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3. Effect of periprocedural furosemide-induced diuresis with matched isotonic intravenous hydration in patients with chronic kidney disease undergoing transcatheter aortic valve implantation

Author

Voigtländer-Buschmann, Lisa, Schäfer, Sarina, Schmidt-Lauber, Christian, Weimann, Jessica, Shenas, Mina, Giraldo Cortes, Julian, Kuta, Piotr Mariusz, Zeller, Tanja, Twerenbold, Raphael, Seiffert, Moritz, Schofer, Niklas, Schneeberger, Yvonne, Schäfer, Andreas, Schirmer, Johannes, Reichenspurner, Hermann, Blankenberg, Stefan, Conradi, Lenard, and Schäfer, Ulrich

Published
2024
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4. Personalized diagnosis in suspected myocardial infarction.

Author

Neumann, Johannes, Twerenbold, Raphael, Ojeda, Francisco, Aldous, Sally, Allen, Brandon, Apple, Fred, Babel, Hugo, Christenson, Robert, Cullen, Louise, Di Carluccio, Eleonora, Doudesis, Dimitrios, Ekelund, Ulf, Giannitsis, Evangelos, Greenslade, Jaimi, Inoue, Kenji, Jernberg, Tomas, Kavsak, Peter, Keller, Till, Lee, Kuan, Lindahl, Bertil, Lorenz, Thiess, Mahler, Simon, Mills, Nicholas, Mokhtari, Arash, Parsonage, William, Pickering, John, Pemberton, Christopher, Reich, Christoph, Richards, A, Sandoval, Yader, Than, Martin, Toprak, Betül, Troughton, Richard, Worster, Andrew, Zeller, Tanja, Ziegler, Andreas, and Blankenberg, Stefan

Subjects
Acute myocardial infarction, Biomarker, Machine learning, Probability, Super learner, Troponin, Validation, Humans, Angina Pectoris, Biomarkers, Myocardial Infarction, ROC Curve, Troponin I, Troponin T, Clinical Studies as Topic
Abstract

BACKGROUND: In suspected myocardial infarction (MI), guidelines recommend using high-sensitivity cardiac troponin (hs-cTn)-based approaches. These require fixed assay-specific thresholds and timepoints, without directly integrating clinical information. Using machine-learning techniques including hs-cTn and clinical routine variables, we aimed to build a digital tool to directly estimate the individual probability of MI, allowing for numerous hs-cTn assays. METHODS: In 2,575 patients presenting to the emergency department with suspected MI, two ensembles of machine-learning models using single or serial concentrations of six different hs-cTn assays were derived to estimate the individual MI probability (ARTEMIS model). Discriminative performance of the models was assessed using area under the receiver operating characteristic curve (AUC) and logLoss. Model performance was validated in an external cohort with 1688 patients and tested for global generalizability in 13 international cohorts with 23,411 patients. RESULTS: Eleven routinely available variables including age, sex, cardiovascular risk factors, electrocardiography, and hs-cTn were included in the ARTEMIS models. In the validation and generalization cohorts, excellent discriminative performance was confirmed, superior to hs-cTn only. For the serial hs-cTn measurement model, AUC ranged from 0.92 to 0.98. Good calibration was observed. Using a single hs-cTn measurement, the ARTEMIS model allowed direct rule-out of MI with very high and similar safety but up to tripled efficiency compared to the guideline-recommended strategy. CONCLUSION: We developed and validated diagnostic models to accurately estimate the individual probability of MI, which allow for variable hs-cTn use and flexible timing of resampling. Their digital application may provide rapid, safe and efficient personalized patient care. TRIAL REGISTRATION NUMBERS: Data of following cohorts were used for this project: BACC ( www. CLINICALTRIALS: gov ; NCT02355457), stenoCardia ( www. CLINICALTRIALS: gov ; NCT03227159), ADAPT-BSN ( www.australianclinicaltrials.gov.au ; ACTRN12611001069943), IMPACT ( www.australianclinicaltrials.gov.au , ACTRN12611000206921), ADAPT-RCT ( www.anzctr.org.au ; ANZCTR12610000766011), EDACS-RCT ( www.anzctr.org.au ; ANZCTR12613000745741); DROP-ACS ( https://www.umin.ac.jp , UMIN000030668); High-STEACS ( www. CLINICALTRIALS: gov ; NCT01852123), LUND ( www. CLINICALTRIALS: gov ; NCT05484544), RAPID-CPU ( www. CLINICALTRIALS: gov ; NCT03111862), ROMI ( www. CLINICALTRIALS: gov ; NCT01994577), SAMIE ( https://anzctr.org.au ; ACTRN12621000053820), SEIGE and SAFETY ( www. CLINICALTRIALS: gov ; NCT04772157), STOP-CP ( www. CLINICALTRIALS: gov ; NCT02984436), UTROPIA ( www. CLINICALTRIALS: gov ; NCT02060760).

Published
2023

5. Association of an impaired GH-IGF-I axis with cardiac wasting in patients with advanced cancer

Author

Fröhlich, Ann-Kathrin, Porthun, Jan, Talha, Khawaja M., Lena, Alessia, Hadzibegovic, Sara, Wilkenshoff, Ursula, Sonntag, Frederike, Nikolski, Anja, Ramer, Luisa Valentina, Zeller, Tanja, Keller, Ulrich, Bullinger, Lars, Anker, Stefan D., Haverkamp, Wilhelm, von Haehling, Stephan, Doehner, Wolfram, Rauch, Ursula, Skurk, Carsten, Cleland, John G. F., Butler, Javed, Coats, Andrew J. S., Landmesser, Ulf, Karakas, Mahir, and Anker, Markus S.

Published
2024
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7. Association of genetic risk and outcomes in patients with atrial fibrillation: interactions with early rhythm control in the EAST-AFNET4 trial.

Author

Kany, Shinwan, Al-Taie, Christoph, Roselli, Carolina, Borof, Katrin, Reinbold, Carla, Suling, Anna, Krause, Linda, Reissmann, Bruno, Schnabel, Renate, Zeller, Tanja, Zapf, Antonia, Wegscheider, Karl, Fabritz, Larissa, Ellinor, Patrick, Kirchhof, Paulus, and Pirruccello, James

Subjects
Atrial fibrillation, Heart failure, Polygenic risk scores, Rhythm control, Stroke, Humans, Female, Aged, Male, Atrial Fibrillation, Brain Ischemia, Stroke, Risk Factors, Heart Failure
Abstract

AIMS: The randomized Early Treatment of Atrial Fibrillation for Stroke Prevention Trial found that early rhythm control reduces cardiovascular events in patients with recently diagnosed atrial fibrillation (AF) compared with usual care. How genetic predisposition to AF and stroke interacts with early rhythm-control therapy is not known. METHODS AND RESULTS: Array genotyping and imputation for common genetic variants were performed. Polygenic risk scores (PRS) were calculated for AF (PRS-AF) and ischaemic stroke risk (PRS-stroke). The effects of PRS-AF and PRS-stroke on the primary outcome (composite of cardiovascular death, stroke, and hospitalization for acute coronary syndrome or worsening heart failure), its components, and recurrent AF were determined.A total of 1567 of the 2789 trial patients were analysed [793 randomized to early rhythm control; 774 to usual care, median age 71 years (65-75), 704 (44%) women]. Baseline characteristics were similar between randomized groups. Early rhythm control reduced the primary outcome compared with usual care [HR 0.67, 95% CI: (0.53, 0.84), P < 0.001]. The randomized intervention, early rhythm control, did not interact with PRS-AF (interaction P = 0.806) or PRS-stroke (interaction P = 0.765). PRS-AF was associated with recurrent AF [HR 1.08 (01.0, 1.16), P = 0.047]. PRS-stroke showed an association with the primary outcome [HR 1.13 (1.0, 1.27), P = 0.048], driven by more heart failure events [HR 1.23 (1.05-1.43), P = 0.010] without differences in stroke [HR 1.0 (0.75, 1.34), P = 0.973] in this well-anticoagulated cohort. In a replication analysis, PRS-stroke was associated with incident AF [HR 1.16 (1.14, 1.67), P < 0.001] and with incident heart failure in the UK Biobank [HR 1.08 (1.06, 1.10), P < 0.001]. The association with heart failure was weakened when excluding AF patients [HR 1.03 (1.01, 1.05), P = 0.001]. CONCLUSIONS: Early rhythm control is effective across the spectrum of genetic AF and stroke risk. The association between genetic stroke risk and heart failure calls for research to understand the interactions between polygenic risk and treatment. REGISTRATION: ISRCTN04708680, NCT01288352, EudraCT2010-021258-20, www.easttrial.org.

Published
2023

8. Author Correction: GPR15-mediated T cell recruitment during acute viral myocarditis facilitated virus elimination and improved outcome

Author

Stoffers, Bastian, Wolf, Hanna, Bacmeister, Lucas, Kupsch, Svenja, Vico, Tamara, Marchini, Timoteo, Brehm, Maria A., Yan, Isabell, Becher, P. Moritz, Ardeshirdavani, Armin, Escher, Felicitas, Kim, Sangwon V., Klingel, Karin, Kirchhof, Paulus, Blankenberg, Stefan, Zeller, Tanja, Wolf, Dennis, Hilgendorf, Ingo, Westermann, Dirk, and Lindner, Diana

Published
2024
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9. GPR15-mediated T cell recruitment during acute viral myocarditis facilitated virus elimination and improved outcome

Author

Stoffers, Bastian, Wolf, Hanna, Bacmeister, Lucas, Kupsch, Svenja, Vico, Tamara, Marchini, Timoteo, Brehm, Maria A., Yan, Isabell, Becher, P. Moritz, Ardeshirdavani, Armin, Escher, Felicitas, Kim, Sangwon V., Klingel, Karin, Kirchhof, Paulus, Blankenberg, Stefan, Zeller, Tanja, Wolf, Dennis, Hilgendorf, Ingo, Westermann, Dirk, and Lindner, Diana

Published
2024
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13. An arrhythmogenic metabolite in atrial fibrillation

Author

Krause, Julia, Nickel, Alexander, Madsen, Alexandra, Aitken-Buck, Hamish M., Stoter, A. M. Stella, Schrapers, Jessica, Ojeda, Francisco, Geiger, Kira, Kern, Melanie, Kohlhaas, Michael, Bertero, Edoardo, Hofmockel, Patrick, Hübner, Florian, Assum, Ines, Heinig, Matthias, Müller, Christian, Hansen, Arne, Krause, Tobias, Park, Deung-Dae, Just, Steffen, Aïssi, Dylan, Börnigen, Daniela, Lindner, Diana, Friedrich, Nele, Alhussini, Khaled, Bening, Constanze, Schnabel, Renate B., Karakas, Mahir, Iacoviello, Licia, Salomaa, Veikko, Linneberg, Allan, Tunstall-Pedoe, Hugh, Kuulasmaa, Kari, Kirchhof, Paulus, Blankenberg, Stefan, Christ, Torsten, Eschenhagen, Thomas, Lamberts, Regis R., Maack, Christoph, Stenzig, Justus, and Zeller, Tanja

Published
2023
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15. Drinking alcohol in moderation is associated with lower rate of all-cause mortality in individuals with higher rather than lower educational level: findings from the MORGAM project

Author

Di Castelnuovo, Augusto, Bonaccio, Marialaura, Costanzo, Simona, McElduff, Patrick, Linneberg, Allen, Salomaa, Veikko, Männistö, Satu, Ferrières, Jean, Dallongeville, Jean, Thorand, Barbara, Brenner, Hermann, Ferrario, Marco, Veronesi, Giovanni, Tamosiunas, Abdonas, Grimsgaard, Sameline, Drygas, Wojciech, Malyutina, Sofia, Söderberg, Stefan, Nordendahl, Maria, Kee, Frank, Grassi, Guido, Dabboura, Salim, Borchini, Rossana, Westermann, Dirk, Schrage, Benedikt, Zeller, Tanja, Kuulasmaa, Kari, Blankenberg, Stefan, Donati, Maria Benedetta, Iacoviello, Licia, and de Gaetano, Giovanni

Published
2023
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16. The DZHK research platform: maximisation of scientific value by enabling access to health data and biological samples collected in cardiovascular clinical studies

Author

Hoffmann, Julia, Hanß, Sabine, Kraus, Monika, Schaller, Jens, Schäfer, Christian, Stahl, Dana, Anker, Stefan D., Anton, Gabriele, Bahls, Thomas, Blankenberg, Stefan, Blumentritt, Arne, Boldt, Leif-Hendrik, Cordes, Steffen, Desch, Steffen, Doehner, Wolfram, Dörr, Marcus, Edelmann, Frank, Eitel, Ingo, Endres, Matthias, Engelhardt, Stefan, Erdmann, Jeanette, Eulenburg, Katharina, Falk, Volkmar, Felix, Stephan B., Frank, Derk, Franke, Thomas, Frey, Norbert, Friede, Tim, Geidel, Lars, Germans, Lisa, Grabmaier, Ulrich, Halle, Martin, Hausleiter, Jörg, Jakobi, Vera, Jebran, Ahmad-Fawad, Jobs, Alexander, Kääb, Stefan, Karakas, Mahir, Katus, Hugo A., Klatt, Alexandra, Knosalla, Christoph, Krebser, Joachim, Landmesser, Ulf, Lee, Mahsa, Lehnert, Kristin, Lesser, Stephanie, Leyh, Katrin, Lorbeer, Roberto, Mach-Kolb, Stephanie, Meder, Benjamin, Nagel, Eike, Nolte, Christian H., Parwani, Abdul S., Petersmann, Astrid, Puls, Miriam, Rau, Henriette, Reiser, Maximilian, Rienhoff, Otto, Scharfe, Tabea, Schattschneider, Mario, Scheel, Heiko, Schnabel, Renate B., Schuster, Andreas, Schmitt, Boris, Seidler, Tim, Seiffert, Moritz, Stähli, Barbara-Elisabeth, Stas, Adriane, J. Stocker, Thomas, von Stülpnagel, Lukas, Thiele, Holger, Wachter, Rolf, Wakili, Reza, Weis, Tanja, Weitmann, Kerstin, Wichmann, Heinz-Erich, Wild, Philipp, Zeller, Tanja, Hoffmann, Wolfgang, Zeisberg, Elisabeth Maria, Zimmermann, Wolfram-Hubertus, Krefting, Dagmar, Kühne, Titus, Peters, Annette, Hasenfuß, Gerd, Massberg, Steffen, Sommer, Thomas, Dimmeler, Stefanie, Eschenhagen, Thomas, and Nauck, Matthias

Published
2023
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17. Metabolic Communication by SGLT2 Inhibition

Author

Billing, Anja M., Kim, Young Chul, Gullaksen, Søren, Schrage, Benedikt, Raabe, Janice, Hutzfeldt, Arvid, Demir, Fatih, Kovalenko, Elina, Lassé, Moritz, Dugourd, Aurelien, Fallegger, Robin, Klampe, Birgit, Jaegers, Johannes, Li, Qing, Kravtsova, Olha, Crespo-Masip, Maria, Palermo, Amelia, Fenton, Robert A., Hoxha, Elion, Blankenberg, Stefan, Kirchhof, Paulus, Huber, Tobias B., Laugesen, Esben, Zeller, Tanja, Chrysopolou, Maria, Saez-Rodriguez, Julio, Magnussen, Christina, Eschenhagen, Thomas, Staruschenko, Alexander, Siuzdak, Gary, Poulsen, Per L., Schwab, Clarissa, Cuello, Friederike, Vallon, Volker, and Rinschen, Markus M.

Published
2023
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22. Author Correction: Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases.

Author

Iglesias, Adriana I, Mishra, Aniket, Vitart, Veronique, Bykhovskaya, Yelena, Höhn, René, Springelkamp, Henriët, Cuellar-Partida, Gabriel, Gharahkhani, Puya, Bailey, Jessica N Cooke, Willoughby, Colin E, Li, Xiaohui, Yazar, Seyhan, Nag, Abhishek, Khawaja, Anthony P, Polašek, Ozren, Siscovick, David, Mitchell, Paul, Tham, Yih Chung, Haines, Jonathan L, Kearns, Lisa S, Hayward, Caroline, Shi, Yuan, van Leeuwen, Elisabeth M, Taylor, Kent D, Blue Mountains Eye Study - GWAS group, Bonnemaijer, Pieter, Rotter, Jerome I, Martin, Nicholas G, Zeller, Tanja, Mills, Richard A, Souzeau, Emmanuelle, Staffieri, Sandra E, Jonas, Jost B, Schmidtmann, Irene, Boutin, Thibaud, Kang, Jae H, Lucas, Sionne EM, Wong, Tien Yin, Beutel, Manfred E, Wilson, James F, Wellcome Trust Case Control Consortium 2 (WTCCC2), NEIGHBORHOOD consortium, Uitterlinden, André G, Vithana, Eranga N, Foster, Paul J, Hysi, Pirro G, Hewitt, Alex W, Khor, Chiea Chuen, Pasquale, Louis R, Montgomery, Grant W, Klaver, Caroline CW, Aung, Tin, Pfeiffer, Norbert, Mackey, David A, Hammond, Christopher J, Cheng, Ching-Yu, Craig, Jamie E, Rabinowitz, Yaron S, Wiggs, Janey L, Burdon, Kathryn P, van Duijn, Cornelia M, and MacGregor, Stuart

Subjects
Blue Mountains Eye Study - GWAS group, Wellcome Trust Case Control Consortium 2, NEIGHBORHOOD consortium, Eye Disease and Disorders of Vision
Abstract

Emmanuelle Souzeau, who contributed to analysis of data, was inadvertently omitted from the author list in the originally published version of this Article. This has now been corrected in both the PDF and HTML versions of the Article.

Published
2019

24. Cardiovascular profiling in the diabetic continuum: results from the population-based Gutenberg Health Study

Author

Schmitt, Volker H., Leuschner, Anja, Jünger, Claus, Pinto, Antonio, Hahad, Omar, Schulz, Andreas, Arnold, Natalie, Tröbs, Sven-Oliver, Panova-Noeva, Marina, Keller, Karsten, Zeller, Tanja, Beutel, Manfred, Pfeiffer, Norbert, Strauch, Konstantin, Blankenberg, Stefan, Lackner, Karl J., Prochaska, Jürgen H., Wild, Philipp S., and Münzel, Thomas

Published
2022
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25. Cross-sectional study on the association of periodontitis with arterial hypertension in the Hamburg City Health Study

Author

Könnecke, Henrieke, Schnabel, Renate B., Walther, Carolin, Lamprecht, Ragna, Heydecke, Guido, Seedorf, Udo, Jagodzinski, Annika, Borof, Katrin, Zeller, Tanja, Beikler, Thomas, Smeets, Ralf, Gosau, Martin, Behrendt, Christian-Alexander, Wenzel, Ulrich, Börschel, Christin S., Karakas, Mahir, Blankenberg, Stefan, and Aarabi, Ghazal

Published
2022
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30. Single-dose of adrecizumab versus placebo in acute cardiogenic shock (ACCOST-HH): an investigator-initiated, randomised, double-blinded, placebo-controlled, multicentre trial

Author

Karakas, Mahir, Akin, Ibrahim, Burdelski, Christoph, Clemmensen, Peter, Grahn, Hanno, Jarczak, Dominik, Keßler, Mirjam, Kirchhof, Paulus, Landmesser, Ulf, Lezius, Susanne, Lindner, Diana, Mebazaa, Alexandre, Nierhaus, Axel, Ocak, Anil, Rottbauer, Wolfgang, Sinning, Christoph, Skurk, Carsten, Söffker, Gerold, Westermann, Dirk, Zapf, Antonia, Zengin, Elvin, Zeller, Tanja, and Kluge, Stefan

Published
2022
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32. Physiologists as medical scientists: An early warning from the German academic system.

Author

Streckfuss‐Bömeke, Katrin, Kränkel, Nicolle, Maack, Christoph, Schnabel, Renate B., Zelarayán, Laura C., Frey, Norbert, Jezzard, Peter, Krüger, Martina, Lachmann, Nico, Lutz, Susanne, Noack, Claudia, Schoger, Eric, Schröder, Katrin, Sommerfeld, Laura C., Steffens, Sabine, Winkels, Holger, Würtz, Christina, Zeller, Tanja, Rog‐Zielinska, Eva A., and Kohl, Peter

Abstract

"Medical scientists" are postgraduate investigators who are engaged in biomedical research, and either hold a biomedical PhD or are qualified in medicine but do not participate in patient care. Medical scientists constitute ~40% of staff at medical faculties and >90% at nonuniversity medical research institutions in Germany. However, medical scientists in Germany face limited long‐term career prospects and a lack of dedicated training and support programmes. They also face time limits on their career progression arising from national academic employment legislation, and imminent reforms by the German government are likely to make this worse. Nevertheless, recent developments in the educational landscape including the introduction of increasingly focused MSc, pre‐PhD, and doctoral programmes to train medically aware basic scientists, as well as improved general recognition of the roles and relevance of medical scientists in health research, are encouraging. Physiologists have taken essential steps to improve the recognition of medical scientists in Germany by introducing a "specialist physiologist" qualification; this initiative could be applied to support medical scientists in other fields and countries. In this review, we describe the particular challenges facing medical scientists in Germany and make recommendations that may apply to other academic systems. [ABSTRACT FROM AUTHOR]

Published
2024
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33. Decomposing the educational gradient in allostatic load across European populations. What matters the most : differentials in exposure or in susceptibility?

Author

Veronesi, Giovanni, Kee, Frank, Hicks, Blanaid, Forrest, Hannah, Tunstall-Pedoe, Hugh, Kuulasmaa, Kari, Sans, Susana, Salomaa, Veikko, Thorand, Barbara, Di Castelnuovo, Augusto, Soderberg, Stefan, Cesana, Giancarlo, Bobak, Martin, De Ponti, Roberto, Iacoviello, Licia, Palmieri, Luigi, Zeller, Tanja, Blankenberg, Stefan, and Ferrario, Marco M

Published
2020

34. Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases.

Author

Iglesias, Adriana I, Mishra, Aniket, Vitart, Veronique, Bykhovskaya, Yelena, Höhn, René, Springelkamp, Henriët, Cuellar-Partida, Gabriel, Gharahkhani, Puya, Bailey, Jessica N Cooke, Willoughby, Colin E, Li, Xiaohui, Yazar, Seyhan, Nag, Abhishek, Khawaja, Anthony P, Polašek, Ozren, Siscovick, David, Mitchell, Paul, Tham, Yih Chung, Haines, Jonathan L, Kearns, Lisa S, Hayward, Caroline, Shi, Yuan, van Leeuwen, Elisabeth M, Taylor, Kent D, Blue Mountains Eye Study—GWAS group, Bonnemaijer, Pieter, Rotter, Jerome I, Martin, Nicholas G, Zeller, Tanja, Mills, Richard A, Souzeau, Emmanuelle, Staffieri, Sandra E, Jonas, Jost B, Schmidtmann, Irene, Boutin, Thibaud, Kang, Jae H, Lucas, Sionne EM, Wong, Tien Yin, Beutel, Manfred E, Wilson, James F, NEIGHBORHOOD Consortium, Wellcome Trust Case Control Consortium 2 (WTCCC2), Uitterlinden, André G, Vithana, Eranga N, Foster, Paul J, Hysi, Pirro G, Hewitt, Alex W, Khor, Chiea Chuen, Pasquale, Louis R, Montgomery, Grant W, Klaver, Caroline CW, Aung, Tin, Pfeiffer, Norbert, Mackey, David A, Hammond, Christopher J, Cheng, Ching-Yu, Craig, Jamie E, Rabinowitz, Yaron S, Wiggs, Janey L, Burdon, Kathryn P, van Duijn, Cornelia M, and MacGregor, Stuart

Subjects
Blue Mountains Eye Study—GWAS group, NEIGHBORHOOD Consortium, Wellcome Trust Case Control Consortium 2, Cornea, Humans, Marfan Syndrome, Corneal Diseases, Corneal Dystrophies, Hereditary, Keratoconus, Eye Diseases, Hereditary, Glaucoma, Open-Angle, Myopia, Ehlers-Danlos Syndrome, Proteoglycans, Gene Expression, Quantitative Trait, Heritable, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Genome, Human, Asian Continental Ancestry Group, European Continental Ancestry Group, Transforming Growth Factor beta2, Genome-Wide Association Study, Loeys-Dietz Syndrome, Mendelian Randomization Analysis, Decorin, Lumican, Fibrillin-1, ADAMTS Proteins, Corneal Dystrophies, Hereditary, Eye Diseases, Glaucoma, Open-Angle, Quantitative Trait, Heritable, Polymorphism, Single Nucleotide, Genome, Human
Abstract

Central corneal thickness (CCT) is a highly heritable trait associated with complex eye diseases such as keratoconus and glaucoma. We perform a genome-wide association meta-analysis of CCT and identify 19 novel regions. In addition to adding support for known connective tissue-related pathways, pathway analyses uncover previously unreported gene sets. Remarkably, >20% of the CCT-loci are near or within Mendelian disorder genes. These included FBN1, ADAMTS2 and TGFB2 which associate with connective tissue disorders (Marfan, Ehlers-Danlos and Loeys-Dietz syndromes), and the LUM-DCN-KERA gene complex involved in myopia, corneal dystrophies and cornea plana. Using index CCT-increasing variants, we find a significant inverse correlation in effect sizes between CCT and keratoconus (r = -0.62, P = 5.30 × 10-5) but not between CCT and primary open-angle glaucoma (r = -0.17, P = 0.2). