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1.
PLoS Genet ; 18(4): e1010113, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35482673

RESUMO

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 data 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 ABO locus (rs495828, rs505922) associated with the largest number of phenotypes (nrs495828 = 53 and nrs505922 = 59); strongest association with venous embolism, odds ratio (ORrs495828 1.33 (p = 1.32 x 10-199), and thrombosis ORrs505922 1.33, p = 2.2 x10-265. Among 67 respiratory conditions tested, 11 had significant associations including MUC5B locus (rs35705950) with increased risk of idiopathic fibrosing alveolitis OR 2.83, p = 4.12 × 10-191; CRHR1 (rs61667602) associated with reduced risk of pulmonary fibrosis, OR 0.84, p = 2.26× 10-12. The TYK2 locus (rs11085727) associated with reduced risk for autoimmune conditions, e.g., psoriasis OR 0.88, p = 6.48 x10-23, lupus OR 0.84, p = 3.97 x 10-06. PheWAS stratified by ancestry demonstrated differences in genotype-phenotype associations. LMNA (rs581342) associated with neutropenia OR 1.29 p = 4.1 x 10-13 among Veterans of African and Hispanic ancestry but not European. Overall, we observed a 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.


Assuntos
COVID-19 , Veteranos , COVID-19/epidemiologia , COVID-19/genética , Estudos de Associação Genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Polimorfismo de Nucleotídeo Único/genética
2.
PLoS One ; 17(4): e0266381, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35468170

RESUMO

BACKGROUND: In response to the novel Coronavirus Disease 2019 (COVID-19) pandemic, the Department of Veterans Affairs (VA) Million Veteran Program (MVP) organized efforts to better understand the impact of COVID-19 on Veterans by developing and deploying a self-reported survey. METHODS: The MVP COVID-19 Survey was developed to collect COVID-19 specific elements including symptoms, diagnosis, hospitalization, behavioral and psychosocial factors and to augment existing MVP data with longitudinal collection of key domains in physical and mental health. Due to the rapidly evolving nature of the pandemic, a multipronged strategy was implemented to widely disseminate the COVID-19 Survey and capture data using both the online platform and mailings. RESULTS: We limited the findings of this paper to the initial phase of survey dissemination which began in May 2020. A total of 729,625 eligible MVP Veterans were invited to complete version 1 of the COVID-19 Survey. As of October 31, 2020, 58,159 surveys have been returned. The mean and standard deviation (SD) age of responders was 71 (11) years, 8.6% were female, 8.2% were Black, 5.6% were Hispanic, and 446 (0.8%) self-reported a COVID-19 diagnosis. Over 90% of responders reported wearing masks, practicing social distancing, and frequent hand washing. CONCLUSION: The MVP COVID-19 Survey provides a systematic collection of data regarding COVID-19 behaviors among Veterans and represents one of the first large-scale, national surveillance efforts of COVID-19 in the Veteran population. Continued work will examine the overall response to the survey with comparison to available VA health record data.


Assuntos
COVID-19 , Veteranos , Idoso , COVID-19/epidemiologia , Teste para COVID-19 , Feminino , Humanos , Masculino , Saúde Mental , Inquéritos e Questionários , Veteranos/psicologia
3.
Vasc Med ; : 1358863X211067564, 2022 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-35287516

RESUMO

INTRODUCTION: Peripheral artery disease (PAD) is a major cause of cardiovascular morbidity and mortality, yet timely diagnosis is elusive. Larger genome-wide association studies (GWAS) have now provided the ability to evaluate whether genetic data, in the form of genome-wide polygenic risk scores (PRS), can help improve our ability to identify patients at high risk of having PAD. METHODS: Using summary statistic data from the largest PAD GWAS from the Million Veteran Program, we developed PRSs with genome data from UK Biobank. We then evaluated the clinical utility of adding the best-performing PRS to a PAD clinical risk score. RESULTS: A total of 487,320 participants (5759 PAD cases) were included in our final genetic analysis. Compared to participants in the lowest 10% of PRS, those in the highest decile had 3.1 higher odds of having PAD (95% CI, 3.06-3.21). Additionally, a PAD PRS was associated with increased risk of having coronary artery disease, congestive heart failure, and cerebrovascular disease. The PRS significantly improved a clinical risk model (Net Reclassification Index = 0.07, p < 0.001), with most of the performance seen in downgrading risk of controls. Combining clinical and genetic data to detect risk of PAD resulted in a model with an area under the curve of 0.76 (95% CI, 0.75-0.77). CONCLUSION: We demonstrate that a genome-wide PRS can discriminate risk of PAD and other cardiovascular diseases. Adding a PAD PRS to clinical risk models may help improve detection of prevalent, but undiagnosed disease.

4.
Hum Mol Genet ; 2022 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-35234888

RESUMO

Progressive dilation of the infrarenal aortic diameter is a consequence of the ageing process and is considered the main determinant of Abdominal Aortic Aneurysm (AAA). We aimed to investigate the genetic and clinical determinants of abdominal aortic diameter (AAD). We conducted a meta-analysis of genome-wide association studies in ten cohorts (n = 13 542) imputed to the 1000 Genome Project reference panel including 12 815 subjects in the discovery phase and 727 subjects (PBIO) as replication. Maximum anterior-posterior diameter of the infrarenal aorta was used as AAD. We also included exome array data (n = 14 480) from seven epidemiologic studies. Single-variant and gene-based associations were done using SeqMeta package. A Mendelian randomization analysis was applied to investigate the causal effect of a number of clinical risk factors on AAD. In GWAS on AAD, rs74448815 in the intronic region of LDLRAD4 reached genome-wide significance (beta = -0.02, SE = 0.004, p-value = 2.10 × 10-8). The association replicated in the PBIO1 cohort (p-value = 8.19 × 10-4). In exome-array single-variant analysis (p-value threshold = 9 × 10-7), the lowest p-value was found for rs239259 located in SLC22A20 (beta = 0.007, p-value =1.2 × 10-5). In the gene-based analysis (p-value threshold = 1.85 × 10-6), PCSK5 showed an association with AAD (p-value = 8.03 × 10-7). Furthermore, in Mendelian randomization analyses, we found evidence for genetic association of pulse pressure (beta = -0.003, p-value = 0.02), triglycerides (beta = -0.16, p-value = 0.008) and height (beta = 0.03, p-value<0.0001), known risk factors for AAA, consistent with a causal association with AAD. Our findings point to new biology as well as highlighting gene regions in mechanisms that have previously been implicated in the genetics of other vascular diseases.

5.
Circ Genom Precis Med ; 15(2): e003501, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35143253

RESUMO

BACKGROUND: Familial hypercholesterolemia (FH) genetic variants confer risk for coronary artery disease independent of LDL-C (low-density lipoprotein cholesterol) when considering a single measurement. In real clinical settings, longitudinal LDL-C data are often available through the electronic health record. It is unknown whether genetic testing for FH variants provides additional risk-stratifying information once longitudinal LDL-C is considered. METHODS: We used the extensive electronic health record data available through the Million Veteran Program to conduct a nested case-control study. The primary outcome was coronary artery disease, derived from electronic health record codes for acute myocardial infarction and coronary revascularization. Incidence density sampling was used to match case/control exposure windows, defined by the date of the first LDL-C measurement to the date of the first coronary artery disease code of the index case. Adjustments for the first, maximum, or mean LDL-C were analyzed. FH variants in LDLR, APOB, and PCSK9 (Proprotein convertase subtilisin/kexin type 9) were assessed by custom genotype array. RESULTS: In a cohort of 23 091 predominantly prevalent cases at enrollment and 230 910 matched controls, FH variant carriers had an increased risk for coronary artery disease (odds ratio [OR], 1.53 [95% CI, 1.24-1.89]). Adjusting for mean LDL-C led to the greatest attenuation of the risk estimate, but significant risk remained (odds ratio, 1.33 [95% CI, 1.08-1.64]). The degree of attenuation was not affected by the number and the spread of LDL-C measures available. CONCLUSIONS: The risk associated with carrying an FH variant cannot be fully captured by the LDL-C data available in the electronic health record, even when considering multiple LDL-C measurements spanning more than a decade.


