Publications by authors named "Scott M Damrauer"

109 Publications

MitoScape: A big-data, machine-learning platform for obtaining mitochondrial DNA from next-generation sequencing data.

PLoS Comput Biol 2021 Nov 11;17(11):e1009594. Epub 2021 Nov 11.

Center for Mitochondrial and Epigenomic Medicine, Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America.

The growing number of next-generation sequencing (NGS) data presents a unique opportunity to study the combined impact of mitochondrial and nuclear-encoded genetic variation in complex disease. Mitochondrial DNA variants and in particular, heteroplasmic variants, are critical for determining human disease severity. While there are approaches for obtaining mitochondrial DNA variants from NGS data, these software do not account for the unique characteristics of mitochondrial genetics and can be inaccurate even for homoplasmic variants. We introduce MitoScape, a novel, big-data, software for extracting mitochondrial DNA sequences from NGS. MitoScape adopts a novel departure from other algorithms by using machine learning to model the unique characteristics of mitochondrial genetics. We also employ a novel approach of using rho-zero (mitochondrial DNA-depleted) data to model nuclear-encoded mitochondrial sequences. We showed that MitoScape produces accurate heteroplasmy estimates using gold-standard mitochondrial DNA data. We provide a comprehensive comparison of the most common tools for obtaining mtDNA variants from NGS and showed that MitoScape had superior performance to compared tools in every statistically category we compared, including false positives and false negatives. By applying MitoScape to common disease examples, we illustrate how MitoScape facilitates important heteroplasmy-disease association discoveries by expanding upon a reported association between hypertrophic cardiomyopathy and mitochondrial haplogroup T in men (adjusted p-value = 0.003). The improved accuracy of mitochondrial DNA variants produced by MitoScape will be instrumental in diagnosing disease in the context of personalized medicine and clinical diagnostics.
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http://dx.doi.org/10.1371/journal.pcbi.1009594DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8610268PMC
November 2021

Toward Population-Based Genetic Screening for Hereditary Amyloidosis.

JACC CardioOncol 2021 Oct 19;3(4):562-564. Epub 2021 Oct 19.

Division of Vascular Surgery and Endovascular Therapy, Department of Surgery, and Department of Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.

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http://dx.doi.org/10.1016/j.jaccao.2021.09.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8543136PMC
October 2021

Derivation and Validation of Genome-Wide Polygenic Score for Ischemic Heart Failure.

J Am Heart Assoc 2021 Nov 29;10(22):e021916. Epub 2021 Oct 29.

The Charles Bronfman Institute for Personalized MedicineIcahn School of Medicine at Mount Sinai New York NY.

Background Despite advances in cardiovascular disease and risk factor management, mortality from ischemic heart failure (HF) in patients with coronary artery disease (CAD) remains high. Given the partial role of genetics in HF and lack of reliable risk stratification tools, we developed and validated a polygenic risk score for HF in patients with CAD, which we term HF-PRS. Methods and Results Using summary statistics from a recent genome-wide association study for HF, we developed candidate PRSs in the Mount Sinai Bio CAD patient cohort (N=6274) by using the pruning and thresholding method and LDPred. We validated the best score in the Penn Medicine BioBank (N=7250) and performed a subgroup analysis in a high-risk cohort who had undergone coronary catheterization. We observed a significant association between HF-PRS score and ischemic HF even after adjusting for evidence of obstructive CAD in patients of European ancestry in both Bio (odds ratio [OR], 1.14 per SD; 95% CI, 1.05-1.24; =0.003) and Penn Medicine BioBank (OR, 1.07 per SD; 95% CI, 1.01-1.13; =0.016). In European patients with CAD in Penn Medicine BioBank who had undergone coronary catheterization, individuals in the top 10th percentile of PRS had a 2-fold increased odds of ischemic HF (OR, 2.0; 95% CI, 1.1-3.7; =0.02) compared with the bottom 10th percentile. Conclusions A PRS for HF enables risk stratification in patients with CAD. Future prospective studies aimed at demonstrating clinical utility are warranted for adoption in the patient setting.
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http://dx.doi.org/10.1161/JAHA.121.021916DOI Listing
November 2021

Association of Inherited Mutations in DNA Repair Genes with Localized Prostate Cancer.

