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1. Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure.

Author

Shah, Sonia, Henry, Albert, Roselli, Carolina, Lin, Honghuang, Sveinbjörnsson, Garðar, Fatemifar, Ghazaleh, Hedman, Åsa K, Wilk, Jemma B, Morley, Michael P, Chaffin, Mark D, Helgadottir, Anna, Verweij, Niek, Dehghan, Abbas, Almgren, Peter, Andersson, Charlotte, Aragam, Krishna G, Ärnlöv, Johan, Backman, Joshua D, Biggs, Mary L, Bloom, Heather L, Brandimarto, Jeffrey, Brown, Michael R, Buckbinder, Leonard, Carey, David J, Chasman, Daniel I, Chen, Xing, Chen, Xu, Chung, Jonathan, Chutkow, William, Cook, James P, Delgado, Graciela E, Denaxas, Spiros, Doney, Alexander S, Dörr, Marcus, Dudley, Samuel C, Dunn, Michael E, Engström, Gunnar, Esko, Tõnu, Felix, Stephan B, Finan, Chris, Ford, Ian, Ghanbari, Mohsen, Ghasemi, Sahar, Giedraitis, Vilmantas, Giulianini, Franco, Gottdiener, John S, Gross, Stefan, Guðbjartsson, Daníel F, Gutmann, Rebecca, Haggerty, Christopher M, van der Harst, Pim, Hyde, Craig L, Ingelsson, Erik, Jukema, J Wouter, Kavousi, Maryam, Khaw, Kay-Tee, Kleber, Marcus E, Køber, Lars, Koekemoer, Andrea, Langenberg, Claudia, Lind, Lars, Lindgren, Cecilia M, London, Barry, Lotta, Luca A, Lovering, Ruth C, Luan, Jian'an, Magnusson, Patrik, Mahajan, Anubha, Margulies, Kenneth B, März, Winfried, Melander, Olle, Mordi, Ify R, Morgan, Thomas, Morris, Andrew D, Morris, Andrew P, Morrison, Alanna C, Nagle, Michael W, Nelson, Christopher P, Niessner, Alexander, Niiranen, Teemu, O'Donoghue, Michelle L, Owens, Anjali T, Palmer, Colin NA, Parry, Helen M, Perola, Markus, Portilla-Fernandez, Eliana, Psaty, Bruce M, Regeneron Genetics Center, Rice, Kenneth M, Ridker, Paul M, Romaine, Simon PR, Rotter, Jerome I, Salo, Perttu, Salomaa, Veikko, van Setten, Jessica, Shalaby, Alaa A, Smelser, Diane T, Smith, Nicholas L, Stender, Steen, and Stott, David J

Subjects
Regeneron Genetics Center, Humans, Atrial Fibrillation, Cardiomyopathies, Microfilament Proteins, Adaptor Proteins, Signal Transducing, Carrier Proteins, Muscle Proteins, Risk Factors, Case-Control Studies, Ventricular Function, Left, Cyclin-Dependent Kinase Inhibitor p21, Apoptosis Regulatory Proteins, Coronary Artery Disease, Heart Failure, Genome-Wide Association Study, Mendelian Randomization Analysis, Adaptor Proteins, Signal Transducing, Ventricular Function, Left
Abstract

Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies.

Published
2020

2. Abstract 13828: Aptamer Proteomics for Biomarker Discovery in Heart Failure With Preserved Ejection Fraction: The PARADIGM-HF Proteomic Sub-Study

Author

Patel-Murray, Natasha, Zhang, Luqing, Claggett, Brian, Xu, Dongchu, Serrano-Fernandez, Pablo, Wandel, Simon, Xu, Huilei, Healey, Margaret, Turner, Gordon, Chen, Chien-Wei, Zhao, Faye, CHUTKOW, WILLIAM A, Yates, Denise, ODonnell, Christopher, Prescott, Margaret, Lefkowitz, Martin P, Gimpelewicz, Claudio R, Beste, Michael, Gou, Liangke, Desai, Akshay S, Jhund, Pardeep S, Packer, Milton, Pfeffer, Marc A, Redfield, Margaret M, Rouleau, Jean L, ZANNAD, Faiez, Zile, Michael R, McMurray, John J, Mendelson, Michael, Solomon, Scott D, and Cunningham, Jonathan

Published
2023
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3. Aptamer Proteomics for Biomarker Discovery in Heart Failure With Preserved Ejection Fraction: The PARAGON-HF Proteomic Substudy.

Author

Patel-Murray, Natasha L., Luqing Zhang, Claggett, Brian L., Dongchu Xu, Serrano-Fernandez, Pablo, Healey, Margaret, Wandel, Simon, Chien-Wei Chen, Jacob, Jaison, Huilei Xu, Turner, Gordon M., Chutkow, William, Yates, Denise P., O'Donnell, Christopher J., Prescott, Margaret F., Lefkowitz, Martin, Gimpelewicz, Claudio R., Beste, Michael T., Zhao, Faye, and Liangke Gou

Published
2024
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4. Machine Learning for Proteomic Risk Scores in Heart Failure

Author

XU, DONGCHU, primary, CUNNINGHAM, JONATHAN, additional, MARTI-CASTELLOTE, PABLO-MIKI, additional, ZHANG, LUQING, additional, PATEL-MURRAY, NATASHA L., additional, PRESCOTT, MARGARET F., additional, CHUTKOW, WILLIAM, additional, MENDELSON, MICHAEL M., additional, SOLOMON, SCOTT D., additional, and CLAGGETT, BRIAN L., additional

Published
2023
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6. Sensory ataxia and cardiac hypertrophy caused by neurovascular oxidative stress in chemogenetic transgenic mouse lines

Author

Yadav, Shambhu, primary, Waldeck-Weiermair, Markus, additional, Spyropoulos, Fotios, additional, Bronson, Roderick, additional, Pandey, Arvind K., additional, Das, Apabrita Ayan, additional, Sisti, Alexander C., additional, Covington, Taylor A., additional, Thulabandu, Venkata, additional, Caplan, Shari, additional, Chutkow, William, additional, Steinhorn, Benjamin, additional, and Michel, Thomas, additional

Published
2023
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7. Clinical characteristics of HFrEF patients with rare pathogenic variants in DCM ‐associated genes: a subgroup analysis of the PARADIGM‐HF trial

Author

Barat, Ana, primary, Chen, Chien‐Wei, additional, Patel‐Murray, Natasha, additional, McMurray, John J.V., additional, Packer, Milton, additional, Solomon, Scott D., additional, Desai, Akshay S., additional, Rouleau, Jean L., additional, Zile, Michael R., additional, Attari, Zenab, additional, Zhang, Cong, additional, Xu, Huilei, additional, Hartman, Nicole, additional, Hon, Claudia, additional, Healey, Margaret, additional, Chutkow, William, additional, O'Donnell, Christopher J., additional, Jacob, Jaison, additional, Lefkowitz, Marty, additional, Mendelson, Michael M., additional, Wandel, Simon, additional, Yates, Denise, additional, and Gimpelewicz, Claudio, additional

Published
2023
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8. Aptamer Proteomics for Biomarker Discovery in Heart Failure With Reduced Ejection Fraction

Author

Zhang, Luqing, primary, Cunningham, Jonathan W., additional, Claggett, Brian L., additional, Jacob, Jaison, additional, Mendelson, Michael M., additional, Serrano-Fernandez, Pablo, additional, Kaiser, Sergio, additional, Yates, Denise P., additional, Healey, Margaret, additional, Chen, Chien-Wei, additional, Turner, Gordon M., additional, Patel-Murray, Natasha L., additional, Zhao, Faye, additional, Beste, Michael T., additional, Laramie, Jason M., additional, Abraham, William T., additional, Jhund, Pardeep S., additional, Kober, Lars, additional, Packer, Milton, additional, Rouleau, Jean, additional, Zile, Michael R., additional, Prescott, Margaret F., additional, Lefkowitz, Martin, additional, McMurray, John J.V., additional, Solomon, Scott D., additional, and Chutkow, William, additional

Published
2022
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9. Clinical characteristics of heart failure with reduced ejection fraction patients with rare pathogenic variants in dilated cardiomyopathy‐associated genes: A subgroup analysis of the PARADIGM‐HF trial.

