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1.
EBioMedicine ; 80: 104038, 2022 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-35500537

RESUMO

BACKGROUND: Maintaining a healthy lifestyle to reduce type 2 diabetes (T2D) risk is challenging and additional strategies for T2D prevention are needed. We evaluated several lipid control medications as potential therapeutic options for T2D prevention using tissue-specific predicted gene expression summary statistics in a two-sample Mendelian randomisation (MR) design. METHODS: Large-scale European genome-wide summary statistics for lipids and T2D were leveraged in our multi-stage analysis to estimate changes in either lipid levels or T2D risk driven by tissue-specific predicted gene expression. We incorporated tissue-specific predicted gene expression summary statistics to proxy therapeutic effects of three lipid control medications [i.e., statins, icosapent ethyl (IPE), and proprotein convertase subtilisin/kexin type-9 inhibitors (PCSK-9i)] on T2D susceptibility using two-sample Mendelian randomisation (MR). FINDINGS: IPE, as proxied via increased FADS1 expression, was predicted to lower triglycerides and was associated with a 53% reduced risk of T2D. Statins and PCSK-9i, as proxied by reduced HMGCR and PCSK9 expression, respectively, were predicted to lower LDL-C levels but were not associated with T2D susceptibility. INTERPRETATION: Triglyceride lowering via IPE may reduce the risk of developing T2D in populations of European ancestry. However, experimental validation using animal models is needed to substantiate our results and to motivate randomized control trials (RCTs) for IPE as putative treatment for T2D prevention. FUNDING: Only summary statistics were used in this analysis. Funding information is detailed under Acknowledgments.

3.
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
4.
Commun Biol ; 5(1): 329, 2022 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-35393509

RESUMO

South Asians are at high risk of developing type 2 diabetes (T2D). We carried out a genome-wide association meta-analysis with South Asian T2D cases (n = 16,677) and controls (n = 33,856), followed by combined analyses with Europeans (neff = 231,420). We identify 21 novel genetic loci for significant association with T2D (P = 4.7 × 10-8 to 5.2 × 10-12), to the best of our knowledge at the point of analysis. The loci are enriched for regulatory features, including DNA methylation and gene expression in relevant tissues, and highlight CHMP4B, PDHB, LRIG1 and other genes linked to adiposity and glucose metabolism. A polygenic risk score based on South Asian-derived summary statistics shows ~4-fold higher risk for T2D between the top and bottom quartile. Our results provide further insights into the genetic mechanisms underlying T2D, and highlight the opportunities for discovery from joint analysis of data from across ancestral populations.


Assuntos
Diabetes Mellitus Tipo 2 , Estudo de Associação Genômica Ampla , /genética , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/genética , Predisposição Genética para Doença , Humanos , Polimorfismo de Nucleotídeo Único
5.
EBioMedicine ; 78: 103953, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35325778

RESUMO

BACKGROUND: Dyslipidaemia is highly prevalent in individuals with type 2 diabetes mellitus (T2DM). Numerous studies have sought to disentangle the causal relationship between dyslipidaemia and T2DM liability. However, conventional observational studies are vulnerable to confounding. Mendelian Randomization (MR) studies (which address this bias) on lipids and T2DM liability have focused on European ancestry individuals, with none to date having been performed in individuals of African ancestry. We therefore sought to use MR to investigate the causal effect of various lipid traits on T2DM liability in African ancestry individuals. METHODS: Using univariable and multivariable two-sample MR, we leveraged summary-level data for lipid traits and T2DM liability from the African Partnership for Chronic Disease Research (APCDR) (N = 13,612, 36.9% men) and from African ancestry individuals in the Million Veteran Program (Ncases = 23,305 and Ncontrols = 30,140, 87.2% men), respectively. Genetic instruments were thus selected from the APCDR after which they were clumped to obtain independent instruments. We used a random-effects inverse variance weighted method in our primary analysis, complementing this with additional sensitivity analyses robust to the presence of pleiotropy. FINDINGS: Increased genetically proxied low-density lipoprotein cholesterol (LDL-C) and total cholesterol (TC) levels were associated with increased T2DM liability in African ancestry individuals (odds ratio (OR) [95% confidence interval, P-value] per standard deviation (SD) increase in LDL-C = 1.052 [1.000 to 1.106, P = 0.046] and per SD increase in TC = 1.089 [1.014 to 1.170, P = 0.019]). Conversely, increased genetically proxied high-density lipoprotein cholesterol (HDL-C) was associated with reduced T2DM liability (OR per SD increase in HDL-C = 0.915 [0.843 to 0.993, P = 0.033]). The OR on T2DM per SD increase in genetically proxied triglyceride (TG) levels was 0.884 [0.773 to 1.011, P = 0.072] . With respect to lipid-lowering drug targets, we found that genetically proxied 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) inhibition was associated with increased T2DM liability (OR per SD decrease in genetically proxied LDL-C = 1.68 [1.03-2.72, P = 0.04]) but we did not find evidence of a relationship between genetically proxied proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition and T2DM liability. INTERPRETATION: Consistent with MR findings in Europeans, HDL-C exerts a protective effect on T2DM liability and HMGCR inhibition increases T2DM liability in African ancestry individuals. However, in contrast to European ancestry individuals, LDL-C may increase T2DM liability in African ancestry individuals. This raises the possibility of ethnic differences in the metabolic effects of dyslipidaemia in T2DM. FUNDING: See the Acknowledgements section for more information.