Eur Urol 2021 Oct 25. Epub 2021 Oct 25.

Department of Medicine, Division of Hematology/Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Corporal Michael J. Crescenz Veterans Affairs Medical Center, Philadelphia, PA, USA. Electronic address:

Background: Identification of germline mutations in DNA repair genes has significant implications for the personalized treatment of individuals with prostate cancer (PrCa).

Objective: To determine DNA repair genes associated with localized PrCa in a diverse academic biobank and to determine genetic testing burden.

Design, Setting, And Participants: A cross-sectional study of 2391 localized PrCa patients was carried out.

Outcome Measurements And Statistical Analysis: Genetic ancestry and mutation rates (excluding somatic interference) in 17 DNA repair genes were determined in 1588 localized PrCa patients and 3273 cancer-free males. Burden testing within individuals of genetically determined European (EUR) and African (AFR) ancestry was performed between biobank PrCa cases and cancer-free biobank and gnomAD males.

Results And Limitations: AFR individuals with localized PrCa had lower DNA repair gene mutation rates than EUR individuals (1.4% vs 4.0%, p = 0.02). Mutation rates in localized PrCa patients were similar to those in biobank and gnomAD controls (EUR: 4.0% vs 2.8%, p = 0.15, vs 3.1%, p = 0.04; AFR: 1.4% vs 1.8%, p = 0.8, vs 2.1%, p = 0.5). Gene-based rare variant association testing revealed that only BRCA2 mutations were significantly enriched compared with gnomAD controls of EUR ancestry (1.0% vs 0.28%, p = 0.03). Of the participants, 21% and 11% met high-risk and very-high-risk criteria; of them, 3.7% and 6.2% had any germline genetic mutation and 1.0% and 2.5% had a BRCA2 mutation, respectively. Limitations of this study include an analysis of a relatively small, single-institution cohort.

Conclusions: DNA repair gene germline mutation rates are low in an academic biobank cohort of localized PrCa patients, particularly among individuals of AFR genetic ancestry. Mutation rates in genes with published evidence of association with PrCa exceed 2.5% only in high-risk, very-high-risk localized, and node-positive PrCa patients. These findings highlight the importance of risk stratification in localized PrCa patients to identify appropriate patients for germline genetic testing.

Patient Summary: In the majority of patients who develop localized prostate cancer, germline genetic testing is unlikely to reveal an inherited DNA repair mutation, regardless of race. High-risk features increase the possibility of a germline DNA repair mutation.
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http://dx.doi.org/10.1016/j.eururo.2021.09.029DOI Listing
October 2021

Cardiometabolic, Lifestyle, and Nutritional Factors in Relation to Varicose Veins: A Mendelian Randomization Study.

J Am Heart Assoc 2021 Nov 20;10(21):e022286. Epub 2021 Oct 20.

Unit of Cardiovascular and Nutritional Epidemiology Institute of Environmental Medicine Karolinska Institutet Stockholm Sweden.

Background We conducted a 2-sample Mendelian randomization study to assess the associations of cardiometabolic, lifestyle, and nutritional factors with varicose veins. Methods and Results Independent single-nucleotide polymorphisms associated with height (positive control), body mass index, type 2 diabetes, diastolic and systolic blood pressure, smoking, alcohol and coffee consumption, 7 circulating vitamins (A, B6, B9, B12, C, 25-hydroxyvitamin D, and E), and 5 circulating minerals (calcium, iron, magnesium, selenium, and zinc) at the genome-wide significance level were used as instrumental variables. Summary-level data for the genetic associations with varicose veins were obtained from the UK Biobank (8763 cases and 352 431 noncases) and the FinnGen consortium (13 928 cases and 153 951 noncases). Genetically predicted higher height, body mass index, smoking, and circulating iron levels were associated with an increased risk of varicose veins. The odds ratios (ORs) per 1-SD increase in the exposure were 1.34 (95% CI, 1.25-1.43) for height, 1.39 (95% CI, 1.27-1.52) for body mass index, 1.12 (95% CI, 1.04-1.22) for the prevalence of smoking initiation, and 1.24 (95% CI, 1.16-1.33) for iron. Higher genetically predicted systolic blood pressure and circulating calcium and zinc levels were associated with a reduced risk of varicose veins, whereas the association for systolic blood pressure did not persist after adjustment for genetically predicted height. The OR was 0.75 (95% CI, 0.62-0.92) per 1-SD increase in calcium levels and 0.97 (95% CI, 0.95-0.98) for zinc. Conclusions This study identified several modifiable risk factors for varicose veins.
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http://dx.doi.org/10.1161/JAHA.121.022286DOI Listing
November 2021

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

A genome-first approach to rare variants in hypertrophic cardiomyopathy genes MYBPC3 and MYH7 in a medical biobank.

Hum Mol Genet 2021 Sep 20. Epub 2021 Sep 20.

Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.

'Genome-first' approaches to analyzing rare variants can reveal new insights into human biology and disease. Because pathogenic variants are often rare, new discovery requires aggregating rare coding variants into 'gene burdens' for sufficient power. However, a major challenge is deciding which variants to include in gene burden tests. Pathogenic variants in MYBPC3 and MYH7 are well-known causes of hypertrophic cardiomyopathy (HCM), and focusing on these 'positive control' genes in a genome-first approach could help inform variant selection methods and gene burdening strategies for other genes and diseases. Integrating exome sequences with electronic health records among 41 759 participants in the Penn Medicine BioBank, we evaluated the performance of aggregating predicted loss-of-function (pLOF) and/or predicted deleterious missense (pDM) variants in MYBPC3 and MYH7 for gene burden phenome-wide association studies (PheWAS). The approach to grouping rare variants for these two genes produced very different results: pLOFs but not pDM variants in MYBPC3 were strongly associated with HCM, whereas the opposite was true for MYH7. Detailed review of clinical charts revealed that only 38.5% of patients with HCM diagnoses carrying an HCM-associated variant in MYBPC3 or MYH7 had a clinical genetic test result. Additionally, 26.7% of MYBPC3 pLOF carriers without HCM diagnoses had clear evidence of left atrial enlargement and/or septal/LV hypertrophy on echocardiography. Our study shows the importance of evaluating both pLOF and pDM variants for gene burden testing in future studies to uncover novel gene-disease relationships and identify new pathogenic loss-of-function variants across the human genome through genome-first analyses of healthcare-based populations.
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http://dx.doi.org/10.1093/hmg/ddab249DOI Listing
September 2021

Geographic and Socioeconomic Disparities in Major Lower Extremity Amputation Rates in Metropolitan Areas.

J Am Heart Assoc 2021 09 25;10(17):e021456. Epub 2021 Aug 25.

Penn Cardiovascular Outcomes, Quality and Evaluative Research Center University of Pennsylvania Philadelphia PA.

Background Rates of major lower extremity amputation in patients with peripheral artery disease are higher in rural communities with markers of low socioeconomic status, but most Americans live in metropolitan areas. Whether amputation rates vary within US metropolitan areas is unclear, as are characteristics of high amputation rate urban communities. Methods and Results We estimated rates of major lower extremity amputation per 100 000 Medicare beneficiaries between 2010 and 2018 at the ZIP code level among ZIP codes with ≥100 beneficiaries. We described demographic characteristics of high and low amputation ZIP codes, and the association between major amputation rate and 3 ZIP code-level markers of socioeconomic status-the proportion of patients with dual eligibility for Medicaid, median household income, and Distressed Communities Index score-for metropolitan, micropolitan, and rural ZIP code cohorts. Between 2010 and 2018, 188 995 Medicare fee-for-service patients living in 31 391 ZIP codes with ≥100 beneficiaries had a major lower extremity amputation. The median (interquartile range) ZIP code-level number of amputations per 100 000 beneficiaries was 262 (75-469). Though nonmetropolitan ZIP codes had higher rates of major amputation than metropolitan areas, 78.2% of patients undergoing major amputation lived in metropolitan areas. Compared with ZIP codes with lower amputation rates, top quartile amputation rate ZIP codes had a greater proportion of Black residents (4.4% versus 17.5%, <0.001). In metropolitan areas, after adjusting for clinical comorbidities and demographics, every $10 000 lower median household income was associated with a 4.4% (95% CI, 3.9-4.8) higher amputation rate, and a 10-point higher Distressed Communities Index score was associated with a 3.8% (95% CI, 3.4%-4.2%) higher amputation rate; there was no association between the proportion of patients eligible for Medicaid and amputation rate. These findings were comparable to the associations identified across all ZIP codes. Conclusions In metropolitan areas, where most individuals undergoing lower extremity amputation live, markers of lower socioeconomic status and Black race were associated with higher rates of major lower extremity amputation. Development of community-based tools for peripheral artery disease diagnosis and management targeted to communities with high amputation rates in urban areas may help reduce inequities in peripheral artery disease outcomes.
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http://dx.doi.org/10.1161/JAHA.121.021456DOI Listing
September 2021