Author

Barat, Ana, Chen, Chien‐Wei, Patel‐Murray, Natasha, McMurray, John J.V., Packer, Milton, Solomon, Scott D., Desai, Akshay S., Rouleau, Jean L., Zile, Michael R., Attari, Zenab, Zhang, Cong, Xu, Huilei, Hartman, Nicole, Hon, Claudia, Healey, Margaret, Chutkow, William, O'Donnell, Christopher J., Jacob, Jaison, Lefkowitz, Marty, and Mendelson, Michael M.

Subjects
HEART failure, VENTRICULAR ejection fraction, CLINICAL trials, SUBGROUP analysis (Experimental design), GENES, DILATED cardiomyopathy
Abstract

Aims: To evaluate the prevalence of pathogenic variants in genes associated with dilated cardiomyopathy (DCM) in a clinical trial population with heart failure and reduced ejection fraction (HFrEF) and describe the baseline characteristics by variant carrier status. Methods and results: This was a post hoc analysis of the Phase 3 PARADIGM‐HF trial. Forty‐four genes, divided into three tiers, based on definitive, moderate or limited evidence of association with DCM, were assessed for rare predicted loss‐of‐function (pLoF) variants, which were prioritized using ClinVar annotations, measures of gene transcriptional output and evolutionary constraint, and pLoF confidence predictions. Prevalence was reported for pLoF variant carriers based on DCM‐associated gene tiers. Clinical features were compared between carriers and non‐carriers. Of the 1412 HFrEF participants with whole‐exome sequence data, 68 (4.8%) had at least one pLoF variant in the 8 tier‐1 genes (definitive/strong association with DCM), with Titin being most commonly affected. The prevalence increased to 7.5% when considering all 44 genes. Among patients with idiopathic aetiology, 10.0% (23/229) had tier‐1 variants only and 12.6% (29/229) had tier‐1, ‐2 or ‐3 variants. Compared to non‐carriers, tier‐1 carriers were younger (4 years; adjusted p‐value [padj] = 4 × 10−3), leaner (27.8 kg/m2 vs. 29.4 kg/m2; padj = 3.2 × 10−3), had lower ejection fraction (27.3% vs. 29.8%; padj = 5.8 × 10−3), and less likely to have ischaemic aetiology (37.3% vs. 67.4%; padj = 4 × 10−4). Conclusion: Deleterious pLoF variants in genes with definitive/strong association with DCM were identified in ∼5% of HFrEF patients from a PARADIGM‐HF trial subset, who were younger, had lower ejection fraction and were less likely to have had an ischaemic aetiology. [ABSTRACT FROM AUTHOR]

Published
2023
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10. Aptamer Proteomics for Biomarker Discovery in Heart Failure With Reduced Ejection Fraction

Author

Zhang, Luqing, Cunningham, Jonathan W., Claggett, Brian L., Jacob, Jaison, Mendelson, Michael M., Serrano-Fernandez, Pablo, Kaiser, Sergio, Yates, Denise P., Healey, Margaret, Chen, Chien-Wei, Turner, Gordon M., Patel-Murray, Natasha L., Zhao, Faye, Beste, Michael T., Laramie, Jason M., Abraham, William T., Jhund, Pardeep S., Kober, Lars, Packer, Milton, Rouleau, Jean, Zile, Michael R., Prescott, Margaret F., Lefkowitz, Martin, McMurray, John J. V., Solomon, Scott D., Chutkow, William, Zhang, Luqing, Cunningham, Jonathan W., Claggett, Brian L., Jacob, Jaison, Mendelson, Michael M., Serrano-Fernandez, Pablo, Kaiser, Sergio, Yates, Denise P., Healey, Margaret, Chen, Chien-Wei, Turner, Gordon M., Patel-Murray, Natasha L., Zhao, Faye, Beste, Michael T., Laramie, Jason M., Abraham, William T., Jhund, Pardeep S., Kober, Lars, Packer, Milton, Rouleau, Jean, Zile, Michael R., Prescott, Margaret F., Lefkowitz, Martin, McMurray, John J. V., Solomon, Scott D., and Chutkow, William

Published
2022

15. Deletion of thioredoxin-interacting protein in mice impairs mitochondrial function but protects the myocardium from ischemia-reperfusion injury

Author

Yoshioka, Jun, Chutkow, William A., Lee, Samuel, Kim, Jae Bum, Yan, Jie, Tian, Rong, Lindsey, Merry L., Feener, Edward P., Seidman, Christine E., Seidman, Jonathan G., and Lee, Richard T.

Subjects
Diagnosis, Care and treatment, Research, Genetic aspects, Risk factors, Health aspects, Heart diseases -- Diagnosis -- Care and treatment -- Research -- Risk factors -- Genetic aspects, Antioxidants (Nutrients) -- Health aspects -- Analysis -- Research, Gene expression -- Health aspects -- Analysis -- Research, Antioxidants -- Health aspects -- Analysis -- Research
Abstract

Introduction The clinical profile of ischemic heart disease has changed profoundly over the last decade, with a growing prevalence of systemic metabolic disorders. As the metabolic syndrome can decrease the [...], Classic therapeutics for ischemic heart disease are less effective in individuals with the metabolic syndrome. As the prevalence of the metabolic syndrome is increasing, better understanding of cardiac metabolism is needed to identify potential new targets for therapeutic intervention. Thioredoxin-interacting protein (Txnip) is a regulator of metabolism and an inhibitor of the antioxidant thioredoxins, but little is known about its roles in the myocardium. We examined hearts from Txnip-KO mice by polony multiplex analysis of gene expression and an independent proteomic approach; both methods indicated suppression of genes and proteins participating in mitochondrial metabolism. Consistently, Txnip-KO mitochondria were functionally and structurally altered, showing reduced oxygen consumption and ultrastructural derangements. Given the central role that mitochondria play during hypoxia, we hypothesized that Txnip deletion would enhance ischemia-reperfusion damage. Surprisingly, Txnip-KO hearts had greater recovery of cardiac function after an ischemia-reperfusion insult. Similarly, cardiomyocyte-specific Txnip deletion reduced infarct size after reversible coronary ligation. Coordinated with reduced mitochondrial function, deletion of Txnip enhanced anaerobic glycolysis. Whereas mitochondrial ATP synthesis was minimally decreased by Txnip deletion, cellular ATP content and lactate formation were higher in Txnip-KO hearts after ischemia-reperfusion injury. Pharmacologic inhibition of glycolytic metabolism completely abolished the protection afforded the heart by Txnip deficiency under hypoxic conditions. Thus, although Txnip deletion suppresses mitochondrial function, protection from myocardial ischemia is enhanced as a result of a coordinated shift to enhanced anaerobic metabolism, which provides an energy source outside of mitochondria.

Published
2012
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17. A crisis in late pregnancy

Author

Desai, Akshay S., Chutkow, William A., Economy, Katherine E., Edelman, Elazer, and Dec, William G. Jr.

Subjects
Pregnancy -- Health aspects, Pregnancy, Complications of
Abstract

The case of a 37-year-old woman in the 37th week of pregnancy, that has so far been uncomplicated, admitted with sudden onset of severe bitemporal headache and shortness of breath is discussed to understand the root causes. The patient was suffering from pheochromocytomas, potentially lethal neuroendocrine tumors, and treatment methodologies for the same are highlighted.