Assuntos
Diabetes Mellitus Tipo 2 , Pró-Proteína Convertase 9 , HDL-Colesterol/genética , LDL-Colesterol/genética , Diabetes Mellitus Tipo 2/genética , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo Único , Pró-Proteína Convertase 9/genética , Fatores de Risco
6.
Am J Gastroenterol ; 2022 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-35288522

RESUMO

INTRODUCTION: Vitamin E supplementation is recommended for the treatment of non-alcoholic fatty liver disease (NAFLD) for nondiabetic patients, but its preventative effects are unclear. METHODS: We assessed dietary Vitamin E intake with disease phenotypes and evaluated Vitamin E levels with the development of NAFLD. RESULTS: Data from >210,000 participants demonstrate that increased dietary Vitamin E associates with reduced rates of several gastrointestinal diseases and reduced overall mortality. Diabetic and overweight subjects with increased Vitamin E intake have fewer NAFLD diagnoses. CONCLUSION: Our findings reveal the relevance of Vitamin E consumption for several gastrointestinal diseases and warrant further mechanistic and therapeutic investigations.

7.
Diabetologia ; 65(5): 790-799, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35129650

RESUMO

AIMS/HYPOTHESIS: Type 2 diabetes and atherosclerotic CVD share many risk factors. This study aimed to systematically assess a broad range of continuous traits to separate their direct effects on coronary and peripheral artery disease from those mediated by type 2 diabetes. METHODS: Our main analysis was a two-step Mendelian randomisation for mediation to quantify the extent to which the associations observed between continuous traits and liability to atherosclerotic CVD were mediated by liability to type 2 diabetes. To support this analysis, we performed several univariate Mendelian randomisation analyses to examine the associations between our continuous traits, liability to type 2 diabetes and liability to atherosclerotic CVD. RESULTS: Eight traits were eligible for the two-step Mendelian randomisation with liability to coronary artery disease as the outcome and we found similar direct and total effects in most cases. Exceptions included fasting insulin and hip circumference where the proportion mediated by liability to type 2 diabetes was estimated as 56% and 52%, respectively. Six traits were eligible for the analysis with liability to peripheral artery disease as the outcome. Again, we found limited evidence to support mediation by liability to type 2 diabetes for all traits apart from fasting insulin (proportion mediated: 70%). CONCLUSIONS/INTERPRETATION: Most traits were found to affect liability to atherosclerotic CVD independently of their relationship with liability to type 2 diabetes. These traits are therefore important for understanding atherosclerotic CVD risk regardless of an individual's liability to type 2 diabetes.


Assuntos
Aterosclerose , Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Doença Arterial Periférica , Estudo de Associação Genômica Ampla , Humanos , Insulina , Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo Único , Fatores de Risco
8.
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.

