Publications by authors named "Philip S Tsao"

175 Publications

A Phenome-Wide Association Study of genes associated with COVID-19 severity reveals shared genetics with complex diseases in the Million Veteran Program.

medRxiv 2021 Oct 6. Epub 2021 Oct 6.

The study aims to determine the shared genetic architecture between COVID-19 severity with existing medical conditions using electronic health record (EHR) data. We conducted a Phenome-Wide Association Study (PheWAS) of genetic variants associated with critical illness (n=35) or hospitalization (n=42) due to severe COVID-19 using genome-wide association summary from the Host Genetics Initiative. PheWAS analysis was performed using genotype-phenotype data from the Veterans Affairs Million Veteran Program (MVP). Phenotypes were defined by International Classification of Diseases (ICD) codes mapped to clinically relevant groups using published PheWAS methods. Among 658,582 Veterans, variants associated with severe COVID-19 were tested for association across 1,559 phenotypes. Variants at the locus (rs495828, rs505922) associated with the largest number of phenotypes (n = 53 and n =59); strongest association with venous embolism, odds ratio (OR 1.33 (p=1.32 × 10 ), and thrombosis OR 1.33, p=2.2 x10 . Among 67 respiratory conditions tested, 11 had significant associations including locus (rs35705950) with increased risk of idiopathic fibrosing alveolitis OR 2.83, p=4.12 × 10 ; rs61667602) associated with reduced risk of pulmonary fibrosis, OR 0.84, p=2.26× 10 . The locus (rs11085727) associated with reduced risk for autoimmune conditions, e.g., psoriasis OR 0.88, p=6.48 x10 , lupus OR 0.84, p=3.97 × 10 . PheWAS stratified by genetic ancestry demonstrated differences in genotype-phenotype associations across ancestry. (rs581342) associated with neutropenia OR 1.29 p=4.1 × 10 among Veterans of African ancestry but not European. Overall, we observed shared genetic architecture between COVID-19 severity and conditions related to underlying risk factors for severe and poor COVID-19 outcomes. Differing associations between genotype-phenotype across ancestries may inform heterogenous outcomes observed with COVID-19. Divergent associations between risk for severe COVID-19 with autoimmune inflammatory conditions both respiratory and non-respiratory highlights the shared pathways and fine balance of immune host response and autoimmunity and caution required when considering treatment targets.
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http://dx.doi.org/10.1101/2021.05.18.21257396DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8509103PMC
October 2021

-Adventitial delivery of smooth muscle cells in porous collagen scaffolds for treatment of experimental abdominal aortic aneurysm.

Biomater Sci 2021 Oct 12;9(20):6903-6914. Epub 2021 Oct 12.

Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA.

Abdominal aortic aneurysm (AAA) is associated with the loss of vascular smooth muscle cells (SMCs) within the vessel wall. Direct delivery of therapeutic cells is challenging due to impaired mechanical integrity of the vessel wall. We hypothesized that porous collagen scaffolds can be an effective vehicle for the delivery of human-derived SMCs to the site of AAA. The purpose was to evaluate if the delivery of cell-seeded scaffolds can abrogate progressive expansion in a mouse model of AAA. Collagen scaffolds seeded with either primary human aortic SMCs or induced pluripotent stem cell derived-smooth muscle progenitor cells (iPSC-SMPs) had >80% cell viability and >75% cell penetrance through the scaffold's depth, while preserving smooth muscle phenotype. The cell-seeded scaffolds were successfully transplanted onto the murine aneurysm -adventitia on day 7 following AAA induction using pancreatic porcine elastase infusion. Ultrasound imaging revealed that SMC-seeded scaffolds significantly reduced the aortic diameter by 28 days, compared to scaffolds seeded with iPSC-SMPs or without cells (acellular scaffold), respectively. Bioluminescence imaging demonstrated that both cell-seeded scaffold groups had cellular localization to the aneurysm but a decline in survival with time. Histological analysis revealed that both cell-seeded scaffold groups had more SMC retention and less macrophage invasion into the medial layer of AAA lesions, when compared to the acellular scaffold treatment group. Our data suggest that scaffold-based SMC delivery is feasible and may constitute a platform for cell-based AAA therapy.
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http://dx.doi.org/10.1039/d1bm00685aDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8511090PMC
October 2021

Regulatory variants in TCF7L2 are associated with thoracic aortic aneurysm.

Am J Hum Genet 2021 09 14;108(9):1578-1589. Epub 2021 Jul 14.

K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim 7030, Norway.