Anti-inflammatory diet and venous thromboembolism: Two prospective cohort studies.

Nutr Metab Cardiovasc Dis 2021 09 12;31(10):2831-2838. Epub 2021 Jul 12.

Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; Unit of Medical Epidemiology, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden. Electronic address:

Background And Aims: Inflammation has been revealed to facilitate thrombogenesis and to increase the risk of venous thromboembolism (VTE). However, limited data are available on the association between the anti-inflammatory diet and incident VTE. We conducted a cohort analysis to examine this association and to further examine whether this association is modified by smoking status, a trigger of systemic inflammation.

Methods And Results: We used data from two cohorts including 81,507 middle-aged and older Swedish adults without previous VTE at baseline. An empirically validated anti-inflammatory diet index (AIDI), based on 12 foods with anti-inflammatory potential and 5 foods with pro-inflammatory potential, was employed to estimate the anti-inflammatory potential of diet. Hazard ratios (HRs), with corresponding 95% confidence intervals (CIs), of VTE were estimated by Cox proportional hazards regression models. During a mean follow-up of 17.8-years, 5241 VTE cases were diagnosed. Compared with individuals in the lowest quartile of the AIDI (score ≤4), those in the highest quartile (score ≥8) had a 9% (95% CI, 0-17%) lower risk of VTE. The inverse association was observed in current and past smokers (HR between the two extreme quartiles, 0.80, 95% CI, 0.70-0.91) but not in never smokers (HR, 1.03, 95% CI, 0.91-1.17). French fries (HR per serving, 1.33, 95% CI, 1.06, 1.67) but no other foods included in AIDI was associated with VTE.

Conclusion: The study suggests that a consumption of foods with high anti-inflammatory potential may play a role in the prevention of VTE in smokers.
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http://dx.doi.org/10.1016/j.numecd.2021.06.021DOI Listing
September 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

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

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

Raman microspectroscopy as a useful new tool in understanding thoracic aortic aneurysms.

Cell Rep Med 2021 May 18;2(5):100285. Epub 2021 May 18.

Department of Surgery, University of Pennsylvania, Philadelphia, PA, USA.

Raman spectroscopy is a well-understood technology with novel applications in both research and clinical settings. In their article, Sugiyama and colleagues apply this technology to understand thoracic aortic aneurysm development and biomarker identification..
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http://dx.doi.org/10.1016/j.xcrm.2021.100285DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8149461PMC
May 2021

Venous thromboembolism detected by FDG-PET/CT in cancer patients: a common, yet life-threatening observation.

Am J Nucl Med Mol Imaging 2021 15;11(2):99-106. Epub 2021 Apr 15.

Department of Radiology, Hospital of The University of Pennsylvania Philadelphia, PA, USA.

Cancer patients are at markedly increased risk for venous thromboembolism (VTE). Early detection of VTE may decrease morbidity and mortality in this population. We conducted this study to evaluate the ability of FDG-PET/CT to detect thrombosis in cancer patients. This retrospective study included 131 cancer patients with a history of deep vein thrombosis (DVT) or pulmonary embolism (PE) referred for 2-deoxy-2-[F]-fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT). All subjects underwent PET/CT imaging 60 minutes after FDG injection. Images were visually assessed for increased FDG uptake within the venous lumen. For positive cases, clinical follow-up and Doppler ultrasonography and/or contrast-enhanced CT scans were reviewed. FDG-PET/CT revealed abnormal uptake in the venous system of 26 (19.8%) patients. Eighteen (69.2%) had a history of DVT, and 13 (50%) had a history of PE. The most common site of thrombosis was the inferior vena cava (IVC) (n=14, 53.8%), followed by lower extremities veins (n=9, 34.6%), jugular veins (n=2, 7.7%), and superior vena cava (n=1, 3.8%). The presence of thrombi was confirmed by reviewing clinical follow-up in 6 (23.1%) patients. Among this group, thrombosis was detected in lower extremity veins (n=4, 15.8%), jugular veins (n=1, 3.8%), and IVC (n=1, 3.8%). Our study demonstrates that thrombi prior to their clinical manifestation can be detected by FDG-PET/CT in cancer patients. Moving forward, physicians must carefully consider the venous system when reporting FDG-PET/CT for cancer patients.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8165725PMC
April 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

Metabolic Traits and Stroke Risk in Individuals of African Ancestry: Mendelian Randomization Analysis.

Stroke 2021 Aug 3;52(8):2680-2684. Epub 2021 Jun 3.

Department of Epidemiology and Biostatistics, Medical School Building, St Mary's Hospital, Imperial College London, United Kingdom (V.K., M.-R.J., D.G.).

Background And Purpose: Metabolic traits affect ischemic stroke (IS) risk, but the degree to which this varies across different ethnic ancestries is not known. Our aim was to apply Mendelian randomization to investigate the causal effects of type 2 diabetes (T2D) liability and lipid traits on IS risk in African ancestry individuals, and to compare them to estimates obtained in European ancestry individuals.

Methods: For African ancestry individuals, genetic proxies for T2D liability and circulating lipids were obtained from a meta-analysis of the African Partnership for Chronic Disease Research study, the UK Biobank, and the Million Veteran Program (total N=77 061). Genetic association estimates for IS risk were obtained from the Consortium of Minority Population Genome-Wide Association Studies of Stroke (3734 cases and 18 317 controls). For European ancestry individuals, genetic proxies for the same metabolic traits were obtained from Million Veteran Program (lipids N=297 626, T2D N=148 726 cases, and 965 732 controls), and genetic association estimates for IS risk were obtained from the MEGASTROKE study (34 217 cases and 406 111 controls). Random-effects inverse-variance weighted Mendelian randomization was used as the main method, complemented with sensitivity analyses more robust to pleiotropy.

Results: Higher genetically proxied T2D liability, LDL-C (low-density lipoprotein cholesterol), total cholesterol and lower genetically proxied HDL-C (high-density lipoprotein cholesterol) were associated with increased risk of IS in African ancestry individuals (odds ratio per doubling the odds of T2D liability [95% CI], 1.09 [1.07-1.11]; per standard-deviation increase in LDL-C, 1.12 [1.04-1.21]; total cholesterol: 1.23 [1.06-1.43]; HDL-C, 0.93 [0.89-0.99]). There was no evidence for differences in these estimates when performing analyses in European ancestry individuals.

Conclusions: Our analyses support a causal effect of T2D liability and lipid traits on IS risk in African ancestry individuals, with Mendelian randomization estimates similar to those obtained in European ancestry individuals.
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http://dx.doi.org/10.1161/STROKEAHA.121.034747DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8312569PMC
August 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

Derivation and validation of a machine learning risk score using biomarker and electronic patient data to predict progression of diabetic kidney disease.

Diabetologia 2021 07 2;64(7):1504-1515. Epub 2021 Apr 2.

Department of Surgery, Perelman School of Medicine at University of Pennsylvania, Philadelphia, PA, USA.

Aim: Predicting progression in diabetic kidney disease (DKD) is critical to improving outcomes. We sought to develop/validate a machine-learned, prognostic risk score (KidneyIntelX™) combining electronic health records (EHR) and biomarkers.

Methods: This is an observational cohort study of patients with prevalent DKD/banked plasma from two EHR-linked biobanks. A random forest model was trained, and performance (AUC, positive and negative predictive values [PPV/NPV], and net reclassification index [NRI]) was compared with that of a clinical model and Kidney Disease: Improving Global Outcomes (KDIGO) categories for predicting a composite outcome of eGFR decline of ≥5 ml/min per year, ≥40% sustained decline, or kidney failure within 5 years.

Results: In 1146 patients, the median age was 63 years, 51% were female, the baseline eGFR was 54 ml min [1.73 m], the urine albumin to creatinine ratio (uACR) was 6.9 mg/mmol, follow-up was 4.3 years and 21% had the composite endpoint. On cross-validation in derivation (n = 686), KidneyIntelX had an AUC of 0.77 (95% CI 0.74, 0.79). In validation (n = 460), the AUC was 0.77 (95% CI 0.76, 0.79). By comparison, the AUC for the clinical model was 0.62 (95% CI 0.61, 0.63) in derivation and 0.61 (95% CI 0.60, 0.63) in validation. Using derivation cut-offs, KidneyIntelX stratified 46%, 37% and 17% of the validation cohort into low-, intermediate- and high-risk groups for the composite kidney endpoint, respectively. The PPV for progressive decline in kidney function in the high-risk group was 61% for KidneyIntelX vs 40% for the highest risk strata by KDIGO categorisation (p < 0.001). Only 10% of those scored as low risk by KidneyIntelX experienced progression (i.e., NPV of 90%). The NRI for the high-risk group was 41% (p < 0.05).

Conclusions: KidneyIntelX improved prediction of kidney outcomes over KDIGO and clinical models in individuals with early stages of DKD.
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http://dx.doi.org/10.1007/s00125-021-05444-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8187208PMC
July 2021

Genetically Downregulated Interleukin-6 Signaling Is Associated With a Favorable Cardiometabolic Profile: A Phenome-Wide Association Study.

Circulation 2021 Mar 15;143(11):1177-1180. Epub 2021 Mar 15.

Institute for Stroke and Dementia Research, University Hospital, Ludwig-Maximilians-University LMU, Munich, Germany (M.K.G., R.M., M.D.).

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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.052604DOI Listing
March 2021

Quantification of abdominal fat from computed tomography using deep learning and its association with electronic health records in an academic biobank.

J Am Med Inform Assoc 2021 06;28(6):1178-1187

Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Objective: The objective was to develop a fully automated algorithm for abdominal fat segmentation and to deploy this method at scale in an academic biobank.

Materials And Methods: We built a fully automated image curation and labeling technique using deep learning and distributive computing to identify subcutaneous and visceral abdominal fat compartments from 52,844 computed tomography scans in 13,502 patients in the Penn Medicine Biobank (PMBB). A classification network identified the inferior and superior borders of the abdomen, and a segmentation network differentiated visceral and subcutaneous fat. Following technical evaluation of our method, we conducted studies to validate known relationships with visceral and subcutaneous fat.

Results: When compared with 100 manually annotated cases, the classification network was on average within one 5-mm slice for both the superior (0.4 ± 1.1 slice) and inferior (0.4 ± 0.6 slice) borders. The segmentation network also demonstrated excellent performance with intraclass correlation coefficients of 1.00 (P < 2 × 10-16) for subcutaneous and 1.00 (P < 2 × 10-16) for visceral fat on 100 testing cases. We performed integrative analyses of abdominal fat with the phenome extracted from the electronic health record and found highly significant associations with diabetes mellitus, hypertension, and renal failure, among other phenotypes.

Conclusions: This work presents a fully automated and highly accurate method for the quantification of abdominal fat that can be applied to routine clinical imaging studies to fuel translational scientific discovery.
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http://dx.doi.org/10.1093/jamia/ocaa342DOI Listing
June 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

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

Kidney disease genetic risk variants alter lysosomal beta-mannosidase () expression and disease severity.

Sci Transl Med 2021 01;13(576)

Department of Medicine Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

More than 800 million people in the world suffer from chronic kidney disease (CKD). Genome-wide association studies (GWAS) have identified hundreds of loci where genetic variants are associated with kidney function; however, causal genes and pathways for CKD remain unknown. Here, we performed integration of kidney function GWAS and human kidney-specific expression quantitative trait analysis and identified that the expression of beta-mannosidase () was lower in kidneys of subjects with CKD risk genotype. We also show an increased incidence of renal failure in subjects with rare heterozygous loss-of-function coding variants in using phenome-wide association analysis of 40,963 subjects with exome sequencing data. is a lysosomal gene highly expressed in kidney tubule cells. Deep phenotyping revealed structural and functional lysosomal alterations in human kidneys from subjects with CKD risk alleles and mice with genetic deletion of heterozygous and knockout mice developed more severe kidney fibrosis when subjected to toxic injury induced by cisplatin or folic acid. loss altered multiple pathways, including endocytosis and autophagy. In the absence of toxic acute tubule injury induced inflammasome activation and fibrosis. Together, these results illustrate the convergence of common noncoding and rare coding variants in in kidney disease development and demonstrate the role of the endolysosomal system in kidney disease development.
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http://dx.doi.org/10.1126/scitranslmed.aaz1458DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8627675PMC
January 2021

Exome-wide evaluation of rare coding variants using electronic health records identifies new gene-phenotype associations.

Nat Med 2021 01 11;27(1):66-72. Epub 2021 Jan 11.

Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX, USA.

The clinical impact of rare loss-of-function variants has yet to be determined for most genes. Integration of DNA sequencing data with electronic health records (EHRs) could enhance our understanding of the contribution of rare genetic variation to human disease. By leveraging 10,900 whole-exome sequences linked to EHR data in the Penn Medicine Biobank, we addressed the association of the cumulative effects of rare predicted loss-of-function variants for each individual gene on human disease on an exome-wide scale, as assessed using a set of diverse EHR phenotypes. After discovering 97 genes with exome-by-phenome-wide significant phenotype associations (P < 10), we replicated 26 of these in the Penn Medicine Biobank, as well as in three other medical biobanks and the population-based UK Biobank. Of these 26 genes, five had associations that have been previously reported and represented positive controls, whereas 21 had phenotype associations not previously reported, among which were genes implicated in glaucoma, aortic ectasia, diabetes mellitus, muscular dystrophy and hearing loss. These findings show the value of aggregating rare predicted loss-of-function variants into 'gene burdens' for identifying new gene-disease associations using EHR phenotypes in a medical biobank. We suggest that application of this approach to even larger numbers of individuals will provide the statistical power required to uncover unexplored relationships between rare genetic variation and disease phenotypes.
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http://dx.doi.org/10.1038/s41591-020-1133-8DOI Listing
January 2021

Genetically Predicted Blood Pressure and Risk of Atrial Fibrillation.

Hypertension 2021 02 4;77(2):376-382. Epub 2021 Jan 4.

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

Observational studies have shown an association between hypertension and atrial fibrillation (AF). Aggressive blood pressure management in patients with known AF reduces overall arrhythmia burden, but it remains unclear whether hypertension is causative for AF. To address this question, this study explored the relationship between genetic predictors of blood pressure and risk of AF. We secondarily explored the relationship between genetically proxied use of antihypertensive drugs and risk of AF. Two-sample Mendelian randomization was performed using an inverse-variance weighted meta-analysis with weighted median Mendelian randomization and Egger intercept tests performed as sensitivity analyses. Summary statistics for systolic blood pressure, diastolic blood pressure, and pulse pressure were obtained from the International Consortium of Blood Pressure and the UK Biobank discovery analysis and AF from the 2018 Atrial Fibrillation Genetics Consortium multiethnic genome-wide association studies. Increases in genetically proxied systolic blood pressure, diastolic blood pressure, or pulse pressure by 10 mm Hg were associated with increased odds of AF (systolic blood pressure: odds ratio [OR], 1.17 [95% CI, 1.11-1.22]; =1×10; diastolic blood pressure: OR, 1.25 [95% CI, 1.16-1.35]; =3×10; pulse pressure: OR, 1.1 [95% CI, 1.0-1.2]; =0.05). Decreases in systolic blood pressure by 10 mm Hg estimated by genetic proxies of antihypertensive medications showed calcium channel blockers (OR, 0.66 [95% CI, 0.57-0.76]; =8×10) and β-blockers (OR, 0.61 [95% CI, 0.46-0.81]; =6×10) decreased the risk of AF. Blood pressure-increasing genetic variants were associated with increased risk of AF, consistent with a causal relationship between blood pressure and AF. These data support the concept that blood pressure reduction with calcium channel blockade or β-blockade could reduce the risk of AF.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.16191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7803440PMC
February 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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