Published
2009

18. The genomics of heart failure : design and rationale of the HERMES consortium

Author

Lumbers, R. Thomas, Shah, Sonia, Lin, Honghuang, Czuba, Tomasz, Henry, Albert, Swerdlow, Daniel I., Mälarstig, Anders, Andersson, Charlotte, Verweij, Niek, Holmes, Michael V., Ärnlöv, Johan, Svensson, Per, Hemingway, Harry, Sallah, Neneh, Almgren, Peter, Aragam, Krishna G., Asselin, Geraldine, Backman, Joshua D., Biggs, Mary L., Bloom, Heather L., Boersma, Eric, Brandimarto, Jeffrey, Brown, Michael R., Brunner‐La Rocca, Hans‐Peter, Carey, David J., Chaffin, Mark D., Chasman, Daniel I., Chazara, Olympe, Chen, Xing, Chen, Xu, Chung, Jonathan H., Chutkow, William, Cleland, John G.F., Cook, James P., Denus, Simon, Dehghan, Abbas, Delgado, Graciela E., Denaxas, Spiros, Doney, Alexander S., Dörr, Marcus, Dudley, Samuel C., Engström, Gunnar, Esko, Tõnu, Fatemifar, Ghazaleh, Felix, Stephan B., Finan, Chris, Ford, Ian, Fougerousse, Francoise, Fouodjio, René, Ghanbari, Mohsen, Giedraitis, Vilmantas, Lind, Lars, Smith, J. Gustav, Lumbers, R. Thomas, Shah, Sonia, Lin, Honghuang, Czuba, Tomasz, Henry, Albert, Swerdlow, Daniel I., Mälarstig, Anders, Andersson, Charlotte, Verweij, Niek, Holmes, Michael V., Ärnlöv, Johan, Svensson, Per, Hemingway, Harry, Sallah, Neneh, Almgren, Peter, Aragam, Krishna G., Asselin, Geraldine, Backman, Joshua D., Biggs, Mary L., Bloom, Heather L., Boersma, Eric, Brandimarto, Jeffrey, Brown, Michael R., Brunner‐La Rocca, Hans‐Peter, Carey, David J., Chaffin, Mark D., Chasman, Daniel I., Chazara, Olympe, Chen, Xing, Chen, Xu, Chung, Jonathan H., Chutkow, William, Cleland, John G.F., Cook, James P., Denus, Simon, Dehghan, Abbas, Delgado, Graciela E., Denaxas, Spiros, Doney, Alexander S., Dörr, Marcus, Dudley, Samuel C., Engström, Gunnar, Esko, Tõnu, Fatemifar, Ghazaleh, Felix, Stephan B., Finan, Chris, Ford, Ian, Fougerousse, Francoise, Fouodjio, René, Ghanbari, Mohsen, Giedraitis, Vilmantas, Lind, Lars, and Smith, J. Gustav

Abstract

Aims: The HERMES (HEart failure Molecular Epidemiology for Therapeutic targetS) consortium aims to identify the genomic and molecular basis of heart failure. Methods and results: The consortium currently includes 51 studies from 11 countries, including 68 157 heart failure cases and 949 888 controls, with data on heart failure events and prognosis. All studies collected biological samples and performed genome-wide genotyping of common genetic variants. The enrolment of subjects into participating studies ranged from 1948 to the present day, and the median follow-up following heart failure diagnosis ranged from 2 to 116 months. Forty-nine of 51 individual studies enrolled participants of both sexes; in these studies, participants with heart failure were predominantly male (34–90%). The mean age at diagnosis or ascertainment across all studies ranged from 54 to 84 years. Based on the aggregate sample, we estimated 80% power to genetic variant associations with risk of heart failure with an odds ratio of ≥1.10 for common variants (allele frequency ≥ 0.05) and ≥1.20 for low-frequency variants (allele frequency 0.01–0.05) at P < 5 × 10−8 under an additive genetic model. Conclusions: HERMES is a global collaboration aiming to (i) identify the genetic determinants of heart failure; (ii) generate insights into the causal pathways leading to heart failure and enable genetic approaches to target prioritization; and (iii) develop genomic tools for disease stratification and risk prediction.

Published
2021
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19. The genomics of heart failure:design and rationale of the HERMES consortium

Author

Lumbers, R. Thomas, Shah, Sonia, Lin, Honghuang, Czuba, Tomasz, Henry, Albert, Swerdlow, Daniel I., Mälarstig, Anders, Andersson, Charlotte, Verweij, Niek, Holmes, Michael V., Ärnlöv, Johan, Svensson, Per, Hemingway, Harry, Sallah, Neneh, Almgren, Peter, Aragam, Krishna G., Asselin, Geraldine, Backman, Joshua D., Biggs, Mary L., Bloom, Heather L., Boersma, Eric, Brandimarto, Jeffrey, Brown, Michael R., Brunner-La Rocca, Hans Peter, Carey, David J., Chaffin, Mark D., Chasman, Daniel I., Chazara, Olympe, Chen, Xing, Chen, Xu, Chung, Jonathan H., Chutkow, William, Cleland, John G.F., Cook, James P., de Denus, Simon, Dehghan, Abbas, Delgado, Graciela E., Denaxas, Spiros, Doney, Alexander S., Dörr, Marcus, Dudley, Samuel C., Engström, Gunnar, Esko, Tõnu, Ghanbari, Mohsen, Kardys, Isabella, Kavousi, Maryam, Portilla-Fernandez, Eliana, Teumer, Alexander, Uitterlinden, Andre G., Yang, Jian, Vasan, RS, Smith, JG, Lumbers, R. Thomas, Shah, Sonia, Lin, Honghuang, Czuba, Tomasz, Henry, Albert, Swerdlow, Daniel I., Mälarstig, Anders, Andersson, Charlotte, Verweij, Niek, Holmes, Michael V., Ärnlöv, Johan, Svensson, Per, Hemingway, Harry, Sallah, Neneh, Almgren, Peter, Aragam, Krishna G., Asselin, Geraldine, Backman, Joshua D., Biggs, Mary L., Bloom, Heather L., Boersma, Eric, Brandimarto, Jeffrey, Brown, Michael R., Brunner-La Rocca, Hans Peter, Carey, David J., Chaffin, Mark D., Chasman, Daniel I., Chazara, Olympe, Chen, Xing, Chen, Xu, Chung, Jonathan H., Chutkow, William, Cleland, John G.F., Cook, James P., de Denus, Simon, Dehghan, Abbas, Delgado, Graciela E., Denaxas, Spiros, Doney, Alexander S., Dörr, Marcus, Dudley, Samuel C., Engström, Gunnar, Esko, Tõnu, Ghanbari, Mohsen, Kardys, Isabella, Kavousi, Maryam, Portilla-Fernandez, Eliana, Teumer, Alexander, Uitterlinden, Andre G., Yang, Jian, Vasan, RS, and Smith, JG

Abstract

Aims: The HERMES (HEart failure Molecular Epidemiology for Therapeutic targetS) consortium aims to identify the genomic and molecular basis of heart failure. Methods and results: The consortium currently includes 51 studies from 11 countries, including 68 157 heart failure cases and 949 888 controls, with data on heart failure events and prognosis. All studies collected biological samples and performed genome-wide genotyping of common genetic variants. The enrolment of subjects into participating studies ranged from 1948 to the present day, and the median follow-up following heart failure diagnosis ranged from 2 to 116 months. Forty-nine of 51 individual studies enrolled participants of both sexes; in these studies, participants with heart failure were predominantly male (34–90%). The mean age at diagnosis or ascertainment across all studies ranged from 54 to 84 years. Based on the aggregate sample, we estimated 80% power to genetic variant associations with risk of heart failure with an odds ratio of ≥1.10 for common variants (allele frequency ≥ 0.05) and ≥1.20 for low-frequency variants (allele frequency 0.01–0.05) at P < 5 × 10−8 under an additive genetic model. Conclusions: HERMES is a global collaboration aiming to (i) identify the genetic determinants of heart failure; (ii) generate insights into the causal pathways leading to heart failure and enable genetic approaches to target prioritization; and (iii) develop genomic tools for disease stratification and risk prediction.

Published
2021

20. TXNIP regulates peripheral glucose metabolism in humans

Author

Parikh, Hemang, Carlsson, Emma, Chutkow, William A., Johansson, Lovisa E., Storgaard, Heidi, Poulsen, Pernille, Saxena, Richa, Ladd, Christine, Schulze, P. Christian, Mazzini, Michael J., Jensen, Christine Bjorn, Krook, Anna, Bjornholm, Marie, Tornqvist, Hans, Zierath, Juleen R., Ridderstrale, Martin, Altshuler, David, Lee, Richard T., Vaag, Allan, Groop, Leif C., and Mootha, Vamsi K.

Subjects
Observations, Health aspects, Glucose metabolism -- Health aspects, Medical research -- Health aspects, Gene expression -- Observations -- Health aspects, Proteins -- Health aspects, Medicine, Experimental -- Health aspects
Abstract

Background Type 2 diabetes mellitus (T2DM) is characterized by defects in insulin secretion and action. Impaired glucose uptake in skeletal muscle is believed to be one of the earliest features [...]

Published
2007

28. Cloning, tissue expression, and chromosomal localization of SUR2, the putative drug-binding subunit of cardiac, skeletal muscle, and vascular K-ATP channels

Author

Chutkow, William A., Simon, M. Celeste, Le Beau, Michelle M., and Burant, Charles F.

Subjects
Physiological aspects, Models, Cloning -- Models -- Physiological aspects, Potassium channels -- Physiological aspects -- Models
Abstract

ATP-sensitive inwardly rectifying potassium channels are expressed in a variety of tissues, including heart, skeletal, and smooth muscle, and pancreatic β-cells. Physiological and pharmacological studies suggest the presence of distinct [...]