9.
Diabetologia ; 64(12): 2773-2778, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34505161

RESUMO

AIMS/HYPOTHESIS: The aim of this study was to leverage human genetic data to investigate the cardiometabolic effects of glucose-dependent insulinotropic polypeptide (GIP) signalling. METHODS: Data were obtained from summary statistics of large-scale genome-wide association studies. We examined whether genetic associations for type 2 diabetes liability in the GIP and GIPR genes co-localised with genetic associations for 11 cardiometabolic outcomes. For those outcomes that showed evidence of co-localisation (posterior probability >0.8), we performed Mendelian randomisation analyses to estimate the association of genetically proxied GIP signalling with risk of cardiometabolic outcomes, and to test whether this exceeded the estimate observed when considering type 2 diabetes liability variants from other regions of the genome. RESULTS: Evidence of co-localisation with genetic associations of type 2 diabetes liability at both the GIP and GIPR genes was observed for five outcomes. Mendelian randomisation analyses provided evidence for associations of lower genetically proxied type 2 diabetes liability at the GIP and GIPR genes with lower BMI (estimate in SD units -0.16, 95% CI -0.30, -0.02), C-reactive protein (-0.13, 95% CI -0.19, -0.08) and triacylglycerol levels (-0.17, 95% CI -0.22, -0.12), and higher HDL-cholesterol levels (0.19, 95% CI 0.14, 0.25). For all of these outcomes, the estimates were greater in magnitude than those observed when considering type 2 diabetes liability variants from other regions of the genome. CONCLUSIONS/INTERPRETATION: This study provides genetic evidence to support a beneficial role of sustained GIP signalling on cardiometabolic health greater than that expected from improved glycaemic control alone. Further clinical investigation is warranted. DATA AVAILABILITY: All data used in this study are publicly available. The scripts for the analysis are available at: https://github.com/vkarhune/GeneticallyProxiedGIP .


Assuntos
Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Receptores dos Hormônios Gastrointestinais , Doenças Cardiovasculares/genética , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Polipeptídeo Inibidor Gástrico/genética , Polipeptídeo Inibidor Gástrico/metabolismo , Estudo de Associação Genômica Ampla , Glucose/metabolismo , Genética Humana , Humanos , Receptores dos Hormônios Gastrointestinais/genética , Receptores dos Hormônios Gastrointestinais/metabolismo
10.
Med (N Y) ; 2(7): 851-863.e3, 2021 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-34258604

RESUMO

BACKGROUND: A coding variant in MTARC1 (rs2642438; p.Ala165Thr) was recently associated with protection from cirrhosis in European individuals. However, its impact on overall and cause-specific mortality remained elusive. METHODS: Using a genome-first approach, we explored a range of metabolic phenotypes and outcomes associated with MTARC1 p.Ala165Thr in the UKBiobank and the Penn-Medicine BioBank. FINDINGS: MTARC1 p.Ala165Thr was significantly associated with higher triglycerides, lower total cholesterol, lower LDL-C, lower ApoB, lower HDL-C, lower ApoA-I and higher IGF-1. Per each minor allele, the risk of NAFLD was reduced by ~15%. The ALT-lowering and NAFLD-protective effect of MTARC1 p.Ala165Thr was amplified by obesity, diabetes mellitus and presence of PNPLA3 rs738409:G. In African-American and Black-British individuals, the allele frequency of MTARC1 p.Ala165Thr was lower, but carriers showed the same distinctive lipid phenotype. Importantly, MTARC1 p.Ala165Thr carriers did not show higher cardiovascular disease burden as evidenced by cardiac MRI and carotid ultrasound. In prospective analyses, the homozygous minor allele was associated with up to 39% lower rates of liver-related mortality, while no risk of increased overall or cardiovascular death could be observed. Strikingly, liver-related mortality was more than 50% reduced in diabetic participants or carriers of PNPLA3 rs738409:G. CONCLUSIONS: Together these data highlight MTARC1 as an important liver disease modifier that influences plasma lipids in an allele-dose-dependent manner without increasing cardiovascular outcomes. Our results point toward potential mechanisms and reveal a remarkable association with liver-related mortality calling for future studies exploring its therapeutic potential. FUNDING: This study was funded by the German Research Foundation (DFG).


Assuntos
Hepatopatia Gordurosa não Alcoólica , Heterozigoto , Homozigoto , Humanos , Lipase/genética , Proteínas de Membrana/genética , Hepatopatia Gordurosa não Alcoólica/complicações , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Estudos Prospectivos
11.
Stroke ; 52(8): 2680-2684, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34078102

RESUMO

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.


Assuntos
/genética , Análise da Randomização Mendeliana/métodos , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/genética , Adulto , HDL-Colesterol/sangue , HDL-Colesterol/genética , LDL-Colesterol/sangue , LDL-Colesterol/genética , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/genética , Feminino , Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Acidente Vascular Cerebral/epidemiologia , Triglicerídeos/sangue , Triglicerídeos/genética , Reino Unido/epidemiologia
12.
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
13.
Nat Commun ; 12(1): 2579, 2021 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-33972514

RESUMO

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


Assuntos
Alanina Transaminase/genética , Fosfatase Alcalina/genética , Doenças Cardiovasculares/genética , Fígado/enzimologia , Doenças Metabólicas/genética , gama-Glutamiltransferase/genética , Idoso , Alanina Transaminase/sangue , Fosfatase Alcalina/sangue , Doenças Cardiovasculares/enzimologia , Estudos de Coortes , Bases de Dados Genéticas , Feminino , Regulação Enzimológica da Expressão Gênica/genética , Predisposição Genética para Doença , Testes Genéticos , Estudo de Associação Genômica Ampla , Humanos , Resistência à Insulina/genética , Metabolismo dos Lipídeos/genética , Fígado/metabolismo , Masculino , Análise da Randomização Mendeliana , Doenças Metabólicas/enzimologia , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fatores de Risco , gama-Glutamiltransferase/sangue
14.
Nat Med ; 27(4): 668-676, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33837377

RESUMO

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


Assuntos
COVID-19/genética , Reposicionamento de Medicamentos , Análise da Randomização Mendeliana/métodos , SARS-CoV-2 , Enzima de Conversão de Angiotensina 2/genética , Enzima de Conversão de Angiotensina 2/fisiologia , COVID-19/tratamento farmacológico , Estudo de Associação Genômica Ampla , Humanos , Subunidade beta de Receptor de Interleucina-10/genética , Subunidade beta de Receptor de Interleucina-10/fisiologia , Locos de Características Quantitativas , Receptor de Interferon alfa e beta/genética , Receptor de Interferon alfa e beta/fisiologia
17.
Hum Genet ; 140(6): 957-967, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33745059

RESUMO

While newborns and children with hearing loss are routinely offered genetic testing, adults are rarely clinically tested for a genetic etiology. One clinically actionable result from genetic testing in children is the discovery of variants in syndromic hearing loss genes. EYA4 is a known hearing loss gene which is also involved in important pathways in cardiac tissue. The pleiotropic effects of rare EYA4 variants are poorly understood and their prevalence in a large cohort has not been previously reported. We investigated cardio-auditory phenotypes in 11,451 individuals in a large biobank using a rare variant, genome-first approach to EYA4. We filtered 256 EYA4 variants carried by 6737 participants to 26 rare and predicted deleterious variants carried by 42 heterozygotes. We aggregated predicted deleterious EYA4 gene variants into a combined variable (i.e. "gene burden") and performed association studies across phenotypes compared to wildtype controls. We validated findings with replication in three independent cohorts and human tissue expression data. EYA4 gene burden was significantly associated with audiometric-proven HL (p = [Formula: see text], Mobitz Type II AV block (p = [Formula: see text]) and the syndromic presentation of HL and primary cardiomyopathy (p = 0.0194). Analyses on audiogram, echocardiogram, and electrocardiogram data validated these associations. Prior reports have focused on identifying variants in families with severe or syndromic phenotypes. In contrast, we found, using a genotype-first approach, that gene burden in EYA4 is associated with more subtle cardio-auditory phenotypes in an adult medical biobank population, including cardiac conduction disorders which have not been previously reported. We show the value of using a focused approach to uncover human disease related to pleiotropic gene variants and suggest a role for genetic testing in adults presenting with hearing loss.


Assuntos
Cardiomiopatias/genética , Genoma Humano , Perda Auditiva/genética , Mutação , Transativadores/genética , Audiometria , Bancos de Espécimes Biológicos , Cardiomiopatias/diagnóstico por imagem , Cardiomiopatias/etnologia , Cardiomiopatias/patologia , Ecocardiografia , Eletrocardiografia , Expressão Gênica , Perda Auditiva/diagnóstico por imagem , Perda Auditiva/etnologia , Perda Auditiva/patologia , Humanos , Masculino , Pennsylvania , Fenótipo , Índice de Gravidade de Doença , Sequenciamento Completo do Exoma
18.
J Am Med Inform Assoc ; 28(6): 1178-1187, 2021 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-33576413

RESUMO

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.


Assuntos
Aprendizado Profundo , Gordura Abdominal , Bancos de Espécimes Biológicos , Registros Eletrônicos de Saúde , Humanos , Tomografia Computadorizada por Raios X
19.
Front Genet ; 12: 787545, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-35186008

RESUMO

Although affecting different arterial territories, the related atherosclerotic vascular diseases coronary artery disease (CAD) and peripheral artery disease (PAD) share similar risk factors and have shared pathobiology. To identify novel pleiotropic loci associated with atherosclerosis, we performed a joint analysis of their shared genetic architecture, along with that of common risk factors. Using summary statistics from genome-wide association studies of nine known atherosclerotic (CAD, PAD) and atherosclerosis risk factors (body mass index, smoking initiation, type 2 diabetes, low density lipoprotein, high density lipoprotein, total cholesterol, and triglycerides), we perform 15 separate multi-trait genetic association scans which resulted in 25 novel pleiotropic loci not yet reported as genome-wide significant for their respective traits. Colocalization with single-tissue eQTLs identified candidate causal genes at 14 of the detected signals. Notably, the signal between PAD and LDL-C at the PCSK6 locus affects PCSK6 splicing in human liver tissue and induced pluripotent derived hepatocyte-like cells. These results show that joint analysis of related atherosclerotic disease traits and their risk factors allowed identification of unified biology that may offer the opportunity for therapeutic manipulation. The signal at PCSK6 represent possible shared causal biology where existing inhibitors may be able to be leveraged for novel therapies.

20.
Alzheimers Dement ; 17 Suppl 3: e057314, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35109305

RESUMO

BACKGROUND: Diabetes and dementia are diseases of high healthcare burden worldwide, and there is evidence that diabetes is a risk factor for dementia. Compared to those without diabetes, the relative risk of dementia in individuals with diabetes ranges from 1.4 to 2.2. Our goal was to evaluate shared genetic susceptibility for diabetes and dementia. METHOD: Using imputed genotype data from MVP, we built a weighted genetic risk score (GRS) for T2D using 331 variants and their effect sizes from published genome-wide association studies of T2D. We evaluated associations with four nested definitions of dementia: strict Alzheimer's Disease (AD), AD plus non-specific dementias (AD-Plus), AD-related dementia (AD-RD), and all-cause dementia. We used logistic regression to assess associations of the GRS with dementia sub-types, stratified by European, African, and Hispanic ancestries, using a significance threshold of 0.0033 to account for multiple testing. As a sensitivity test, we removed the rs429358 variant near the APOE gene from the GRS as it has known genome-wide significant associations with AD. RESULT: In 19,562 cases and 252,893 controls of European ancestry, we found associations of the T2D GRS with all-cause dementia (p=1.30e-07, OR 1.06), and in 14,455 cases and 258,000 controls with AD-RD (p=3.35e-07, OR = 1.07), but not with AD-Plus or strict AD. The T2D GRS was not associated with any of the dementia outcomes in participants of African (p =0.27 to 0.48) or Hispanic (p = 0.15 to 0.94) ancestries. When removing the APOE locus, we found that the effect size estimates for the GRS increased and the probability of association by chance decreased: all-cause dementia (p=2.08e-12, OR = 1.08), AD-RD (p=1.37e-12, OR = 1.10), and AD-Plus (p=3.97e-06, OR = 1.08). CONCLUSION: We found evidence of shared genetic susceptibility between diabetes and dementia. Future work will evaluate causality of the diabetes-dementia association using Mendelian Randomization. This research is based on data from the Million Veteran Program, Office of Research and Development, Veterans Health Administration, and was supported by awards MVP009 and MVP022. This publication does not represent the views of the Department of Veteran Affairs or the United States Government.

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