Assuntos
Doença da Artéria Coronariana , Hiperlipoproteinemia Tipo II , Estudos de Casos e Controles , LDL-Colesterol , Doença da Artéria Coronariana/epidemiologia , Humanos , Hiperlipoproteinemia Tipo II/epidemiologia , Hiperlipoproteinemia Tipo II/genética , Pró-Proteína Convertase 9/genética , Receptores de LDL/genética
6.
JAMA Intern Med ; 182(4): 386-395, 2022 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-35089317

RESUMO

IMPORTANCE: Coronavirus disease 2019 (COVID-19) confers significant risk of acute kidney injury (AKI). Patients with COVID-19 with AKI have high mortality rates. OBJECTIVE: Individuals with African ancestry with 2 copies of apolipoprotein L1 (APOL1) variants G1 or G2 (high-risk group) have significantly increased rates of kidney disease. We tested the hypothesis that the APOL1 high-risk group is associated with a higher-risk of COVID-19-associated AKI and death. DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study included 990 participants with African ancestry enrolled in the Million Veteran Program who were hospitalized with COVID-19 between March 2020 and January 2021 with available genetic information. EXPOSURES: The primary exposure was having 2 APOL1 risk variants (RV) (APOL1 high-risk group), compared with having 1 or 0 risk variants (APOL1 low-risk group). MAIN OUTCOMES AND MEASURES: The primary outcome was AKI. The secondary outcomes were stages of AKI severity and death. Multivariable logistic regression analyses adjusted for preexisting comorbidities, medications, and inpatient AKI risk factors; 10 principal components of ancestry were performed to study these associations. We performed a subgroup analysis in individuals with normal kidney function prior to hospitalization (estimated glomerular filtration rate ≥60 mL/min/1.73 m2). RESULTS: Of the 990 participants with African ancestry, 905 (91.4%) were male with a median (IQR) age of 68 (60-73) years. Overall, 392 (39.6%) patients developed AKI, 141 (14%) developed stages 2 or 3 AKI, 28 (3%) required dialysis, and 122 (12.3%) died. One hundred twenty-five (12.6%) of the participants were in the APOL1 high-risk group. Patients categorized as APOL1 high-risk group had significantly higher odds of AKI (adjusted odds ratio [OR], 1.95; 95% CI, 1.27-3.02; P = .002), higher AKI severity stages (OR, 2.03; 95% CI, 1.37-2.99; P < .001), and death (OR, 2.15; 95% CI, 1.22-3.72; P = .007). The association with AKI persisted in the subgroup with normal kidney function (OR, 1.93; 95% CI, 1.15-3.26; P = .01). Data analysis was conducted between February 2021 and April 2021. CONCLUSIONS AND RELEVANCE: In this cohort study of veterans with African ancestry hospitalized with COVID-19 infection, APOL1 kidney risk variants were associated with higher odds of AKI, AKI severity, and death, even among individuals with prior normal kidney function.


Assuntos
Injúria Renal Aguda , COVID-19 , Veteranos , Injúria Renal Aguda/genética , Afro-Americanos/genética , Idoso , Apolipoproteína L1/genética , Estudos de Coortes , Feminino , Hospitalização , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco
7.
J Biomech Eng ; 144(1)2022 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-34244728

RESUMO

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.


Assuntos
Rigidez Vascular , Animais , Aorta Torácica , Camundongos , Camundongos Endogâmicos C57BL , Nicotina/farmacologia , Estresse Mecânico
8.
Proc Natl Acad Sci U S A ; 119(1)2022 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-34930827

RESUMO

Abdominal aortic aneurysm (AAA) is a common degenerative cardiovascular disease whose pathobiology is not clearly understood. The cellular heterogeneity and cell-type-specific gene regulation of vascular cells in human AAA have not been well-characterized. Here, we performed analysis of whole-genome sequencing data in AAA patients versus controls with the aim of detecting disease-associated variants that may affect gene regulation in human aortic smooth muscle cells (AoSMC) and human aortic endothelial cells (HAEC), two cell types of high relevance to AAA disease. To support this analysis, we generated H3K27ac HiChIP data for these cell types and inferred cell-type-specific gene regulatory networks. We observed that AAA-associated variants were most enriched in regulatory regions in AoSMC, compared with HAEC and CD4+ cells. The cell-type-specific regulation defined by this HiChIP data supported the importance of ERG and the KLF family of transcription factors in AAA disease. The analysis of regulatory elements that contain noncoding variants and also are differentially open between AAA patients and controls revealed the significance of the interleukin-6-mediated signaling pathway. This finding was further validated by including information from the deleteriousness effect of nonsynonymous single-nucleotide variants in AAA patients and additional control data from the Medical Genome Reference Bank dataset. These results shed important insights into AAA pathogenesis and provide a model for cell-type-specific analysis of disease-associated variants.


Assuntos
Aneurisma da Aorta Abdominal/genética , Redes Reguladoras de Genes , Estudos de Casos e Controles , Células Cultivadas , Regulação para Baixo , Humanos , Interleucina-6/metabolismo , Fatores de Transcrição Kruppel-Like/genética , Regulador Transcricional ERG/genética
9.
Sci Rep ; 11(1): 23229, 2021 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-34853358

RESUMO

Biomedical studies have become larger in size and yielded large quantities of data, yet efficient data processing remains a challenge. Here we present Trellis, a cloud-based data and task management framework that completely automates the process from data ingestion to result presentation, while tracking data lineage, facilitating information query, and supporting fault-tolerance and scalability. Using a graph database to coordinate the state of the data processing workflows and a scalable microservice architecture to perform bioinformatics tasks, Trellis has enabled efficient variant calling on 100,000 human genomes collected in the VA Million Veteran Program.

10.
Circ Cardiovasc Imaging ; 14(12): 1122-1132, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34915729

RESUMO

BACKGROUND: Computed tomography-based evaluation of aortic stenosis (AS) by calcium scoring does not consider interleaflet differences in leaflet characteristics. Here, we sought to examine the functional implications of these differences. METHODS: We retrospectively reviewed the computed tomography angiograms of 200 male patients with degenerative calcific AS undergoing transcatheter aortic valve replacement and 20 male patients with normal aortic valves. We compared the computed tomography angiography (CTA)-derived aortic valve leaflet calcification load (AVLCCTA), appearance, and systolic leaflet excursion (LEsys) of individual leaflets. We performed computer simulations of normal valves to investigate how interleaflet differences in LEsys affect aortic valve area. We used linear regression to identify predictors of leaflet-specific calcification in patients with AS. RESULTS: In patients with AS, the noncoronary cusp (NCC) carried the greatest AVLCCTA (365.9 [237.3-595.4] Agatston unit), compared to the left coronary cusp (LCC, 278.5 [169.2-478.8] Agatston unit) and the right coronary cusp (RCC, 240.6 [137.3-439.0] Agatston unit; both P<0.001). However, LCC conferred the least LEsys (42.8° [38.8°-49.0°]) compared to NCC (44.8° [41.1°-49.78°], P=0.001) and RCC (47.7° [42.0°-52.3°], P<0.001) and was more often characterized as predominantly thickened (23.5%) compared to NCC (12.5%) and RCC (16.5%). Computer simulations of normal valves revealed greater reductions in aortic valve area following closures of NCC (-32.2 [-38.4 to -25.8]%) and RCC (-35.7 [-40.2 to -32.9]%) than LCC (-24.5 [-28.5 to -18.3]%; both P<0.001). By linear regression, the AVLCCTA of NCC and RCC, but not LCC, predicted LEsys (both P<0.001) in patients with AS. Both ostial occlusion and ostial height of the right coronary artery predicted AVLCCTA, RCC (P=0.005 and P=0.001). CONCLUSIONS: In male patients, the AVLCCTA of NCC and RCC contribute more to AS than that of LCC. LCC's propensity for noncalcific leaflet thickening and worse LEsys, however, should not be underestimated when using calcium scores to assess AS severity.


Assuntos
Estenose da Valva Aórtica/complicações , Estenose da Valva Aórtica/diagnóstico por imagem , Valva Aórtica/patologia , Calcinose/complicações , Calcinose/diagnóstico por imagem , Angiografia por Tomografia Computadorizada/métodos , Cuidados Pré-Operatórios/métodos , Idoso , Idoso de 80 Anos ou mais , Valva Aórtica/diagnóstico por imagem , Estudos Transversais , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
11.
BMC Med Inform Decis Mak ; 21(1): 289, 2021 10 20.
Artigo em Inglês | MEDLINE | ID: mdl-34670548

RESUMO

BACKGROUND: To describe an automated method for assessment of the plausibility of continuous variables collected in the electronic health record (EHR) data for real world evidence research use. METHODS: The most widely used approach in quality assessment (QA) for continuous variables is to detect the implausible numbers using prespecified thresholds. In augmentation to the thresholding method, we developed a score-based method that leverages the longitudinal characteristics of EHR data for detection of the observations inconsistent with the history of a patient. The method was applied to the height and weight data in the EHR from the Million Veteran Program Data from the Veteran's Healthcare Administration (VHA). A validation study was also conducted. RESULTS: The receiver operating characteristic (ROC) metrics of the developed method outperforms the widely used thresholding method. It is also demonstrated that different quality assessment methods have a non-ignorable impact on the body mass index (BMI) classification calculated from height and weight data in the VHA's database. CONCLUSIONS: The score-based method enables automated and scaled detection of the problematic data points in health care big data while allowing the investigators to select the high-quality data based on their need. Leveraging the longitudinal characteristics in EHR will significantly improve the QA performance.


Assuntos
Registros Eletrônicos de Saúde , Veteranos , Big Data , Confiabilidade dos Dados , Gerenciamento de Dados , Humanos
12.
medRxiv ; 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34642702

RESUMO

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 ABO locus (rs495828, rs505922) associated with the largest number of phenotypes (nrs495828=53 and nrs505922=59); strongest association with venous embolism, odds ratio (ORrs495828 1.33 (p=1.32 × 10-199), and thrombosis ORrs505922 1.33, p=2.2 × 10-265. Among 67 respiratory conditions tested, 11 had significant associations including MUC5B locus (rs35705950) with increased risk of idiopathic fibrosing alveolitis OR 2.83, p=4.12 × 10-191; CRHR1 (rs61667602) associated with reduced risk of pulmonary fibrosis, OR 0.84, p=2.26 × 10-12. The TYK2 locus (rs11085727) associated with reduced risk for autoimmune conditions, e.g., psoriasis OR 0.88, p=6.48 × 10-23, lupus OR 0.84, p=3.97 × 10-06. PheWAS stratified by genetic ancestry demonstrated differences in genotype-phenotype associations across ancestry. LMNA (rs581342) associated with neutropenia OR 1.29 p=4.1 × 10-13 among Veterans of African ancestry but not European. Overall, we observed a 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.

14.
Biomater Sci ; 9(20): 6903-6914, 2021 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-34522940

RESUMO

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% in vitro 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 peri-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.


Assuntos
Aneurisma da Aorta Abdominal , Túnica Adventícia , Animais , Aneurisma da Aorta Abdominal/terapia , Células Cultivadas , Colágeno , Camundongos , Miócitos de Músculo Liso , Porosidade , Suínos
16.
Am J Hum Genet ; 108(9): 1578-1589, 2021 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-34265237

RESUMO

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.


Assuntos
Aneurisma da Aorta Torácica/genética , Diabetes Mellitus Tipo 2/genética , Células Endoteliais/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Locos de Características Quantitativas , Proteína 2 Semelhante ao Fator 7 de Transcrição/genética , Aorta/metabolismo , Aorta/patologia , Aneurisma da Aorta Torácica/metabolismo , Aneurisma da Aorta Torácica/patologia , Estudos de Casos e Controles , Caspase 3/genética , Caspase 3/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Células Endoteliais/patologia , Regulação da Expressão Gênica , Genoma Humano , Estudo de Associação Genômica Ampla , Humanos , Íntrons , Michigan , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Mutação , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteína 2 Semelhante ao Fator 7 de Transcrição/metabolismo , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo
17.
Sci Rep ; 11(1): 11645, 2021 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-34079032

RESUMO

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 × 10-5), which was replicated in the Penn Medicine Biobank (OR = 1.6, 95% CI 1.2-2.4, p = 6.0 × 10-3) and Million Veteran Program (OR = 1.5, 95% CI 1.2-1.8, p = 1.8 × 10-4). 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 × 10-5) 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.


Assuntos
Neuropatias Amiloides Familiares/diagnóstico , Cardiomiopatias/diagnóstico , Insuficiência Cardíaca/diagnóstico , Polineuropatias/diagnóstico , Pré-Albumina/genética , Adulto , Idoso , Substituição de Aminoácidos , Neuropatias Amiloides Familiares/complicações , Neuropatias Amiloides Familiares/etnologia , Neuropatias Amiloides Familiares/genética , Bancos de Espécimes Biológicos , Cardiomiopatias/complicações , Cardiomiopatias/etnologia , Cardiomiopatias/genética , Feminino , Expressão Gênica , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/etnologia , Insuficiência Cardíaca/genética , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Fenótipo , Polineuropatias/complicações , Polineuropatias/etnologia , Polineuropatias/genética , Prevalência , Reino Unido/epidemiologia
18.
Circulation ; 144(5): 353-364, 2021 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-34139859

RESUMO

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; P=0.003) and CAD (marginal inclusion probability, 0.92; P=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]; P=9×10-10) and CAD (odds ratio,0.66 [95% CI, 0.63-0.69]; P=4×10-73), with a stronger predicted effect of ApoB lowering on CAD (ratio of effects, 3.09 [95% CI, 2.29-4.60]; P<1×10-6). Extra-small very-low-density lipoprotein particle concentration was identified as the most likely subfraction associated with PAD risk (marginal inclusion probability, 0.91; P=2.3×10-4), whereas large low-density lipoprotein particle concentration was the most likely subfraction associated with CAD risk (marginal inclusion probability, 0.95; P=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]; P=1.0×10-33). 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.


Assuntos
Apolipoproteínas/metabolismo , Suscetibilidade a Doenças , Doença Arterial Periférica/epidemiologia , Doença Arterial Periférica/etiologia , Alelos , Apolipoproteínas/sangue , Biomarcadores , Perfilação da Expressão Gênica , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Metabolismo dos Lipídeos , Doença Arterial Periférica/diagnóstico , Doença Arterial Periférica/metabolismo , Vigilância em Saúde Pública , Característica Quantitativa Herdável , Medição de Risco , Fatores de Risco , Transcriptoma , Reino Unido/epidemiologia
19.
medRxiv ; 2021 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-34189540

RESUMO

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.

20.
J Am Heart Assoc ; 10(13): e020331, 2021 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-34184541

RESUMO

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; P=1.69×10-4), 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; P=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.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Reposicionamento de Medicamentos , Variação Genética , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Receptor do Peptídeo Semelhante ao Glucagon 1/genética , Insuficiência Cardíaca/prevenção & controle , Hipoglicemiantes/uso terapêutico , Incretinas/uso terapêutico , Biomarcadores/sangue , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/genética , Estudo de Associação Genômica Ampla , Hemoglobina A Glicada/metabolismo , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/fisiopatologia , Humanos , Análise da Randomização Mendeliana , Medição de Risco , Fatores de Risco , Volume Sistólico/efeitos dos fármacos , Resultado do Tratamento , Função Ventricular Esquerda/efeitos dos fármacos
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