Published
1996

30. LIK066, a Dual SGLT1/2 Inhibitor, Reduces Weight and Improves Multiple Incretin Hormones in Clinical Proof-of-Concept Studies in Obese Patients With or Without Diabetes

Author

HE, YANLING, primary, HAYNES, WILLIAM G., additional, MEYERS, CHARLES D., additional, AMER, AHMED, additional, ZHANG, YIMING, additional, MAHLING, PING C., additional, MENDONZA, ANISHA E., additional, MA, SHENGLIN, additional, CHUTKOW, WILLIAM, additional, and BACHMAN, ERIC S., additional

Published
2018
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32. Disruption of Sur2-containing [K.sub.ATP] channels enhances insulin-stimulated glucose uptake in skeletal muscle

Author

Chutkow, William A., Samuel, Varman, Hansen, Polly A., Pu, Jielin, Valdivia, Carmen R., Makielski, Jonathan C., and Burant, Charles F.

Subjects
Potassium channels -- Physiological aspects, Glucose metabolism -- Physiological aspects, Diabetes -- Physiological aspects, Insulin -- Physiological transport, Science and technology
Abstract

ATP-sensitive potassium channels ([K.sub.ATP]) are involved in a diverse array of physiologic functions including protection of tissue against ischemic insult, regulation of vascular tone, and modulation of insulin secretion. To improve our understanding of the role of [K.sub.ATP] in these processes, we used a gene-targeting strategy to generate mice with a disruption in the muscle-specific [K.sub.ATP] regulatory subunit, SUR2. Insertional mutagenesis of the Sur2 locus generated homozygous null ([Sur2.sup.-/-]) mice and heterozygote ([Sur2.sup.+/-]) mice that are viable and phenotypically similar to their wild-type littermates to 6 weeks of age despite, respectively, half or no SUR2 mRNA expression or channel activity in skeletal muscle or heart. [Sur2.sup.-/-] animals had lower fasting and fed serum glucose, exhibited improved glucose tolerance during a glucose tolerance test, and demonstrated a more rapid and severe hypoglycemia after administration of insulin. Enhanced glucose use was also observed during in vivo hyperinsulinemic euglycemic clamp studies during which [Sur2.sup.-/-] mice required a greater glucose infusion rate to maintain a target blood glucose level. Enhanced insulin action was intrinsic to the skeletal muscle, as in vitro insulin-stimulated glucose transport was 1.5-fold greater in [Sur2.sup.-/-] muscle than in wild type. Thus, membrane excitability and [K.sub.ATP] activity, to our knowledge, seem to be new components of the insulin-stimulated glucose uptake mechanism, suggesting possible future therapeutic approaches for individuals suffering from diabetes mellitus.

Published
2001

33. The Arrestin Domain Containing 3 (ARRDC3) Protein Regulates Body Mass and Energy Expenditure

Author

Patwari, Parth, Emilsson, Valur, Schadt, Eric E., Chutkow, William A., Lee, Samuel, Marsili, Alessandro, Zhang, Yongzhao, Dobrin, Radu, Cohen, David E., Larsen, P. Reed, Zavacki, Ann Marie, Fong, Loren G., Young, Stephen G., and Lee, Richard T.

Subjects
Male, Mice, Knockout, Sequence Homology, Amino Acid, Arrestins, Adipose Tissue, White, Iceland, Thermogenesis, Adrenergic beta-Agonists, Article, Linkage Disequilibrium, Body Mass Index, Cohort Studies, Mice, Sex Factors, Adipose Tissue, Brown, Genetic Loci, Receptors, Adrenergic, beta, Animals, Chromosomes, Human, Pair 5, Humans, Female, Obesity, Energy Metabolism, Signal Transduction
Abstract

A human genome-wide linkage scan for obesity identified a linkage peak on chromosome 5q13-15. Positional cloning revealed an association of a rare haplotype to high body-mass index (BMI) in males but not females. The risk locus contains a single gene, "arrestin domain-containing 3" (ARRDC3), an uncharacterized α-arrestin. Inactivating Arrdc3 in mice led to a striking resistance to obesity, with greater impact on male mice. Mice with decreased ARRDC3 levels were protected from obesity due to increased energy expenditure through increased activity levels and increased thermogenesis of both brown and white adipose tissues. ARRDC3 interacted directly with β-adrenergic receptors, and loss of ARRDC3 increased the response to β-adrenergic stimulation in isolated adipose tissue. These results demonstrate that ARRDC3 is a gender-sensitive regulator of obesity and energy expenditure and reveal a surprising diversity for arrestin family protein functions.

Published
2011

35. Myocardial Infarction Triggers Chronic Cardiac Autoimmunity in Type 1 Diabetes

Author

Gottumukkala, Raju V. S. R. K., primary, Lv, HuiJuan, additional, Cornivelli, Lizbeth, additional, Wagers, Amy J., additional, Kwong, Raymond Y., additional, Bronson, Roderick, additional, Stewart, Garrick C., additional, Schulze, P. Christian, additional, Chutkow, William, additional, Wolpert, Howard A., additional, Lee, Richard T., additional, and Lipes, Myra A., additional

Published
2012
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36. Targeted Deletion of Thioredoxin-Interacting Protein Regulates Cardiac Dysfunction in Response to Pressure Overload

Author

Yoshioka, Jun, primary, Imahashi, Kenichi, additional, Gabel, Scott A., additional, Chutkow, William A., additional, Burds, Aurora A., additional, Gannon, Joseph, additional, Schulze, P. Christian, additional, MacGillivray, Catherine, additional, London, Robert E., additional, Murphy, Elizabeth, additional, and Lee, Richard T., additional

Published
2007
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39. Deletion of the alpha-arrestin protein Txnip in mice promotes adiposity and adipogenesis while preserving insulin sensitivity.

Author

Chutkow WA, Birkenfeld AL, Brown JD, Lee HY, Frederick DW, Yoshioka J, Patwari P, Kursawe R, Cushman SW, Plutzky J, Shulman GI, Samuel VT, Lee RT, Chutkow, William A, Birkenfeld, Andreas L, Brown, Jonathan D, Lee, Hui-Young, Frederick, David W, Yoshioka, Jun, and Patwari, Parth

Abstract

Objective: Thioredoxin interacting protein (Txnip), a regulator of cellular oxidative stress, is induced by hyperglycemia and inhibits glucose uptake into fat and muscle, suggesting a role for Txnip in type 2 diabetes pathogenesis. Here, we tested the hypothesis that Txnip-null (knockout) mice are protected from insulin resistance induced by a high-fat diet.Research Design and Methods: Txnip gene-deleted (knockout) mice and age-matched wild-type littermate control mice were maintained on a standard chow diet or subjected to 4 weeks of high-fat feeding. Mice were assessed for body composition, fat development, energy balance, and insulin responsiveness. Adipogenesis was measured from ex vivo fat preparations, and in mouse embryonic fibroblasts (MEFs) and 3T3-L1 preadipocytes after forced manipulation of Txnip expression.Results: Txnip knockout mice gained significantly more adipose mass than controls due to a primary increase in both calorie consumption and adipogenesis. Despite increased fat mass, Txnip knockout mice were markedly more insulin sensitive than controls, and augmented glucose transport was identified in both adipose and skeletal muscle. RNA interference gene-silenced preadipocytes and Txnip(-/-) MEFs were markedly adipogenic, whereas Txnip overexpression impaired adipocyte differentiation. As increased adipogenesis and insulin sensitivity suggested aspects of augmented peroxisome proliferator-activated receptor-gamma (PPARgamma) response, we investigated Txnip's regulation of PPARgamma function; manipulation of Txnip expression directly regulated PPARgamma expression and activity.Conclusions: Txnip deletion promotes adiposity in the face of high-fat caloric excess; however, loss of this alpha-arrestin protein simultaneously enhances insulin responsiveness in fat and skeletal muscle, revealing Txnip as a novel mediator of insulin resistance and a regulator of adipogenesis. [ABSTRACT FROM AUTHOR]

Published
2010
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40. Alternative Splicing of sur2Exon 17 Regulates Nucleotide Sensitivity of the ATP-sensitive Potassium Channel*

Author

Chutkow, William A., Makielski, Jonathan C., Nelson, Deborah J., Burant, Charles F., and Fan, Zheng

Abstract

ATP-sensitive potassium channels (KATP) are implicated in a diverse array of physiological functions. Previous work has shown that alternative usage of exons 14, 39, and 40 of the muscle-specific KATPchannel regulatory subunit, sur2, occurs in tissue-specific patterns. Here, we show that exon 17 of the first nucleotide binding fold of sur2is also alternatively spliced. RNase protection demonstrates that SUR2(Δ17) predominates in skeletal muscle and gut and is also expressed in bladder, fat, heart, lung, liver, and kidney. Polymerase chain reaction and restriction digest analysis of sur2cDNA demonstrate the existence of at least five sur2splice variants as follows: SUR2(39), SUR2(40), SUR2(Δ17/39), SUR2(Δ17/40), and SUR2(Δ14/39). Electrophysiological recordings of excised, inside-out patches from COS cells cotransfected with Kir6.2 and the sur2variants demonstrated that exon 17 splicing alters KATPsensitivity to ATP block by 2-fold from ≈40 to ≈90 μmfor exon 17 and Δ17, respectively. Single channel kinetic analysis of SUR2(39) and SUR2(Δ17/39) demonstrated that both exhibited characteristic KATPkinetics but that SUR2(Δ17/39) exhibited longer mean burst durations and shorter mean interburst dwell times. In sum, alternative splicing of sur2enhances the observed diversity of KATPand may contribute to tissue-specific modulation of ATP sensitivity.

Published
1999
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41. Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure

Author

Shah, Sonia, Henry, Albert, Roselli, Carolina, Lin, Honghuang, Sveinbjörnsson, Garðar, Fatemifar, Ghazaleh, Hedman, Åsa K, Wilk, Jemma B, Morley, Michael P, Chaffin, Mark D, Helgadottir, Anna, Verweij, Niek, Dehghan, Abbas, Almgren, Peter, Andersson, Charlotte, Aragam, Krishna G, Ärnlöv, Johan, Backman, Joshua D, Biggs, Mary L, Bloom, Heather L, Brandimarto, Jeffrey, Brown, Michael R, Buckbinder, Leonard, Carey, David J, Chasman, Daniel I, Chen, Xing, Chen, Xu, Chung, Jonathan, Chutkow, William, Cook, James P, Delgado, Graciela E, Denaxas, Spiros, Doney, Alexander S, Dörr, Marcus, Dudley, Samuel C, Dunn, Michael E, Engström, Gunnar, Esko, Tõnu, Felix, Stephan B, Finan, Chris, Ford, Ian, Ghanbari, Mohsen, Ghasemi, Sahar, Giedraitis, Vilmantas, Giulianini, Franco, Gottdiener, John S, Gross, Stefan, Guðbjartsson, Daníel F, Gutmann, Rebecca, Haggerty, Christopher M, Van Der Harst, Pim, Hyde, Craig L, Ingelsson, Erik, Jukema, J Wouter, Kavousi, Maryam, Khaw, Kay-Tee, Kleber, Marcus E, Køber, Lars, Koekemoer, Andrea, Langenberg, Claudia, Lind, Lars, Lindgren, Cecilia M, London, Barry, Lotta, Luca A, Lovering, Ruth C, Luan, Jian'an, Magnusson, Patrik, Mahajan, Anubha, Margulies, Kenneth B, März, Winfried, Melander, Olle, Mordi, Ify R, Morgan, Thomas, Morris, Andrew D, Morris, Andrew P, Morrison, Alanna C, Nagle, Michael W, Nelson, Christopher P, Niessner, Alexander, Niiranen, Teemu, O'Donoghue, Michelle L, Owens, Anjali T, Palmer, Colin NA, Parry, Helen M, Perola, Markus, Portilla-Fernandez, Eliana, Psaty, Bruce M, Regeneron Genetics Center, Rice, Kenneth M, Ridker, Paul M, Romaine, Simon PR, Rotter, Jerome I, Salo, Perttu, Salomaa, Veikko, Van Setten, Jessica, Shalaby, Alaa A, Smelser, Diane T, Smith, Nicholas L, Stender, Steen, Stott, David J, Svensson, Per, Tammesoo, Mari-Liis, Taylor, Kent D, Teder-Laving, Maris, Teumer, Alexander, Thorgeirsson, Guðmundur, Thorsteinsdottir, Unnur, Torp-Pedersen, Christian, Trompet, Stella, Tyl, Benoit, Uitterlinden, Andre G, Veluchamy, Abirami, Völker, Uwe, Voors, Adriaan A, Wang, Xiaosong, Wareham, Nicholas J, Waterworth, Dawn, Weeke, Peter E, Weiss, Raul, Wiggins, Kerri L, Xing, Heming, Yerges-Armstrong, Laura M, Yu, Bing, Zannad, Faiez, Zhao, Jing Hua, Hemingway, Harry, Samani, Nilesh J, McMurray, John JV, Yang, Jian, Visscher, Peter M, Newton-Cheh, Christopher, Malarstig, Anders, Holm, Hilma, Lubitz, Steven A, Sattar, Naveed, Holmes, Michael V, Cappola, Thomas P, Asselbergs, Folkert W, Hingorani, Aroon D, Kuchenbaecker, Karoline, Ellinor, Patrick T, Lang, Chim C, Stefansson, Kari, Smith, J Gustav, Vasan, Ramachandran S, Swerdlow, Daniel I, and Lumbers, R Thomas

Subjects
2. Zero hunger, Cyclin-Dependent Kinase Inhibitor p21, Heart Failure, Microfilament Proteins, Muscle Proteins, Coronary Artery Disease, Mendelian Randomization Analysis, Ventricular Function, Left, 3. Good health, Risk Factors, Case-Control Studies, Atrial Fibrillation, Humans, Apoptosis Regulatory Proteins, Cardiomyopathies, Carrier Proteins, Adaptor Proteins, Signal Transducing, Genome-Wide Association Study
Abstract

Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies.

42. Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure

Author

Shah, Sonia, Henry, Albert, Roselli, Carolina, Lin, Honghuang, Sveinbjörnsson, Garðar, Fatemifar, Ghazaleh, Hedman, Åsa K., Wilk, Jemma B., Morley, Michael P., Chaffin, Mark D., Helgadottir, Anna, Verweij, Niek, Dehghan, Abbas, Almgren, Peter, Andersson, Charlotte, Aragam, Krishna G., Ärnlöv, Johan, Backman, Joshua D., Biggs, Mary L., Bloom, Heather L., Brandimarto, Jeffrey, Brown, Michael R., Buckbinder, Leonard, Carey, David J., Chasman, Daniel I., Chen, Xing, Chen, Xu, Chung, Jonathan, Chutkow, William, Cook, James P., Delgado, Graciela E., Denaxas, Spiros, Doney, Alexander S., Dörr, Marcus, Dudley, Samuel C., Dunn, Michael E., Engström, Gunnar, Esko, Tõnu, Felix, Stephan B., Finan, Chris, Ford, Ian, Ghanbari, Mohsen, Ghasemi, Sahar, Giedraitis, Vilmantas, Giulianini, Franco, Gottdiener, John S., Gross, Stefan, Guðbjartsson, Daníel F., Gutmann, Rebecca, Haggerty, Christopher M., Van Der Harst, Pim, Hyde, Craig L., Ingelsson, Erik, Jukema, J. Wouter, Kavousi, Maryam, Khaw, Kay-Tee, Kleber, Marcus E., Køber, Lars, Koekemoer, Andrea, Langenberg, Claudia, Lind, Lars, Lindgren, Cecilia M., London, Barry, Lotta, Luca A., Lovering, Ruth C., Luan, Jian’an, Magnusson, Patrik, Mahajan, Anubha, Margulies, Kenneth B., März, Winfried, Melander, Olle, Mordi, Ify R., Morgan, Thomas, Morris, Andrew D., Morris, Andrew P., Morrison, Alanna C., Nagle, Michael W., Nelson, Christopher P., Niessner, Alexander, Niiranen, Teemu, O’Donoghue, Michelle L., Owens, Anjali T., Palmer, Colin N. A., Parry, Helen M., Perola, Markus, Portilla-Fernandez, Eliana, Psaty, Bruce M., Rice, Kenneth M., Ridker, Paul M., Romaine, Simon P. R., Rotter, Jerome I., Salo, Perttu, Salomaa, Veikko, Van Setten, Jessica, Shalaby, Alaa A., Smelser, Diane T., Smith, Nicholas L., Stender, Steen, Stott, David J., Svensson, Per, Tammesoo, Mari-Liis, Taylor, Kent D., Teder-Laving, Maris, Teumer, Alexander, Thorgeirsson, Guðmundur, Thorsteinsdottir, Unnur, Torp-Pedersen, Christian, Trompet, Stella, Tyl, Benoit, Uitterlinden, Andre G., Veluchamy, Abirami, Völker, Uwe, Voors, Adriaan A., Wang, Xiaosong, Wareham, Nicholas J., Waterworth, Dawn, Weeke, Peter E., Weiss, Raul, Wiggins, Kerri L., Xing, Heming, Yerges-Armstrong, Laura M., Yu, Bing, Zannad, Faiez, Zhao, Jing Hua, Hemingway, Harry, Samani, Nilesh J., McMurray, John J. V., Yang, Jian, Visscher, Peter M., Newton-Cheh, Christopher, Malarstig, Anders, Holm, Hilma, Lubitz, Steven A., Sattar, Naveed, Holmes, Michael V., Cappola, Thomas P., Asselbergs, Folkert W., Hingorani, Aroon D., Kuchenbaecker, Karoline, Ellinor, Patrick T., Lang, Chim C., Stefansson, Kari, Smith, J. Gustav, Vasan, Ramachandran S., Swerdlow, Daniel I., Lumbers, R. Thomas, Abecasis, Goncalo, Backman, Joshua, Bai, Xiaodong, Balasubramanian, Suganthi, Banerjee, Nilanjana, Baras, Aris, Barnard, Leland, Beechert, Christina, Blumenfeld, Andrew, Cantor, Michael, Chai, Yating, Coppola, Giovanni, Damask, Amy, Dewey, Frederick, Economides, Aris, Eom, Gisu, Forsythe, Caitlin, Fuller, Erin D., Gu, Zhenhua, Gurski, Lauren, Guzzardo, Paloma M., Habegger, Lukas, Hahn, Young, Hawes, Alicia, Van Hout, Cristopher, Jones, Marcus B., Khalid, Shareef, Lattari, Michael, Li, Alexander, Lin, Nan, Liu, Daren, Lopez, Alexander, Manoochehri, Kia, Marchini, Jonathan, Marcketta, Anthony, Maxwell, Evan K., McCarthy, Shane, Mitnaul, Lyndon J., O’Dushlaine, Colm, Overton, John D., Padilla, Maria Sotiropoulos, Paulding, Charles, Penn, John, Pradhan, Manasi, Reid, Jeffrey G., Schleicher, Thomas D., Schurmann, Claudia, Shuldiner, Alan, Staples, Jeffrey C., Sun, Dylan, Toledo, Karina, Ulloa, Ricardo H., Widom, Louis, Wolf, Sarah E., Yadav, Ashish, and Ye, Bin

Subjects
2. Zero hunger, 631/443/592/2727, 631/208/205/2138, 692/699/75/230, 45/43, article, 692/308/174, 3. Good health
Abstract

Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies.

43. The genomics of heart failure: design and rationale of the HERMES consortium

Author

Lumbers, R. Thomas, Shah, Sonia, Lin, Honghuang, Czuba, Tomasz, Henry, Albert, Swerdlow, Daniel I., Mälarstig, Anders, Andersson, Charlotte, Verweij, Niek, Holmes, Michael V., Ärnlöv, Johan, Svensson, Per, Hemingway, Harry, Sallah, Neneh, Almgren, Peter, Aragam, Krishna G., Asselin, Geraldine, Backman, Joshua D., Biggs, Mary L., Bloom, Heather L., Boersma, Eric, Brandimarto, Jeffrey, Brown, Michael R., Brunner‐La Rocca, Hans‐Peter, Carey, David J., Chaffin, Mark D., Chasman, Daniel I., Chazara, Olympe, Chen, Xing, Chen, Xu, Chung, Jonathan H., Chutkow, William, Cleland, John G.F., Cook, James P., De Denus, Simon, Dehghan, Abbas, Delgado, Graciela E., Denaxas, Spiros, Doney, Alexander S., Dörr, Marcus, Dudley, Samuel C., Engström, Gunnar, Esko, Tõnu, Fatemifar, Ghazaleh, Felix, Stephan B., Finan, Chris, Ford, Ian, Fougerousse, Francoise, Fouodjio, René, Ghanbari, Mohsen, Ghasemi, Sahar, Giedraitis, Vilmantas, Giulianini, Franco, Gottdiener, John S., Gross, Stefan, Guðbjartsson, Daníel F., Gui, Hongsheng, Gutmann, Rebecca, Haggerty, Christopher M., Van Der Harst, Pim, Hedman, Åsa K., Helgadottir, Anna, Hillege, Hans, Hyde, Craig L., Jacob, Jaison, Jukema, J. Wouter, Kamanu, Frederick, Kardys, Isabella, Kavousi, Maryam, Khaw, Kay‐Tee, Kleber, Marcus E., Køber, Lars, Koekemoer, Andrea, Kraus, Bill, Kuchenbaecker, Karoline, Langenberg, Claudia, Lind, Lars, Lindgren, Cecilia M., London, Barry, Lotta, Luca A., Lovering, Ruth C., Luan, Jian'an, Magnusson, Patrik, Mahajan, Anubha, Mann, Douglas, Margulies, Kenneth B., Marston, Nicholas A., März, Winfried, McMurray, John J.V., Melander, Olle, Melloni, Giorgio, Mordi, Ify R., Morley, Michael P., Morris, Andrew D., Morris, Andrew P., Morrison, Alanna C., Nagle, Michael W., Nelson, Christopher P., Newton‐Cheh, Christopher, Niessner, Alexander, Niiranen, Teemu, Nowak, Christoph, O'Donoghue, Michelle L., Owens, Anjali T., Palmer, Colin N.A., Paré, Guillaume, Perola, Markus, Perreault, Louis‐Philippe Lemieux, Portilla‐Fernandez, Eliana, Psaty, Bruce M., Rice, Kenneth M., Ridker, Paul M., Romaine, Simon P.R., Roselli, Carolina, Rotter, Jerome I., Ruff, Christian T., Sabatine, Marc S., Salo, Perttu, Salomaa, Veikko, Van Setten, Jessica, Shalaby, Alaa A., Smelser, Diane T., Smith, Nicholas L., Stefansson, Kari, Stender, Steen, Stott, David J., Sveinbjörnsson, Garðar, Tammesoo, Mari‐Liis, Tardif, Jean‐Claude, Taylor, Kent D., Teder‐Laving, Maris, Teumer, Alexander, Thorgeirsson, Guðmundur, Thorsteinsdottir, Unnur, Torp‐Pedersen, Christian, Trompet, Stella, Tuckwell, Danny, Tyl, Benoit, Uitterlinden, Andre G., Vaura, Felix, Veluchamy, Abirami, Visscher, Peter M., Völker, Uwe, Voors, Adriaan A., Wang, Xiaosong, Wareham, Nicholas J., Weeke, Peter E., Weiss, Raul, White, Harvey D., Wiggins, Kerri L., Xing, Heming, Yang, Jian, Yang, Yifan, Yerges‐Armstrong, Laura M., Yu, Bing, Zannad, Faiez, Zhao, Faye, Regeneron Genetics Center, Wilk, Jemma B., Holm, Hilma, Sattar, Naveed, Lubitz, Steven A., Lanfear, David E., Shah, Svati, Dunn, Michael E., Wells, Quinn S., Asselbergs, Folkert W., Hingorani, Aroon D., Dubé, Marie‐Pierre, Samani, Nilesh J., Lang, Chim C., Cappola, Thomas P., Ellinor, Patrick T., Vasan, Ramachandran S., and Smith, J. Gustav

Subjects
Study Design, Cardiomyopathy, FOS: Biological sciences, Study Designs, Genetics, Heart failure, Biomarkers, 3. Good health, Association studies
Abstract

Funder: Knut and Alice Wallenberg Foundation; Id: http://dx.doi.org/10.13039/501100004063, Funder: Swedish National Health Service, Funder: Skåne University Hospital; Id: http://dx.doi.org/10.13039/501100011077, Funder: Crafoord Foundation; Id: http://dx.doi.org/10.13039/501100003173, Funder: Department of Medicine, Boston University School of Medicine; Id: http://dx.doi.org/10.13039/100008748, Funder: Evans Medical Foundation; Id: http://dx.doi.org/10.13039/100015927, Funder: National Heart, Lung, and Blood Institute; Id: http://dx.doi.org/10.13039/100000050, Funder: British Heart Foundation Cardiovascular Biomedicine, Funder: NIHR UCLH Biomedical Research Centre; Id: http://dx.doi.org/10.13039/501100012317, Aims: The HERMES (HEart failure Molecular Epidemiology for Therapeutic targetS) consortium aims to identify the genomic and molecular basis of heart failure. Methods and results: The consortium currently includes 51 studies from 11 countries, including 68 157 heart failure cases and 949 888 controls, with data on heart failure events and prognosis. All studies collected biological samples and performed genome‐wide genotyping of common genetic variants. The enrolment of subjects into participating studies ranged from 1948 to the present day, and the median follow‐up following heart failure diagnosis ranged from 2 to 116 months. Forty‐nine of 51 individual studies enrolled participants of both sexes; in these studies, participants with heart failure were predominantly male (34–90%). The mean age at diagnosis or ascertainment across all studies ranged from 54 to 84 years. Based on the aggregate sample, we estimated 80% power to genetic variant associations with risk of heart failure with an odds ratio of ≥1.10 for common variants (allele frequency ≥ 0.05) and ≥1.20 for low‐frequency variants (allele frequency 0.01–0.05) at P < 5 × 10−8 under an additive genetic model. Conclusions: HERMES is a global collaboration aiming to (i) identify the genetic determinants of heart failure; (ii) generate insights into the causal pathways leading to heart failure and enable genetic approaches to target prioritization; and (iii) develop genomic tools for disease stratification and risk prediction.

44. The genomics of heart failure: design and rationale of the HERMES consortium

Author

Lumbers, R Thomas, Shah, Sonia, Lin, Honghuang, Czuba, Tomasz, Henry, Albert, Swerdlow, Daniel I, Mälarstig, Anders, Andersson, Charlotte, Verweij, Niek, Holmes, Michael V, Ärnlöv, Johan, Svensson, Per, Hemingway, Harry, Sallah, Neneh, Almgren, Peter, Aragam, Krishna G, Asselin, Geraldine, Backman, Joshua D, Biggs, Mary L, Bloom, Heather L, Boersma, Eric, Brandimarto, Jeffrey, Brown, Michael R, Brunner-La Rocca, Hans-Peter, Carey, David J, Chaffin, Mark D, Chasman, Daniel I, Chazara, Olympe, Chen, Xing, Chen, Xu, Chung, Jonathan H, Chutkow, William, Cleland, John GF, Cook, James P, De Denus, Simon, Dehghan, Abbas, Delgado, Graciela E, Denaxas, Spiros, Doney, Alexander S, Dörr, Marcus, Dudley, Samuel C, Engström, Gunnar, Esko, Tõnu, Fatemifar, Ghazaleh, Felix, Stephan B, Finan, Chris, Ford, Ian, Fougerousse, Francoise, Fouodjio, René, Ghanbari, Mohsen, Ghasemi, Sahar, Giedraitis, Vilmantas, Giulianini, Franco, Gottdiener, John S, Gross, Stefan, Guðbjartsson, Daníel F, Gui, Hongsheng, Gutmann, Rebecca, Haggerty, Christopher M, Van Der Harst, Pim, Hedman, Åsa K, Helgadottir, Anna, Hillege, Hans, Hyde, Craig L, Jacob, Jaison, Jukema, J Wouter, Kamanu, Frederick, Kardys, Isabella, Kavousi, Maryam, Khaw, Kay-Tee, Kleber, Marcus E, Køber, Lars, Koekemoer, Andrea, Kraus, Bill, Kuchenbaecker, Karoline, Langenberg, Claudia, Lind, Lars, Lindgren, Cecilia M, London, Barry, Lotta, Luca A, Lovering, Ruth C, Luan, Jian'an, Magnusson, Patrik, Mahajan, Anubha, Mann, Douglas, Margulies, Kenneth B, Marston, Nicholas A, März, Winfried, McMurray, John JV, Melander, Olle, Melloni, Giorgio, Mordi, Ify R, Morley, Michael P, Morris, Andrew D, Morris, Andrew P, Morrison, Alanna C, Nagle, Michael W, Nelson, Christopher P, Newton-Cheh, Christopher, Niessner, Alexander, Niiranen, Teemu, Nowak, Christoph, O'Donoghue, Michelle L, Owens, Anjali T, Palmer, Colin NA, Paré, Guillaume, Perola, Markus, Perreault, Louis-Philippe Lemieux, Portilla-Fernandez, Eliana, Psaty, Bruce M, Rice, Kenneth M, Ridker, Paul M, Romaine, Simon PR, Roselli, Carolina, Rotter, Jerome I, Ruff, Christian T, Sabatine, Marc S, Salo, Perttu, Salomaa, Veikko, Van Setten, Jessica, Shalaby, Alaa A, Smelser, Diane T, Smith, Nicholas L, Stefansson, Kari, Stender, Steen, Stott, David J, Sveinbjörnsson, Garðar, Tammesoo, Mari-Liis, Tardif, Jean-Claude, Taylor, Kent D, Teder-Laving, Maris, Teumer, Alexander, Thorgeirsson, Guðmundur, Thorsteinsdottir, Unnur, Torp-Pedersen, Christian, Trompet, Stella, Tuckwell, Danny, Tyl, Benoit, Uitterlinden, Andre G, Vaura, Felix, Veluchamy, Abirami, Visscher, Peter M, Völker, Uwe, Voors, Adriaan A, Wang, Xiaosong, Wareham, Nicholas J, Weeke, Peter E, Weiss, Raul, White, Harvey D, Wiggins, Kerri L, Xing, Heming, Yang, Jian, Yang, Yifan, Yerges-Armstrong, Laura M, Yu, Bing, Zannad, Faiez, Zhao, Faye, Regeneron Genetics Center, Wilk, Jemma B, Holm, Hilma, Sattar, Naveed, Lubitz, Steven A, Lanfear, David E, Shah, Svati, Dunn, Michael E, Wells, Quinn S, Asselbergs, Folkert W, Hingorani, Aroon D, Dubé, Marie-Pierre, Samani, Nilesh J, Lang, Chim C, Cappola, Thomas P, Ellinor, Patrick T, Vasan, Ramachandran S, and Smith, J Gustav

Subjects
Aged, 80 and over, Heart Failure, Male, Cardiomyopathy, Genomics, Middle Aged, 16. Peace & justice, Prognosis, 3. Good health, FOS: Biological sciences, Genetics, Humans, Female, Biomarkers, Association studies, Aged, Genome-Wide Association Study
Abstract

AIMS: The HERMES (HEart failure Molecular Epidemiology for Therapeutic targetS) consortium aims to identify the genomic and molecular basis of heart failure. METHODS AND RESULTS: The consortium currently includes 51 studies from 11 countries, including 68 157 heart failure cases and 949 888 controls, with data on heart failure events and prognosis. All studies collected biological samples and performed genome-wide genotyping of common genetic variants. The enrolment of subjects into participating studies ranged from 1948 to the present day, and the median follow-up following heart failure diagnosis ranged from 2 to 116 months. Forty-nine of 51 individual studies enrolled participants of both sexes; in these studies, participants with heart failure were predominantly male (34-90%). The mean age at diagnosis or ascertainment across all studies ranged from 54 to 84 years. Based on the aggregate sample, we estimated 80% power to genetic variant associations with risk of heart failure with an odds ratio of ≥1.10 for common variants (allele frequency ≥ 0.05) and ≥1.20 for low-frequency variants (allele frequency 0.01-0.05) at P < 5 × 10-8 under an additive genetic model. CONCLUSIONS: HERMES is a global collaboration aiming to (i) identify the genetic determinants of heart failure; (ii) generate insights into the causal pathways leading to heart failure and enable genetic approaches to target prioritization; and (iii) develop genomic tools for disease stratification and risk prediction.

45. Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure

Author

Shah, Sonia, Henry, Albert, Roselli, Carolina, Lin, Honghuang, Sveinbjörnsson, Garðar, Fatemifar, Ghazaleh, Hedman, Åsa K, Wilk, Jemma B, Morley, Michael P, Chaffin, Mark D, Helgadottir, Anna, Verweij, Niek, Dehghan, Abbas, Almgren, Peter, Andersson, Charlotte, Aragam, Krishna G, Ärnlöv, Johan, Backman, Joshua D, Biggs, Mary L, Bloom, Heather L, Brandimarto, Jeffrey, Brown, Michael R, Buckbinder, Leonard, Carey, David J, Chasman, Daniel I, Chen, Xing, Chen, Xu, Chung, Jonathan, Chutkow, William, Cook, James P, Delgado, Graciela E, Denaxas, Spiros, Doney, Alexander S, Dörr, Marcus, Dudley, Samuel C, Dunn, Michael E, Engström, Gunnar, Esko, Tõnu, Felix, Stephan B, Finan, Chris, Ford, Ian, Ghanbari, Mohsen, Ghasemi, Sahar, Giedraitis, Vilmantas, Giulianini, Franco, Gottdiener, John S, Gross, Stefan, Guðbjartsson, Daníel F, Gutmann, Rebecca, Haggerty, Christopher M, Van Der Harst, Pim, Hyde, Craig L, Ingelsson, Erik, Jukema, J Wouter, Kavousi, Maryam, Khaw, Kay-Tee, Kleber, Marcus E, Køber, Lars, Koekemoer, Andrea, Langenberg, Claudia, Lind, Lars, Lindgren, Cecilia M, London, Barry, Lotta, Luca A, Lovering, Ruth C, Luan, Jian'an, Magnusson, Patrik, Mahajan, Anubha, Margulies, Kenneth B, März, Winfried, Melander, Olle, Mordi, Ify R, Morgan, Thomas, Morris, Andrew D, Morris, Andrew P, Morrison, Alanna C, Nagle, Michael W, Nelson, Christopher P, Niessner, Alexander, Niiranen, Teemu, O'Donoghue, Michelle L, Owens, Anjali T, Palmer, Colin N A, Parry, Helen M, Perola, Markus, Portilla-Fernandez, Eliana, Psaty, Bruce M, Rice, Kenneth M, Ridker, Paul M, Romaine, Simon P R, Rotter, Jerome I, Salo, Perttu, Salomaa, Veikko, Van Setten, Jessica, Shalaby, Alaa A, Smelser, Diane T, Smith, Nicholas L, Stender, Steen, Stott, David J, Svensson, Per, Tammesoo, Mari-Liis, Taylor, Kent D, Teder-Laving, Maris, Teumer, Alexander, Thorgeirsson, Guðmundur, Thorsteinsdottir, Unnur, Torp-Pedersen, Christian, Trompet, Stella, Tyl, Benoit, Uitterlinden, Andre G, Veluchamy, Abirami, Völker, Uwe, Voors, Adriaan A, Wang, Xiaosong, Wareham, Nicholas J, Waterworth, Dawn, Weeke, Peter E, Weiss, Raul, Wiggins, Kerri L, Xing, Heming, Yerges-Armstrong, Laura M, Yu, Bing, Zannad, Faiez, Zhao, Jing Hua, Hemingway, Harry, Samani, Nilesh J, McMurray, John J V, Yang, Jian, Visscher, Peter M, Newton-Cheh, Christopher, Malarstig, Anders, Holm, Hilma, Lubitz, Steven A, Sattar, Naveed, Holmes, Michael V, Cappola, Thomas P, Asselbergs, Folkert W, Hingorani, Aroon D, Kuchenbaecker, Karoline, Ellinor, Patrick T, Lang, Chim C, Stefansson, Kari, Smith, J Gustav, Vasan, Ramachandran S, Swerdlow, Daniel I, and Lumbers, R Thomas

Subjects
2. Zero hunger, 3. Good health
Abstract

Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies.

46. The genomics of heart failure: design and rationale of the HERMES consortium.

Author

Lumbers RT, Shah S, Lin H, Czuba T, Henry A, Swerdlow DI, Mälarstig A, Andersson C, Verweij N, Holmes MV, Ärnlöv J, Svensson P, Hemingway H, Sallah N, Almgren P, Aragam KG, Asselin G, Backman JD, Biggs ML, Bloom HL, Boersma E, Brandimarto J, Brown MR, Brunner-La Rocca HP, Carey DJ, Chaffin MD, Chasman DI, Chazara O, Chen X, Chen X, Chung JH, Chutkow W, Cleland JGF, Cook JP, de Denus S, Dehghan A, Delgado GE, Denaxas S, Doney AS, Dörr M, Dudley SC, Engström G, Esko T, Fatemifar G, Felix SB, Finan C, Ford I, Fougerousse F, Fouodjio R, Ghanbari M, Ghasemi S, Giedraitis V, Giulianini F, Gottdiener JS, Gross S, Guðbjartsson DF, Gui H, Gutmann R, Haggerty CM, van der Harst P, Hedman ÅK, Helgadottir A, Hillege H, Hyde CL, Jacob J, Jukema JW, Kamanu F, Kardys I, Kavousi M, Khaw KT, Kleber ME, Køber L, Koekemoer A, Kraus B, Kuchenbaecker K, Langenberg C, Lind L, Lindgren CM, London B, Lotta LA, Lovering RC, Luan J, Magnusson P, Mahajan A, Mann D, Margulies KB, Marston NA, März W, McMurray JJV, Melander O, Melloni G, Mordi IR, Morley MP, Morris AD, Morris AP, Morrison AC, Nagle MW, Nelson CP, Newton-Cheh C, Niessner A, Niiranen T, Nowak C, O'Donoghue ML, Owens AT, Palmer CNA, Paré G, Perola M, Perreault LL, Portilla-Fernandez E, Psaty BM, Rice KM, Ridker PM, Romaine SPR, Roselli C, Rotter JI, Ruff CT, Sabatine MS, Salo P, Salomaa V, van Setten J, Shalaby AA, Smelser DT, Smith NL, Stefansson K, Stender S, Stott DJ, Sveinbjörnsson G, Tammesoo ML, Tardif JC, Taylor KD, Teder-Laving M, Teumer A, Thorgeirsson G, Thorsteinsdottir U, Torp-Pedersen C, Trompet S, Tuckwell D, Tyl B, Uitterlinden AG, Vaura F, Veluchamy A, Visscher PM, Völker U, Voors AA, Wang X, Wareham NJ, Weeke PE, Weiss R, White HD, Wiggins KL, Xing H, Yang J, Yang Y, Yerges-Armstrong LM, Yu B, Zannad F, Zhao F, Wilk JB, Holm H, Sattar N, Lubitz SA, Lanfear DE, Shah S, Dunn ME, Wells QS, Asselbergs FW, Hingorani AD, Dubé MP, Samani NJ, Lang CC, Cappola TP, Ellinor PT, Vasan RS, and Smith JG

Subjects
Aged, Aged, 80 and over, Female, Genomics, Humans, Male, Middle Aged, Prognosis, Genome-Wide Association Study, Heart Failure genetics
Abstract

Aims: The HERMES (HEart failure Molecular Epidemiology for Therapeutic targetS) consortium aims to identify the genomic and molecular basis of heart failure., Methods and Results: The consortium currently includes 51 studies from 11 countries, including 68 157 heart failure cases and 949 888 controls, with data on heart failure events and prognosis. All studies collected biological samples and performed genome-wide genotyping of common genetic variants. The enrolment of subjects into participating studies ranged from 1948 to the present day, and the median follow-up following heart failure diagnosis ranged from 2 to 116 months. Forty-nine of 51 individual studies enrolled participants of both sexes; in these studies, participants with heart failure were predominantly male (34-90%). The mean age at diagnosis or ascertainment across all studies ranged from 54 to 84 years. Based on the aggregate sample, we estimated 80% power to genetic variant associations with risk of heart failure with an odds ratio of ≥1.10 for common variants (allele frequency ≥ 0.05) and ≥1.20 for low-frequency variants (allele frequency 0.01-0.05) at P < 5 × 10 -8 under an additive genetic model., Conclusions: HERMES is a global collaboration aiming to (i) identify the genetic determinants of heart failure; (ii) generate insights into the causal pathways leading to heart failure and enable genetic approaches to target prioritization; and (iii) develop genomic tools for disease stratification and risk prediction., (© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Published
2021
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47. Clinical problem-solving. A crisis in late pregnancy.

Author

Desai AS, Chutkow WA, Edelman E, Economy KE, and Dec GW Jr

Subjects
Adrenal Gland Neoplasms complications, Adrenal Gland Neoplasms pathology, Adult, Catecholamines blood, Catecholamines urine, Diagnosis, Differential, Diagnostic Errors, Dyspnea etiology, Female, Fetal Death, Headache etiology, Heart Failure etiology, Hemoglobins analysis, Humans, Metanephrine blood, Pheochromocytoma complications, Pheochromocytoma pathology, Postpartum Period, Pre-Eclampsia diagnosis, Pregnancy, Pregnancy Complications etiology, Pregnancy Trimester, Third, Pulmonary Edema diagnosis, Pulmonary Edema etiology, Tachycardia etiology, Ventricular Dysfunction, Left etiology, Adrenal Gland Neoplasms diagnosis, Pheochromocytoma diagnosis, Pregnancy Complications diagnosis
Published
2009
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