424 loci, 201 novel; 9.8% eGFRcrea variance explained by 634 independent signal variants). Our increased sample size in fine-mapping (n = 1,004,040, European) more than doubles the number of signals with resolved fine-mapping (99% credible sets down to 1 variant for 44 signals, ≤5 variants for 138 signals). Cystatin-based eGFR and/or blood urea nitrogen association support 348 loci (n = 460,826 and 852,678, respectively). Our customizable tool for Gene PrioritiSation reveals 23 compelling genes including mechanistic insights and enables navigation through genes and variants likely relevant for kidney function in human to help select targets for experimental follow-up. Identifying causal variants and genes in genome-wide association studies remains a challenge, an issue that is ameliorated with larger sample sizes. Here the authors meta-analyze kidney function genome-wide association studies to identify new loci and fine-map loci to home in on variants and genes involved in kidney function.

Posttraumatic Stress Disorder and Cardiovascular Disease: State of the Science, Knowledge Gaps, and Research Opportunities

Abstract: Posttraumatic stress disorder (PTSD) is characterized by a persistent maladaptive reaction after exposure to severe psychological trauma. Traumatic events that may precipitate PTSD include violent personal assaults, natural and human-made disasters, and exposure to military combat or warfare. There is a growing body of evidence for associations of PTSD with major risk factors for cardiovascular disease (CVD), such as hypertension and diabetes, as well as with major CVD outcomes, such as myocardial infarction and heart failure. However, it is unclear whether these associations are causal or confounded. Furthermore, the biological and behavioral mechanisms underlying these associations are poorly understood. Here, the available evidence on the association of PTSD with CVD from population, basic, and genomic research as well as from clinical and translational research are reviewed, seeking to identify major research gaps, barriers, and opportunities in knowledge acquisition and technology as well as research tools to support and accelerate critical research for near-term and longer-term translational research directions. Large-scale, well-designed prospective studies, capturing diverse and high-risk populations, are warranted that include uniform phenotyping of PTSD as well as broad assessment of biological and behavioral risk factors and CVD outcomes. Available evidence from functional brain imaging studies demonstrates that PTSD pathophysiology includes changes in specific anatomical brain regions and circuits, and studies of immune system function in individuals with PTSD suggest its association with enhanced immune inflammatory activity. However, establishment of animal models and human tissue biobanks is also warranted to elucidate the potential causal connection of PTSD-induced brain changes and/or inflammation with CVD pathophysiology. Emerging large-scale genome-wide association studies of PTSD will provide an opportunity to conduct mendelian randomization studies that test hypotheses regarding the presence, magnitude, and direction of causal associations between PTSD and CVD outcomes. By identifying research gaps in epidemiology and genomics, animal, and human translational research, opportunities to better justify and design future interventional trials are highlighted that may test whether treatment of PTSD or underlying neurobiological or immune dysregulation may improve or prevent CVD risk or outcomes.

Genetic analysis in European ancestry individuals identifies 517 loci associated with liver enzymes

Abstract: Serum concentration of hepatic enzymes are linked to liver dysfunction, metabolic and cardiovascular diseases. We perform genetic analysis on serum levels of alanine transaminase (ALT), alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT) using data on 437,438 UK Biobank participants. Replication in 315,572 individuals from European descent from the Million Veteran Program, Rotterdam Study and Lifeline study confirms 517 liver enzyme SNPs. Genetic risk score analysis using the identified SNPs is strongly associated with serum activity of liver enzymes in two independent European descent studies (The Airwave Health Monitoring study and the Northern Finland Birth Cohort 1966). Gene-set enrichment analysis using the identified SNPs highlights involvement in liver development and function, lipid metabolism, insulin resistance, and vascular formation. Mendelian randomization analysis shows association of liver enzyme variants with coronary heart disease and ischemic stroke. Genetic risk score for elevated serum activity of liver enzymes is associated with higher fat percentage of body, trunk, and liver and body mass index. Our study highlights the role of molecular pathways regulated by the liver in metabolic disorders and cardiovascular disease.

Cholesteryl ester transfer protein (CETP) as a drug target for cardiovascular disease

Abstract: Development of cholesteryl ester transfer protein (CETP) inhibitors for coronary heart disease (CHD) has yet to deliver licensed medicines. To distinguish compound from drug target failure, we compared evidence from clinical trials and drug target Mendelian randomization of CETP protein concentration, comparing this to Mendelian randomization of proprotein convertase subtilisin/kexin type 9 (PCSK9). We show that previous failures of CETP inhibitors are likely compound related, as illustrated by significant degrees of between-compound heterogeneity in effects on lipids, blood pressure, and clinical outcomes observed in trials. On-target CETP inhibition, assessed through Mendelian randomization, is expected to reduce the risk of CHD, heart failure, diabetes, and chronic kidney disease, while increasing the risk of age-related macular degeneration. In contrast, lower PCSK9 concentration is anticipated to decrease the risk of CHD, heart failure, atrial fibrillation, chronic kidney disease, multiple sclerosis, and stroke, while potentially increasing the risk of Alzheimer’s disease and asthma. Due to distinct effects on lipoprotein metabolite profiles, joint inhibition of CETP and PCSK9 may provide added benefit. In conclusion, we provide genetic evidence that CETP is an effective target for CHD prevention but with a potential on-target adverse effect on age-related macular degeneration. Despite being studied in clinical trials, CETP inhibitors are not yet an approved treatment for coronary heart disease. Here, by analyzing results from clinical trials and drug target mendelian randomization studies, the authors demonstrate that previous failure of CETP inhibitors are likely compound and not drug target-related.

Genetics of Smoking and Risk of Atherosclerotic Cardiovascular Diseases: A Mendelian Randomization Study.

Abstract: Importance Smoking is associated with atherosclerotic cardiovascular disease, but the relative contribution to each subtype (coronary artery disease [CAD], peripheral artery disease [PAD], and large-artery stroke) remains less well understood. Objective To determine the association between genetic liability to smoking and risk of CAD, PAD, and large-artery stroke. Design, Setting, and Participants Mendelian randomization study using summary statistics from genome-wide associations of smoking (UK Biobank; up to 462 690 individuals), CAD (Coronary Artery Disease Genome Wide Replication and Meta-analysis plus the Coronary Artery Disease Genetics Consortium; up to 60 801 cases, 123 504 controls), PAD (VA Million Veteran Program; up to 24 009 cases, 150 983 controls), and large-artery stroke (MEGASTROKE; up to 4373 cases, 406 111 controls). This study was conducted using summary statistic data from large, previously described cohorts. Review of those publications does not reveal the total recruitment dates for those cohorts. Data analyses were conducted from August 2019 to June 2020. Exposures Genetic liability to smoking (as proxied by genetic variants associated with lifetime smoking index). Main Outcomes and Measures Risk (odds ratios [ORs]) of CAD, PAD, and large-artery stroke. Results Genetic liability to smoking was associated with increased risk of PAD (OR, 2.13; 95% CI, 1.78-2.56;P = 3.6 × 10−16), CAD (OR, 1.48; 95% CI, 1.25-1.75;P = 4.4 × 10−6), and stroke (OR, 1.40; 95% CI, 1.02-1.92;P = .04). Genetic liability to smoking was associated with greater risk of PAD than risk of large-artery stroke (ratio of ORs, 1.52; 95% CI, 1.05-2.19;P = .02) or CAD (ratio of ORs, 1.44; 95% CI, 1.12-1.84;P = .004). The association between genetic liability to smoking and atherosclerotic cardiovascular diseases remained independent from the effects of smoking on traditional cardiovascular risk factors. Conclusions and Relevance In this mendelian randomization analysis of data from large studies of atherosclerotic cardiovascular diseases, genetic liability to smoking was a strong risk factor for CAD, PAD, and stroke, although the estimated association was strongest between smoking and PAD. The association between smoking and atherosclerotic cardiovascular disease was independent of traditional cardiovascular risk factors.

A genome-wide association study for nonalcoholic fatty liver disease identifies novel genetic loci and trait-relevant candidate genes in the Million Veteran Program

Abstract: Nonalcoholic fatty liver disease (NAFLD) is a prevalent, heritable trait that can progress to cancer and liver failure. Using our recently developed proxy definition for NAFLD based on chronic liver enzyme elevation without other causes of liver disease or alcohol misuse, we performed a multi-ancestry genome-wide association study in the Million Veteran Program with 90,408 NAFLD cases and 128,187 controls. Seventy-seven loci exceeded genome-wide significance of which 70 were novel, with an additional European-American specific and two African-American specific loci. Twelve of these loci were also significantly associated with quantitative hepatic fat on radiological imaging (n=44,289). Gene prioritization based on coding annotations, gene expression from GTEx, and functional genomic annotation identified candidate genes at 97% of loci. At eight loci, the allele associated with lower gene expression in liver was also associated with reduced risk of NAFLD, suggesting potential therapeutic relevance. Functional genomic annotation and gene-set enrichment demonstrated that associated loci were relevant to liver biology. We expand the catalog of genes influencing NAFLD, and provide a novel resource to understand its disease initiation, progression and therapy.

Plasma Protein Profile of Carotid Artery Atherosclerosis and Atherosclerotic Outcomes: Meta-Analyses and Mendelian Randomization Analyses.

Abstract: OBJECTIVE: To identify causal pathophysiological mechanisms for atherosclerosis and incident cardiovascular events using protein measurements. Approach and Results: Carotid artery atherosclerosis was assessed by ultrasound, and 86 cardiovascular-related proteins were measured using the Olink CVD-I panel in 7 Swedish prospective studies (11 754 individuals). The proteins were analyzed in relation to intima-media thickness in the common carotid artery (IMT-CCA), plaque occurrence, and incident cardiovascular events (composite end point of myocardial infarction or ischemic stroke) using a discovery/replication approach in different studies. After adjustments for traditional cardiovascular risk factors, 11 proteins remained significantly associated with IMT-CCA in the replication stage, whereas 9 proteins were replicated for plaque occurrence and 17 proteins for incident cardiovascular events. NT-proBNP (N-terminal pro-B-type natriuretic peptide) and MMP (matrix metalloproteinase)-12 were associated with both IMT-CCA and incident events, but the overlap was considerably larger between plaque occurrence and incident events, including MMP-12, TIM-1 (T-cell immunoglobulin and mucin domain 1), GDF (growth/differentiation factor)-15, IL (interleukin)-6, U-PAR (urokinase plasminogen activator surface receptor), LOX-1 (lectin-like oxidized LDL [low-density lipoprotein] receptor 1), and TRAIL-R2 (TNF [tumor necrosis factor]-related apoptosis-inducing ligand receptor 2). Only MMP-12 was associated with IMT-CCA, plaque, and incident events with a positive and concordant direction of effect. However, a 2-sample Mendelian randomization analysis suggested that increased MMP-12 may be protective against ischemic stroke (P=5.5×10-7), which is in the opposite direction of the observational analyses.CONCLUSIONS: The present meta-analysis discovered several proteins related to carotid atherosclerosis that partly differed in their association with IMT-CCA, plaque, and incident atherosclerotic disease. Mendelian randomization analysis for the top finding, MMP-12, suggests that the increased levels of MMP-12 could be a consequence of atherosclerotic burden rather than the opposite chain of events. (Less)

A trans-ancestry genome-wide association study of unexplained chronic ALT elevation as a proxy for nonalcoholic fatty liver disease with histological and radiological validation

Abstract: Nonalcoholic fatty liver disease (NAFLD) is a growing cause of chronic liver disease. Using a proxy NAFLD definition of chronic alanine aminotransferase elevation (cALT) without other liver diseases, we performed a trans-ancestry genome-wide association study in the Million Veteran Program including 90,408 cALT cases and 128,187 controls. In the Discovery stage, seventy-seven loci exceeded genome-wide significance – including 25 without prior NAFLD or ALT associations – with one additional locus identified in European-American-only and two in African-American-only analyses (P

Phenome-wide association of 1809 phenotypes and COVID-19 disease progression in the Veterans Health Administration Million Veteran Program.

Abstract: BACKGROUND: The risk factors associated with the stages of Coronavirus Disease-2019 (COVID-19) disease progression are not well known. We aim to identify risk factors specific to each state of COVID-19 progression from SARS-CoV-2 infection through death. METHODS AND RESULTS: We included 648,202 participants from the Veteran Affairs Million Veteran Program (2011-). We identified characteristics and 1,809 ICD code-based phenotypes from the electronic health record. We used logistic regression to examine the association of age, sex, body mass index (BMI), race, and prevalent phenotypes to the stages of COVID-19 disease progression: infection, hospitalization, intensive care unit (ICU) admission, and 30-day mortality (separate models for each). Models were adjusted for age, sex, race, ethnicity, number of visit months and ICD codes, state infection rate and controlled for multiple testing using false discovery rate (≤0.1). As of August 10, 2020, 5,929 individuals were SARS-CoV-2 positive and among those, 1,463 (25%) were hospitalized, 579 (10%) were in ICU, and 398 (7%) died. We observed a lower risk in women vs. men for ICU and mortality (Odds Ratio (95% CI): 0.48 (0.30-0.76) and 0.59 (0.31-1.15), respectively) and a higher risk in Black vs. Other race patients for hospitalization and ICU (OR (95%CI): 1.53 (1.32-1.77) and 1.63 (1.32-2.02), respectively). We observed an increased risk of all COVID-19 disease states with older age and BMI ≥35 vs. 20-24 kg/m2. Renal failure, respiratory failure, morbid obesity, acid-base balance disorder, white blood cell diseases, hydronephrosis and bacterial infections were associated with an increased risk of ICU admissions; sepsis, chronic skin ulcers, acid-base balance disorder and acidosis were associated with mortality. CONCLUSIONS: Older age, higher BMI, males and patients with a history of respiratory, kidney, bacterial or metabolic comorbidities experienced greater COVID-19 severity. Future studies to investigate the underlying mechanisms associated with these phenotype clusters and COVID-19 are warranted.

Allele-specific variation at APOE increases nonalcoholic fatty liver disease and obesity but decreases risk of Alzheimer’s disease and myocardial infarction

Abstract: Nonalcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver disease and is highly correlated with metabolic disease. NAFLD results from environmental exposures acting on a susceptible polygenic background. This study performed the largest multiethnic investigation of exonic variation associated with NAFLD and correlated metabolic traits and diseases. An exome array meta-analysis was carried out among eight multiethnic population-based cohorts (n = 16 492) with computed tomography (CT) measured hepatic steatosis. A fixed effects meta-analysis identified five exome-wide significant loci (P < 5.30 × 10-7); including a novel signal near TOMM40/APOE. Joint analysis of TOMM40/APOE variants revealed the TOMM40 signal was attributed to APOE rs429358-T; APOE rs7412 was not associated with liver attenuation. Moreover, rs429358-T was associated with higher serum alanine aminotransferase, liver steatosis, cirrhosis, triglycerides and obesity; as well as, lower cholesterol and decreased risk of myocardial infarction and Alzheimer's disease (AD) in phenome-wide association analyses in the Michigan Genomics Initiative, United Kingdom Biobank and/or public datasets. These results implicate APOE in imaging-based identification of NAFLD. This association may or may not translate to nonalcoholic steatohepatitis; however, these results indicate a significant association with advanced liver disease and hepatic cirrhosis. These findings highlight allelic heterogeneity at the APOE locus and demonstrate an inverse link between NAFLD and AD at the exome level in the largest analysis to date.

A noncoding variant near PPP1R3B promotes liver glycogen storage and MetS, but protects against myocardial infarction

Abstract: Context: Glycogen storage diseases are rare. Increased glycogen in the liver results in increased attenuation. Objective: Investigate the association and function of a noncoding region associated with liver attenuation but not histologic nonalcoholic fatty liver disease. Design: Genetics of Obesity-associated Liver Disease Consortium. Setting: Population-based. Main Outcome: Computed tomography measured liver attenuation. Results: Carriers of rs4841132-A (frequency 2%-19%) do not show increased hepatic steatosis; they have increased liver attenuation indicative of increased glycogen deposition. rs4841132 falls in a noncoding RNA LOC157273 ~190 kb upstream of PPP1R3B. We demonstrate that rs4841132-A increases PPP1R3B through a cis genetic effect. Using CRISPR/Cas9 we engineered a 105-bp deletion including rs4841132-A in human hepatocarcinoma cells that increases PPP1R3B, decreases LOC157273, and increases glycogen perfectly mirroring the human disease. Overexpression of PPP1R3B or knockdown of LOC157273 increased glycogen but did not result in decreased LOC157273 or increased PPP1R3B, respectively, suggesting that the effects may not all occur via affecting RNA levels. Based on electronic health record (EHR) data, rs4841132-A associates with all components of the metabolic syndrome (MetS). However, rs4841132-A associated with decreased low-density lipoprotein (LDL) cholesterol and risk for myocardial infarction (MI). A metabolic signature for rs4841132-A includes increased glycine, lactate, triglycerides, and decreased acetoacetate and beta-hydroxybutyrate. Conclusions: These results show that rs4841132-A promotes a hepatic glycogen storage disease by increasing PPP1R3B and decreasing LOC157273. rs4841132-A promotes glycogen accumulation and development of MetS but lowers LDL cholesterol and risk for MI. These results suggest that elevated hepatic glycogen is one cause of MetS that does not invariably promote MI.

Meta-analysis of epigenome-wide association studies of carotid intima-media thickness

Abstract: Common carotid intima-media thickness (cIMT) is an index of subclinical atherosclerosis that is associated with ischemic stroke and coronary artery disease (CAD). We undertook a cross-sectional epigenome-wide association study (EWAS) of measures of cIMT in 6400 individuals. Mendelian randomization analysis was applied to investigate the potential causal role of DNA methylation in the link between atherosclerotic cardiovascular risk factors and cIMT or clinical cardiovascular disease. The CpG site cg05575921 was associated with cIMT (beta = −0.0264, p value = 3.5 × 10–8) in the discovery panel and was replicated in replication panel (beta = −0.07, p value = 0.005). This CpG is located at chr5:81649347 in the intron 3 of the aryl hydrocarbon receptor repressor gene (AHRR). Our results indicate that DNA methylation at cg05575921 might be in the pathway between smoking, cIMT and stroke. Moreover, in a region-based analysis, 34 differentially methylated regions (DMRs) were identified of which a DMR upstream of ALOX12 showed the strongest association with cIMT (p value = 1.4 × 10–13). In conclusion, our study suggests that DNA methylation may play a role in the link between cardiovascular risk factors, cIMT and clinical cardiovascular disease.

Post-mortem CT lung findings at a medicolegal institute in SARS-CoV-2 RT-PCR positive cases with autopsy correlation.

Abstract: CoVID-19 is a novel viral infection with now well-established clinical radiological findings. There is limited data on post-mortem imaging. We explore the proposition that PMCT could be used as screening test. In an 11-week period, 39 deceased persons were referred for medicolegal investigation with pre-existing or subsequent nasopharyngeal swabs showing positivity on SARS-CoV-2 RT-PCR testing. All 39 had routine whole-body CT scans on admission and 12 underwent medicolegal autopsy. These cases were contrasted with 4 others which were negative on nasopharyngeal swabs despite PMCT findings suggestive of CoVID-19 pneumonia (designated false positive). Nine of the 12 autopsies showed lung histology consistent with those reported in CoVID-19 pneumonia. Typical clinical CoVID-19 lung findings on PMCT were only detected in 5 (42%). In 3 of the 4 false positive cases, lung findings showed non-COVID-19 histology but in 1, findings were identical. PMCT CoVID-19 findings in the lungs are therefore not specific and may not be detected in all cases due to obscuration by expected agonal CT findings or other pathologies that pre-dated SARS-CoV-2 infection. PMCT findings may otherwise be subtle. Although PMCT may hint at CoVID-19, we believe that nasopharyngeal swabs are still required for definitive diagnosis. Even with positive swabs, clinical CoVID-19 lung findings on PMCT are often not detected. PMCT findings can be subtle, extreme or obscured by agonal changes. Given this range of PMCT changes, the challenge for pathologists is to determine whether death has been caused by, or merely associated with, SARS-CoV-2 infection.

Matrix Gla Protein Levels Are Associated With Arterial Stiffness and Incident Heart Failure With Preserved Ejection Fraction.

Abstract: Objective: Arterial stiffness is a risk factor for cardiovascular disease, including heart failure with preserved ejection fraction. MGP (matrix Gla protein) is implicated in vascular calcification...

Genome-wide transcriptome study using deep RNA sequencing for myocardial infarction and coronary artery calcification.

Abstract: Coronary artery calcification (CAC) is a noninvasive measure of coronary atherosclerosis, the proximal pathophysiology underlying most cases of myocardial infarction (MI) We sought to identify expression signatures of early MI and subclinical atherosclerosis in the Framingham Heart Study (FHS) In this study, we conducted paired-end RNA sequencing on whole blood collected from 198 FHS participants (55 with a history of early MI, 72 with high CAC without prior MI, and 71 controls free of elevated CAC levels or history of MI) We applied DESeq2 to identify coding-genes and long intergenic noncoding RNAs (lincRNAs) differentially expressed in MI and high CAC, respectively, compared with the control On average, 150 million paired-end reads were obtained for each sample At the false discovery rate (FDR) < 01, we found 68 coding genes and 2 lincRNAs that were differentially expressed in early MI versus controls Among them, 60 coding genes were detectable and thus tested in an independent RNA-Seq data of 807 individuals from the Rotterdam Study, and 8 genes were supported by p value and direction of the effect Immune response, lipid metabolic process, and interferon regulatory factor were enriched in these 68 genes By contrast, only 3 coding genes and 1 lincRNA were differentially expressed in high CAC versus controls APOD, encoding a component of high-density lipoprotein, was significantly downregulated in both early MI (FDR = 0007) and high CAC (FDR = 001) compared with controls We identified transcriptomic signatures of early MI that include differentially expressed protein-coding genes and lincRNAs, suggesting important roles for protein-coding genes and lincRNAs in the pathogenesis of MI

Trends in cardiovascular procedural volumes in the setting of COVID-19: Insights from the VA clinical assessment, reporting, and tracking program.

Abstract: To the Editor: COVID-19 has resulted in significant changes in healthcare delivery throughout the world. To focus healthcare resources, organizations initially deferred non-urgent procedures under guidance from government organizations. Cardiovascular professional societies endorsed these recommendations, with a consensus document reiterating the importance of avoiding elective coronary procedures for stable ischemic heart disease. Patients with urgent or emergent cardiovascular conditions, such as acute coronary syndromes, were supposed to continue under standard practices. Preliminary reports have suggested that elective coronary procedures declined in line with these recommendations, with a similar unexpected decline in urgent procedures during the early phases of the pandemic. The trends in cases after healthcare facilities began to reopen for elective procedures have not yet been evaluated. With this in mind, we sought to evaluate the temporal changes in procedural volumes for percutaneous coronary intervention (PCI) since the onset of COVID-19 in the largest integrated healthcare system in the United States. To do so, we identified all patients that underwent PCI in the VA Healthcare System from March 1, 2020 to June 27, 2020, with a comparison to the same period in the prior year (March 3, 2019 to June 29, 2019) using data from the VA Clinical Assessment, Reporting and Tracking (CART) Program. The number of facilities providing percutaneous revascularization was the same across the entire study period. Procedural volumes were compared between the same weeks in 2019 and 2020 by evaluating the proportion of cases that were performed each year from the total number of cases with the null hypothesis assuming that they would be equal. Using Bonferroni methods to adjust for multiple comparisons, a p value <.0014 was considered statistically significant. Coronary intervention was performed in 3,859 patients during the time period under investigation in 2019 and 2,192 patients in 2020. The temporal trends in elective coronary intervention are demonstrated in Figure 1a. As shown, the weekly volume of elective coronary intervention was significantly lower (p < .001) than same values reported 1 year prior (2019) after the third week of investigation, corresponding to March 16, 2020, and persisted through June after many facilities had reinitiated normal operating procedures. The temporal trends in urgent or emergent coronary intervention for acute coronary syndromes are demonstrated in Figure 1b. As shown, the weekly volume of coronary intervention was significantly lower (p < .001) than same values reported 1 year prior (2019) after the third week of investigation, before increasing to similar levels at week 8, corresponding to April 20, 2020. The data demonstrate a decline in elective and urgent coronary interventions in a national healthcare system after the spread of COVID-19. The observed decrease in elective cases during the initial stages of the pandemic is consistent with professional society recommendations, wherein non-urgent procedures were deferred to reduce the utilization of healthcare resources. The persistent decrease in elective cases after many facilities began to return to normal operations may reflect non-urgent patients that continue to avoid visiting healthcare facilities to reduce their infectious risk. Urgent or emergent interventions for patients with acute coronary syndromes also transiently declined in the initial stages of the pandemic, consistent with prior reports demonstrating a decrease in catheterization laboratory activations for STEMI. After the eighth week of the crisis, though, the number of urgent or emergent cases for acute coronary syndromes returned to levels more consistent with historical norms. Interestingly, there was not a significant rebound of cases for acute coronary syndromes after the transient decline witnessed in the early stages of the pandemic. The long-term ramifications of this transient decline for the overall cardiovascular health of the population remains unknown. However, data demonstrating restoration of procedural volumes is encouraging in light of other studies demonstrating a decline in hospital admissions for acute indications. Regardless, ensuring that patients with acute coronary syndromes continue to have access to urgent or emergent revascularization is imperative, as we continue to grapple with the persistent effects of COVID-19. The present analysis should be interpreted in the context of several limitations. Data was derived from clinical documentation for care provided within the VA Healthcare System. Care provided to Veterans outside the integrated healthcare system was not incorporated into this analysis, given the significant time required for outside facilities to report clinical data back to the VA. The data presented are from a unique nationally integrated healthcare system with predominantly male patients, which may not reflect the heterogeneous patterns of care in the community. Received: 24 July 2020 Accepted: 2 August 2020

A MUC5B gene polymorphism, rs35705950-T, confers protective effects in COVID-19 infection

Abstract: Rationale A common MUC5B gene polymorphism, rs35705950-T, is associated with idiopathic pulmonary fibrosis, but its role in the SARS-CoV-2 infection and disease severity is unclear. Objectives To assess whether rs35705950-T confers differential risk for clinical outcomes associated with COVID-19 infection among participants in the Million Veteran Program (MVP) and COVID-19 Host Genetics Initiative (HGI). Methods MVP participants were examined for an association between the incidence or severity of COVID-19 and the presence of a MUC5B rs35705950-T allele. Comorbidities and clinical events were extracted from the electronic health records (EHR). The analysis was performed within each ancestry group in the MVP, adjusting for sex, age, age2, and first twenty principal components followed by a trans-ethnic meta-analysis. We then pursued replication and performed a meta-analysis with the trans-ethnic summary statistics from the HGI. A phenome-wide association study (PheWAS) of the rs35705950-T was conducted to explore associated pathophysiologic conditions. Measurements and Main Results A COVID-19 severity scale was modified from the World Health Organization criteria, and phenotypes derived from the International Classification of Disease-9/10 were extracted from EHR. Presence of rs35705950-T was associated with fewer hospitalizations (Ncases=25353, Ncontrols=631,024; OR=0.86 [0.80-0.93], p=7.4 × 10−5) in trans-ethnic meta-analysis within MVP and joint meta-analyses with the HGI (N=1641311; OR=0.89 [0.85-0.93], p =1.9 × 10−6). Moreover, individuals of European Ancestry with at least one copy of rs35705950-T had fewer post-COVID-19 pneumonia events (OR=0.85 [0.76-0.96], p =0.008). PheWAS exclusively revealed pulmonary involvement. Conclusions The MUC5B variant rs35705950-T is protective in COVID-19 infection.

Multi-trait GWAS of atherosclerosis detects novel pleiotropic loci

Abstract: Rationale Although affecting different arterial territories, the related atherosclerotic vascular diseases coronary artery disease (CAD) and peripheral artery disease (PAD) share similar risk factors and have shared pathobiology Analysis of their shared genetic architecture, along with that of common risk factors, may identify novel common biology Objective To identify novel pleiotropic genetic loci associated with atherosclerosis and provide a better understanding of biological pathways underlying atherosclerosis Methods and Results Summary statistics from genome wide association studies (GWAS) of nine known atherosclerotic (CAD, PAD) or atherosclerosis risk factors (body mass index, smoking initiation, type 2 diabetes, low density lipoprotein (LDL), high density lipoprotein, total cholesterol, and triglycerides) were combined to perform 15 separate multi-trait genetic association scans which resulted in 31 unique novel pleiotropic loci not yet reported as genome-wide significant for their respective traits Colocalization with single-tissue eQTLs identified 34 candidate causal genes across 14 of the detected signals Notably, the signal between PAD and CAD at the VDAC2 locus (rs7088974) colocalized with VDAC2 expression in aorta and tibial artery tissues Additionally, the signal between PAD and LDL at the PCSK6 locus (rs1531817) affects PCSK6 splicing in human liver tissue and induced pluripotent derived hepatocyte like cells Conclusions Joint analysis of related atherosclerotic disease traits and their risk factors allowed identification of unified biology that may offer the opportunity for therapeutic manipulation VDAC2 and PCSK6 represent possible shared causal biology where existing inhibitors may be able to be leveraged for novel therapies

Evaluation of height as a disease risk factor through a phenome-wide association study of genetically-predicted height

Abstract: Background Height has been associated with many clinical traits but whether such associations are causal versus secondary to confounding remains unclear in many cases. To systematically examine this question, we performed a Mendelian Randomization-Phenome-wide association study (MR-PheWAS) using clinical and genetic data from a national healthcare system biobank. Methods and Findings Analyses were performed using data from the US Veterans Affairs (VA) Million Veteran Program in non-Hispanic White (EA, n=222,300) and non-Hispanic Black (AA, n=58,151) adults in the US. We estimated height genetic risk based on 3290 height-associated variants from a recent European-ancestry genome-wide meta-analysis. We compared associations of measured and genetically-predicted height with phenome-wide traits derived from the VA electronic health record, adjusting for age, sex, and genetic principal components. We found 345 clinical traits associated with measured height in EA and an additional 17 in AA. Of these, 127 were associated with genetically-predicted height at phenome-wide significance in EA and 2 in AA. These associations were largely independent from body mass index. We confirmed several previously described MR associations between height and cardiovascular disease traits such as hypertension, hyperlipidemia, coronary heart disease (CHD), and atrial fibrillation, and further uncovered MR associations with venous circulatory disorders and peripheral neuropathy. As a number of traits associated with genetically-predicted height frequently co-occur with diabetes mellitus and/or CHD, we evaluated effect modification by diabetes and CHD status of genetically-predicted height associations with risk factors for and complications of diabetes and CHD. We found modification of effects of MR associations by diabetes for skin and bone infections and by CHD status for atrial fibrillation/flutter. Conclusions We conclude that height may be an unrecognized but biologically plausible risk factor for several common conditions in adults. However, more studies are needed to reliably exclude horizontal pleiotropy as a driving force behind at least some of the MR associations observed in this study.

Multiethnic Genome-wide Association Study of Subclinical Atherosclerosis in Individuals with Type 2 Diabetes

Abstract: Background: Coronary artery calcification (CAC) and carotid artery intima-media thickness (cIMT) are measures of subclinical atherosclerosis in asymptomatic individuals and strong risk factors for ...

Effect of Soil Moisture Regimes on the Glyphosate Sensitivity and Morpho-Physiological Traits of Windmill Grass (Chloris truncata R.Br.), Common Sowthistle (Sonchus oleraceus L.), and Flaxleaf Fleabane [Conyza bonariensis (L.) Cronq.].

Abstract: The glasshouse study was conducted with the objectives of (i) investigating the effect of soil moisture variations on the control efficiency of glyphosate on windmill grass (Chloris truncata R.Br.), common sowthistle (Sonchus oleraceus L.), and flaxleaf fleabane [Conyza bonariensis (L.) Cronq.], (ii) evaluating the tolerance of tested weed species under soil moisture variations, and (iii) determining the morphological and physiological characteristics of these species to partially explain herbicide tolerance under periods of reduced soil moisture availability (RSM). The species’ tolerance to glyphosate increased significantly under reduced soil moisture availability (p < 0.001). The lethal dose to cause herbicide injury or biomass reduction by 50% (LD50) and 80% (LD80) in relation to untreated control for water-stressed plants [i.e., moderate soil moisture availability (MSM) and RSM] was significantly higher than that of plants grown under high soil moisture availability (HSM). The tolerance factor (TF) for C. truncata, S. oleraceus, and C. bonariensis, in terms of biomass reduction under RSM, was 2.6, 2.4, and 2.6, respectively, as compared to HSM. The results showed that the glyphosate sensitivity, especially at the sub-lethal rates, of the three weed species under study decreased as soil moisture availability reduced (p< 0.01). Overall glyphosate efficacy, in relation to the recommended rate, was unaffected, except for C. truncata; the weed survived the highest tested glyphosate rate [750 g active ingredient (a.i.) ha−1] under RSM. There was significant interaction between weed species and soil moisture regimes for weed morpho-physiological traits (p < 0.001), with reduced soil moisture having a more influential impact on the growth of C. bonariensis and S. oleraceus compared to C. truncata. Changes in the leaf characteristics, such as increased leaf thickness, higher leaf chlorophyll content, reduced leaf area, and limited stomatal activity for all the tested weed species under MSM and RSM in relation to HSM, partially explain the tolerance of species to glyphosate at sublethal rates.