Thoracic aortic aneurysm (TAA) is characterized by dilation of the aortic root or ascending/descending aorta. TAA is a heritable disease that can be potentially life threatening. While 10%-20% of TAA cases are caused by rare, pathogenic variants in single genes, the origin of the majority of TAA cases remains unknown. A previous study implicated common variants in FBN1 with TAA disease risk. Here, we report a genome-wide scan of 1,351 TAA-affected individuals and 18,295 control individuals from the Cardiovascular Health Improvement Project and Michigan Genomics Initiative at the University of Michigan. We identified a genome-wide significant association with TAA for variants within the third intron of TCF7L2 following replication with meta-analysis of four additional independent cohorts. Common variants in this locus are the strongest known genetic risk factor for type 2 diabetes. Although evidence indicates the presence of different causal variants for TAA and type 2 diabetes at this locus, we observed an opposite direction of effect. The genetic association for TAA colocalizes with an aortic eQTL of TCF7L2, suggesting a functional relationship. These analyses predict an association of higher expression of TCF7L2 with TAA disease risk. In vitro, we show that upregulation of TCF7L2 is associated with BCL2 repression promoting vascular smooth muscle cell apoptosis, a key driver of TAA disease.
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http://dx.doi.org/10.1016/j.ajhg.2021.06.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8456156PMC
September 2021

Nicotine Affects Murine Aortic Stiffness and Fatigue Response During Supraphysiological Cycling.

J Biomech Eng 2022 Jan;144(1)

Mechanical Engineering, San José State University, One Washington Square, San José, CA 95192-0087.

Nicotine exposure is a major risk factor for several cardiovascular diseases. Although the deleterious effects of nicotine on aortic remodeling processes have been studied to some extent, the biophysical consequences are not fully elucidated. In this investigation, we applied quasi-static and dynamic loading to quantify ways in which exposure to nicotine affects the mechanical behavior of murine arterial tissue. Segments of thoracic aortas from C57BL/6 mice exposed to 25 mg/kg/day of subcutaneous nicotine for 28 days were subjected to uniaxial tensile loading in an open-circumferential configuration. Comparing aorta segments from nicotine-treated mice relative to an equal number of control counterparts, stiffness in the circumferential direction was nearly twofold higher (377 kPa ± 165 kPa versus 191 kPa ± 65 kPa, n = 5, p = 0.03) at 50% strain. Using a degradative power-law fit to fatigue data at supraphysiological loading, we observed that nicotine-treated aortas exhibited significantly higher peak stress, greater loss of tension, and wider oscillation band than control aortas (p ≤ 0.01 for all three variables). Compared to simple stress relaxation tests, fatigue cycling is shown to be more sensitive and versatile in discerning nicotine-induced changes in mechanical behavior over many cycles. Supraphysiological fatigue cycling thus may have broader potential to reveal subtle changes in vascular mechanics caused by other exogenous toxins or pathological conditions.
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http://dx.doi.org/10.1115/1.4051706DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8420792PMC
January 2022

Common and rare variant analyses combined with single-cell multiomics reveal cell-type-specific molecular mechanisms of COVID-19 severity.

medRxiv 2021 Jun 21. Epub 2021 Jun 21.

The determinants of severe COVID-19 in non-elderly adults are poorly understood, which limits opportunities for early intervention and treatment. Here we present novel machine learning frameworks for identifying common and rare disease-associated genetic variation, which outperform conventional approaches. By integrating single-cell multiomics profiling of human lungs to link genetic signals to cell-type-specific functions, we have discovered and validated over 1,000 risk genes underlying severe COVID-19 across 19 cell types. Identified risk genes are overexpressed in healthy lungs but relatively downregulated in severely diseased lungs. Genetic risk for severe COVID-19, within both common and rare variants, is particularly enriched in natural killer (NK) cells, which places these immune cells upstream in the pathogenesis of severe disease. Mendelian randomization indicates that failed NKG2D-mediated activation of NK cells leads to critical illness. Network analysis further links multiple pathways associated with NK cell activation, including type-I-interferon-mediated signalling, to severe COVID-19. Our rare variant model, PULSE, enables sensitive prediction of severe disease in non-elderly patients based on whole-exome sequencing; individualized predictions are accurate independent of age and sex, and are consistent across multiple populations and cohorts. Risk stratification based on exome sequencing has the potential to facilitate post-exposure prophylaxis in at-risk individuals, potentially based around augmentation of NK cell function. Overall, our study characterizes a comprehensive genetic landscape of COVID-19 severity and provides novel insights into the molecular mechanisms of severe disease, leading to new therapeutic targets and sensitive detection of at-risk individuals.
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http://dx.doi.org/10.1101/2021.06.15.21258703DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8240695PMC
June 2021

Genetic Evidence for Repurposing of GLP1R (Glucagon-Like Peptide-1 Receptor) Agonists to Prevent Heart Failure.

J Am Heart Assoc 2021 07 29;10(13):e020331. Epub 2021 Jun 29.

Department of Epidemiology and Biostatistics School of Public HealthImperial College London London UK.

Background This study was designed to investigate the genetic evidence for repurposing of GLP1R (glucagon-like peptide-1 receptor) agonists to prevent heart failure (HF) and whether the potential benefit exceeds the benefit conferred by more general glycemic control. Methods and Results We applied 2-sample Mendelian randomization of genetically proxied GLP1R agonism on HF as the main outcome and left ventricular ejection fraction as the secondary outcome. The associations were compared with those of general glycemic control on the same outcomes. Genetic associations were obtained from genome-wide association study summary statistics of type 2 diabetes mellitus (228 499 cases and 1 178 783 controls), glycated hemoglobin (n=344 182), HF (47,309 cases and 930 014 controls), and left ventricular ejection fraction (n=16 923). Genetic proxies for GLP1R agonism associated with reduced risk of HF (odds ratio per 1 mmol/mol decrease in glycated hemoglobin 0.75; 95% CI, 0.64-0.87; =1.69×10), and higher left ventricular ejection fraction (SD change in left ventricular ejection fraction per 1 mmol/mol decrease in glycated hemoglobin 0.22%; 95% CI, 0.03-0.42; =0.03). The magnitude of these benefits exceeded those expected from improved glycemic control more generally. The results were similar in sensitivity analyses, and we did not find evidence to suggest that these associations were mediated by reduced coronary artery disease risk. Conclusions This genetic evidence supports the repurposing of GLP1R agonists for preventing HF.
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http://dx.doi.org/10.1161/JAHA.120.020331DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8403330PMC
July 2021

A multi-ethnic epigenome-wide association study of leukocyte DNA methylation and blood lipids.

Nat Commun 2021 06 28;12(1):3987. Epub 2021 Jun 28.

Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, MI, USA.

Here we examine the association between DNA methylation in circulating leukocytes and blood lipids in a multi-ethnic sample of 16,265 subjects. We identify 148, 35, and 4 novel associations among Europeans, African Americans, and Hispanics, respectively, and an additional 186 novel associations through a trans-ethnic meta-analysis. We observe a high concordance in the direction of effects across racial/ethnic groups, a high correlation of effect sizes between high-density lipoprotein and triglycerides, a modest overlap of associations with epigenome-wide association studies of other cardio-metabolic traits, and a largely non-overlap with lipid loci identified to date through genome-wide association studies. Thirty CpGs reached significance in at least 2 racial/ethnic groups including 7 that showed association with the expression of an annotated gene. CpGs annotated to CPT1A showed evidence of being influenced by triglycerides levels. DNA methylation levels of circulating leukocytes show robust and consistent association with blood lipid levels across multiple racial/ethnic groups.
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http://dx.doi.org/10.1038/s41467-021-23899-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8238961PMC
June 2021

Prioritizing the Role of Major Lipoproteins and Subfractions as Risk Factors for Peripheral Artery Disease.

Circulation 2021 Aug 18;144(5):353-364. Epub 2021 Jun 18.

Department of Surgery (V.M.W., S.M.D.), University of Pennsylvania Perelman School of Medicine, Philadelphia.

Background: Lipoprotein-related traits have been consistently identified as risk factors for atherosclerotic cardiovascular disease, largely on the basis of studies of coronary artery disease (CAD). The relative contributions of specific lipoproteins to the risk of peripheral artery disease (PAD) have not been well defined. We leveraged large-scale genetic association data to investigate the effects of circulating lipoprotein-related traits on PAD risk.

Methods: Genome-wide association study summary statistics for circulating lipoprotein-related traits were used in the mendelian randomization bayesian model averaging framework to prioritize the most likely causal major lipoprotein and subfraction risk factors for PAD and CAD. Mendelian randomization was used to estimate the effect of apolipoprotein B (ApoB) lowering on PAD risk using gene regions proxying lipid-lowering drug targets. Genes relevant to prioritized lipoprotein subfractions were identified with transcriptome-wide association studies.

Results: ApoB was identified as the most likely causal lipoprotein-related risk factor for both PAD (marginal inclusion probability, 0.86; =0.003) and CAD (marginal inclusion probability, 0.92; =0.005). Genetic proxies for ApoB-lowering medications were associated with reduced risk of both PAD (odds ratio,0.87 per 1-SD decrease in ApoB [95% CI, 0.84-0.91]; =9×10) and CAD (odds ratio,0.66 [95% CI, 0.63-0.69]; =4×10), with a stronger predicted effect of ApoB lowering on CAD (ratio of effects, 3.09 [95% CI, 2.29-4.60]; <1×10). Extra-small very-low-density lipoprotein particle concentration was identified as the most likely subfraction associated with PAD risk (marginal inclusion probability, 0.91; =2.3×10), whereas large low-density lipoprotein particle concentration was the most likely subfraction associated with CAD risk (marginal inclusion probability, 0.95; =0.011). Genes associated with extra-small very-low-density lipoprotein particle and large low-density lipoprotein particle concentration included canonical ApoB pathway components, although gene-specific effects were variable. Lipoprotein(a) was associated with increased risk of PAD independently of ApoB (odds ratio, 1.04 [95% CI, 1.03-1.04]; =1.0×10).

Conclusions: ApoB was prioritized as the major lipoprotein fraction causally responsible for both PAD and CAD risk. However, ApoB-lowering drug targets and ApoB-containing lipoprotein subfractions had diverse associations with atherosclerotic cardiovascular disease, and distinct subfraction-associated genes suggest possible differences in the role of lipoproteins in the pathogenesis of PAD and CAD.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.121.053797DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8323712PMC
August 2021

Genetic Determinants of Peripheral Artery Disease.

Circ Res 2021 Jun 10;128(12):1805-1817. Epub 2021 Jun 10.

Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA (S.M.D.).

Peripheral artery disease-atherosclerosis of the abdominal aorta and lower extremity vascular bed-is a complex disease with both environmental and genetic determinants. Unmitigated disease is associated with major functional decline and can lead to chronic limb-threatening ischemia, amputation, and increased mortality. Over the last 10 years, major advances have been made in identifying the genetic basis of this common, complex disease. In this review, we provide an overview of the primary types of genetic analyses performed for peripheral artery disease, including heritability and linkage studies, and more recently biobank-based genome-wide association studies. Looking forward, we highlight areas of future study including efforts to identify causal peripheral artery disease genes, rare variant and structural variant analyses using whole-exome and whole-genome sequencing data, and the need to include individuals of diverse genetic ancestries.
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http://dx.doi.org/10.1161/CIRCRESAHA.121.318327DOI Listing
June 2021

Association of the transthyretin variant V122I with polyneuropathy among individuals of African ancestry.

Sci Rep 2021 06 2;11(1):11645. Epub 2021 Jun 2.

Alnylam Pharmaceuticals, 300 3rd St., Cambridge, MA, 02142, USA.

Hereditary transthyretin-mediated (hATTR) amyloidosis is an underdiagnosed, progressively debilitating disease caused by mutations in the transthyretin (TTR) gene. V122I, a common pathogenic TTR mutation, is found in 3-4% of individuals of African ancestry in the United States and has been associated with cardiomyopathy and heart failure. To better understand the phenotypic consequences of carrying V122I, we conducted a phenome-wide association study scanning 427 ICD diagnosis codes in UK Biobank participants of African ancestry (n = 6062). Significant associations were tested for replication in the Penn Medicine Biobank (n = 5737) and the Million Veteran Program (n = 82,382). V122I was significantly associated with polyneuropathy in the UK Biobank (odds ratio [OR] = 6.4, 95% confidence interval [CI] 2.6-15.6, p = 4.2 × 10), which was replicated in the Penn Medicine Biobank (OR = 1.6, 95% CI 1.2-2.4, p = 6.0 × 10) and Million Veteran Program (OR = 1.5, 95% CI 1.2-1.8, p = 1.8 × 10). Polyneuropathy prevalence among V122I carriers was 2.1%, 9.0%, and 4.8% in the UK Biobank, Penn Medicine Biobank, and Million Veteran Program, respectively. The cumulative incidence of common hATTR amyloidosis manifestations (carpal tunnel syndrome, polyneuropathy, cardiomyopathy, heart failure) was significantly enriched in V122I carriers compared with non-carriers (HR = 2.8, 95% CI 1.7-4.5, p = 2.6 × 10) in the UK Biobank, with 37.4% of V122I carriers having at least one of these manifestations by age 75. Our findings show that V122I carriers are at increased risk of polyneuropathy. These results also emphasize the underdiagnosis of disease in V122I carriers with a significant proportion of subjects showing phenotypic changes consistent with hATTR amyloidosis. Greater understanding of the manifestations associated with V122I is critical for earlier diagnosis and treatment.
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http://dx.doi.org/10.1038/s41598-021-91113-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8172853PMC
June 2021

Risk factors mediating the effect of body mass index and waist-to-hip ratio on cardiovascular outcomes: Mendelian randomization analysis.

Int J Obes (Lond) 2021 07 17;45(7):1428-1438. Epub 2021 May 17.

Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.

Background: Higher body mass index (BMI) and waist-to-hip ratio (WHR) increase the risk of cardiovascular disease, but the extent to which this is mediated by blood pressure, diabetes, lipid traits, and smoking is not fully understood.

Methods: Using consortia and UK Biobank genetic association summary data from 140,595 to 898,130 participants predominantly of European ancestry, Mendelian randomization mediation analysis was performed to investigate the degree to which systolic blood pressure (SBP), diabetes, lipid traits, and smoking mediated an effect of BMI and WHR on the risk of coronary artery disease (CAD), peripheral artery disease (PAD) and stroke.

Results: The odds ratio of CAD per 1-standard deviation increase in genetically predicted BMI was 1.49 (95% CI 1.39 to 1.60). This attenuated to 1.34 (95% CI 1.24 to 1.45) after adjusting for genetically predicted SBP (proportion mediated 27%, 95% CI 3% to 50%), to 1.27 (95% CI 1.17 to 1.37) after adjusting for genetically predicted diabetes (41% mediated, 95% CI 18% to 63%), to 1.47 (95% CI 1.36 to 1.59) after adjusting for genetically predicted lipids (3% mediated, 95% -23% to 29%), and to 1.46 (95% CI 1.34 to 1.58) after adjusting for genetically predicted smoking (6% mediated, 95% CI -20% to 32%). Adjusting for all the mediators together, the estimate attenuated to 1.14 (95% CI 1.04 to 1.26; 66% mediated, 95% CI 42% to 91%). A similar pattern was observed when considering genetically predicted WHR as the exposure, and PAD or stroke as the outcome.

Conclusions: Measures to reduce obesity will lower the risk of cardiovascular disease primarily by impacting downstream metabolic risk factors, particularly diabetes and hypertension. Reduction of obesity prevalence alongside control and management of its mediators is likely to be most effective for minimizing the burden of obesity.
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http://dx.doi.org/10.1038/s41366-021-00807-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8236409PMC
July 2021

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

PLoS One 2021 13;16(5):e0251651. Epub 2021 May 13.

Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, Massachusetts, United States of America.

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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0251651PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8118298PMC
May 2021

Swarm: A federated cloud framework for large-scale variant analysis.

PLoS Comput Biol 2021 05 12;17(5):e1008977. Epub 2021 May 12.

Palo Alto Epidemiology Research and Information Center for Genomics, VA Palo Alto, California, United States of America.

Genomic data analysis across multiple cloud platforms is an ongoing challenge, especially when large amounts of data are involved. Here, we present Swarm, a framework for federated computation that promotes minimal data motion and facilitates crosstalk between genomic datasets stored on various cloud platforms. We demonstrate its utility via common inquiries of genomic variants across BigQuery in the Google Cloud Platform (GCP), Athena in the Amazon Web Services (AWS), Apache Presto and MySQL. Compared to single-cloud platforms, the Swarm framework significantly reduced computational costs, run-time delays and risks of security breach and privacy violation.
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http://dx.doi.org/10.1371/journal.pcbi.1008977DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8143397PMC
May 2021

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

Nat Commun 2021 05 10;12(1):2579. Epub 2021 May 10.

Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

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.
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http://dx.doi.org/10.1038/s41467-021-22338-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8110798PMC
May 2021

Unresolved Issues in RNA Therapeutics in Vascular Diseases With a Focus on Aneurysm Disease.

Front Cardiovasc Med 2021 15;8:571076. Epub 2021 Apr 15.

Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, United States.

New technologies have greatly shaped the scientific and medical landscape within the last years. The unprecedented expansion of data and information on RNA biology has led to the discovery of new RNA classes with unique functions and unexpected modifications. Today, the biggest challenge is to transfer the large number of findings in basic RNA biology into corresponding clinical RNA-based therapeutics. Lately, this research begins to yield positive outcomes. RNA drugs advance to the final phases of clinical trials or even receive FDA approval. Furthermore, the introduction of the RNA-guided gene-editing technology CRISPR and advances in the delivery of messenger RNAs have triggered a major progression in the field of RNA-therapeutics. Especially short interfering RNAs and antisense oligonucleotides are promising examples for novel categories of therapeutics. However, several issues need to be addressed including intracellular delivery, toxicity, and immune responses before utilizing RNAs in a clinical setting. In this review, we provide an overview on opportunities and challenges for clinical translation of RNA-based therapeutics, with an emphasis on advances in novel delivery technologies and abdominal aortic aneurysm disease where non-coding RNAs have been shown to play a crucial regulatory role.
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http://dx.doi.org/10.3389/fcvm.2021.571076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8081859PMC
April 2021

Response by Pan and Tsao to Letter Regarding Article, "Genetic Architecture of Abdominal Aortic Aneurysm in the Million Veteran Program".

Circulation 2021 Apr 26;143(17):e873-e874. Epub 2021 Apr 26.

Palo Alto Epidemiology Research and Information Center for Genomics, VA Palo Alto, CA (C.P., P.S.T.).

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http://dx.doi.org/10.1161/CIRCULATIONAHA.121.053669DOI Listing
April 2021

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

Nat Med 2021 04 9;27(4):668-676. Epub 2021 Apr 9.

Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, MA, USA.

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; IFNAR2, P = 9.8 × 10 and IL-10RB, P = 2.3 × 10) 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.
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http://dx.doi.org/10.1038/s41591-021-01310-zDOI Listing
April 2021

MicroRNA miR-29b regulates diabetic aortic remodeling and stiffening.

Mol Ther Nucleic Acids 2021 Jun 24;24:188-199. Epub 2021 Feb 24.

Department of Cardiology and Pneumology, Heart Center at the University Medical Center Göttingen, Göttingen, Germany.

Patients with type 2 diabetes (T2D) are threatened by excessive cardiovascular morbidity and mortality. While accelerated arterial stiffening may represent a critical mechanistic factor driving cardiovascular risk in T2D, specific therapies to contain the underlying diabetic arterial remodeling have been elusive. The present translational study investigates the role of microRNA-29b (miR-29b) as a driver and therapeutic target of diabetic aortic remodeling and stiffening. Using a murine model (db/db mice), as well as human aortic tissue samples, we find that diabetic aortic remodeling and stiffening is associated with medial fibrosis, as well as fragmentation of aortic elastic layers. miR-29b is significantly downregulated in T2D and miR-29b repression is sufficient to induce both aortic medial fibrosis and elastin breakdown through upregulation of its direct target genes and thereby increasing aortic stiffness. Moreover, antioxidant treatment restores aortic miR-29b levels and counteracts diabetic aortic remodeling. Concluding, we identify miR-29b as a comprehensive-and therefore powerful-regulator of aortic remodeling and stiffening in T2D that moreover qualifies as a (redox-sensitive) target for therapeutic intervention.
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http://dx.doi.org/10.1016/j.omtn.2021.02.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7957025PMC
June 2021

E-Cigarettes and Cardiopulmonary Health.

Function (Oxf) 2021 8;2(2):zqab004. Epub 2021 Feb 8.

Dorothy M. Davis Heart and Lung Research Institute, Colleges of Medicine and Nursing, The Ohio State University, Columbus, OH, USA.

E-cigarettes have surged in popularity over the last few years, particularly among youth and young adults. These battery-powered devices aerosolize e-liquids, comprised of propylene glycol and vegetable glycerin, typically with nicotine, flavors, and stabilizers/humectants. Although the use of combustible cigarettes is associated with several adverse health effects including multiple pulmonary and cardiovascular diseases, the effects of e-cigarettes on both short- and long-term health have only begun to be investigated. Given the recent increase in the popularity of e-cigarettes, there is an urgent need for studies to address their potential adverse health effects, particularly as many researchers have suggested that e-cigarettes may pose less of a health risk than traditional combustible cigarettes and should be used as nicotine replacements. This report is prepared for clinicians, researchers, and other health care providers to provide the current state of knowledge on how e-cigarette use might affect cardiopulmonary health, along with research gaps to be addressed in future studies.
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http://dx.doi.org/10.1093/function/zqab004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7948134PMC
February 2021

Exosome miR-501-3p Elevation Contributes to Progression of Vascular Stiffness.

Circ Rep 2021 Feb 17;3(3):170-177. Epub 2021 Feb 17.

Department of Pharmacology, Ehime University Graduate School of Medicine Toon Japan.

Tight junction (TJ) disruption and dysfunction are involved in the progression of arteriosclerosis. miR-501-3p regulates endothelial TJ protein-1, resulting in TJ disruption. Because exosomal microRNAs can travel to distant tissues and influence cell behavior, patients with elevated miR-501-3p may experience accelerated vascular disease progression secondary to miR-501-3p-induced reductions in TJ. This study investigated whether plasma exosome miR-501-3p levels are associated with vascular stiffness, an indicator for arteriosclerotic changes. Fifty-one subjects (mean [±SD] age 70±8 years, 37% male) enrolled in a medical checkup program were recruited to the study. Brachial-ankle arterial pulse wave velocity (baPWV) and plasma exosome miR-501-3p expression were measured. Patients were divided into 2 groups depending on whether their miR-501-3p ∆C values were above ("High"; n=24) or below ("Low"; n=27) the cut-off levels determined by receiver operating characteristic (ROC) curve analysis. Median (interquartile range) baPWV levels were significantly higher in the miR-501-3p High than Low group (1,664 [1,496-1,859] vs. 1,450 [1,353-1,686] cm/s, respectively; P<0.05). Multivariate logistic regression analysis showed a significant association between increased baPWV and High miR-501-3p expression (odds ratio 4.66). At follow-up visits (mean 62 months later), baPWV remained significantly higher in the miR-501-3p High than Low group (1,830 [1,624-2,056] vs. 1,620 [1,377-1,816] cm/s, respectively; P<0.05). High expression levels of exosome miR-501-3p contribute to arteriosclerotic changes.
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http://dx.doi.org/10.1253/circrep.CR-20-0135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7956882PMC
February 2021

Hummingbird: Efficient Performance Prediction for Executing Genomic Applications in the Cloud.

Bioinformatics 2021 Mar 8. Epub 2021 Mar 8.

Palo Alto Epidemiology Research and Information Center for Genomics, VA Palo Alto, CA.

Motivation: A major drawback of executing genomic applications on cloud computing facilities is the lack of tools to predict which instance type is the most appropriate, often resulting in an over- or under- matching of resources. Determining the right configuration before actually running the applications will save money and time. Here, we introduce Hummingbird, a tool for predicting performance of computing instances with varying memory and CPU on multiple cloud platforms.

Results: Our experiments on three major genomic data pipelines, including GATK HaplotypeCaller, GATK MuTect2, and ENCODE ATAC-seq, showed that Hummingbird was able to address applications in command line specified in JSON format or workflow description language (WDL) format, and accurately predicted the fastest, the cheapest, and the most cost-efficient compute instances in an economic manner.

Availability: Hummingbird is available as an open source tool at: https://github.com/StanfordBioinformatics/Hummingbird.

Supplementary Information: Supplementary data are available at Bioinformatics online.
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http://dx.doi.org/10.1093/bioinformatics/btab161DOI Listing
March 2021

Multi-trait association studies discover pleiotropic loci between Alzheimer's disease and cardiometabolic traits.

Alzheimers Res Ther 2021 02 4;13(1):34. Epub 2021 Feb 4.

Corporal Michael Crescenz VA Medical Center, Philadelphia, PA, 19104, USA.

Background: Identification of genetic risk factors that are shared between Alzheimer's disease (AD) and other traits, i.e., pleiotropy, can help improve our understanding of the etiology of AD and potentially detect new therapeutic targets. Previous epidemiological correlations observed between cardiometabolic traits and AD led us to assess the pleiotropy between these traits.

Methods: We performed a set of bivariate genome-wide association studies coupled with colocalization analysis to identify loci that are shared between AD and eleven cardiometabolic traits. For each of these loci, we performed colocalization with Genotype-Tissue Expression (GTEx) project expression quantitative trait loci (eQTL) to identify candidate causal genes.

Results: We identified three previously unreported pleiotropic trait associations at known AD loci as well as four novel pleiotropic loci. One associated locus was tagged by a low-frequency coding variant in the gene DOCK4 and is potentially implicated in its alternative splicing. Colocalization with GTEx eQTL data identified additional candidate genes for the loci we detected, including ACE, the target of the hypertensive drug class of ACE inhibitors. We found that the allele associated with decreased ACE expression in brain tissue was also associated with increased risk of AD, providing human genetic evidence of a potential increase in AD risk from use of an established anti-hypertensive therapeutic.

Conclusion: Our results support a complex genetic relationship between AD and these cardiometabolic traits, and the candidate causal genes identified suggest that blood pressure and immune response play a role in the pleiotropy between these traits.
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http://dx.doi.org/10.1186/s13195-021-00773-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7860582PMC
February 2021

Chitinase 3 like 1 (CHI3L1) is a regulator of smooth muscle cell physiology and atherosclerotic lesion stability.

Cardiovasc Res 2021 Jan 20. Epub 2021 Jan 20.

Division of Vascular Surgery, Stanford University School of Medicine, Stanford, USA.

Aims: Atherosclerotic cerebrovascular disease underlies the majority of ischemic strokes and is a major cause of death and disability. While plaque burden is a predictor of adverse outcomes, plaque vulnerability is increasingly recognized as a driver of lesion rupture and risk for clinical events. Defining the molecular regulators of carotid instability could inform the development of new biomarkers and/or translational targets for at-risk individuals.

Methods And Results: Using two independent human endarterectomy biobanks, we found that the understudied glycoprotein, Chitinase 3 like 1 (CHI3L1), is upregulated in patients with carotid disease compared to healthy controls. Further, CHI3L1 levels were found to stratify individuals based on symptomatology and histopathological evidence of an unstable fibrous cap. Gain- and loss-of-function studies in cultured human carotid artery smooth muscle cells (SMCs) showed that CHI3L1 prevents a number of maladaptive changes in that cell type, including phenotype switching towards a synthetic and hyperproliferative state. Using two murine models of carotid remodelling and lesion vulnerability, we found that knockdown of Chil1 resulted in larger neointimal lesions comprised by de-differentiated SMCs that failed to invest within and stabilize the fibrous cap. Exploratory mechanistic studies identified alterations in potential downstream regulatory genes, including large tumor suppressor kinase 2 (LATS2), which mediates macrophage marker and inflammatory cytokine expression on SMCs, and may explain how CHI3L1 modulates cellular plasticity.

Conclusion: CHI3L1 is upregulated in humans with carotid artery disease and appears to be a strong mediator of plaque vulnerability. Mechanistic studies suggest this change may be a context-dependent adaptive response meant to maintain vascular SMCs in a differentiated state and to prevent rupture of the fibrous cap. Part of this effect may be mediated through downstream suppression of LATS2. Future studies should determine how these changes occur at the molecular level, and whether this gene can be targeted as a novel translational therapy for subjects at risk of stroke.

Translational Perspective: Taken together, CHI3L1 has the potential to become a new translational target for cardiovascular disease. With further studies to understand its full causal relationship to inflammatory pathways, it could have a role in the diagnosis and management of patients with cerebrovascular disease at risk for stroke.
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http://dx.doi.org/10.1093/cvr/cvab014DOI Listing
January 2021

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

JAMA Netw Open 2021 01 4;4(1):e2034461. Epub 2021 Jan 4.

Corporal Michael J. Crescenz VA Medical Center, Philadelphia, Pennsylvania.

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.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.34461DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7816104PMC
January 2021

Urate, Blood Pressure, and Cardiovascular Disease: Evidence From Mendelian Randomization and Meta-Analysis of Clinical Trials.

Hypertension 2021 02 28;77(2):383-392. Epub 2020 Dec 28.

Department of Epidemiology and Biostatistics, School of Public Health (D.G., V.K., V.Z., E.E., P.E., A.D., I.T.), Imperial College London, United Kingdom.

Serum urate has been implicated in hypertension and cardiovascular disease, but it is not known whether it is exerting a causal effect. To investigate this, we performed Mendelian randomization analysis using data from UK Biobank, Million Veterans Program and genome-wide association study consortia, and meta-analysis of randomized controlled trials. The main Mendelian randomization analyses showed that every 1-SD increase in genetically predicted serum urate was associated with an increased risk of coronary heart disease (odds ratio, 1.19 [95% CI, 1.10-1.30]; =4×10), peripheral artery disease (1.12 [95% CI, 1.03-1.21]; =9×10), and stroke (1.11 [95% CI, 1.05-1.18]; =2×10). In Mendelian randomization mediation analyses, elevated blood pressure was estimated to mediate approximately one-third of the effect of urate on cardiovascular disease risk. Systematic review and meta-analysis of randomized controlled trials showed a favorable effect of urate-lowering treatment on systolic blood pressure (mean difference, -2.55 mm Hg [95% CI, -4.06 to -1.05]; =1×10) and major adverse cardiovascular events in those with previous cardiovascular disease (odds ratio, 0.40 [95% CI, 0.22-0.73]; =3×10) but no significant effect on major adverse cardiovascular events in all individuals (odds ratio, 0.67 [95% CI, 0.44-1.03]; =0.07). In summary, these Mendelian randomization and clinical trial data support an effect of higher serum urate on increasing blood pressure, which may mediate a consequent effect on cardiovascular disease risk. High-quality trials are necessary to provide definitive evidence on the specific clinical contexts where urate lowering may be of cardiovascular benefit.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.16547DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7803439PMC
February 2021
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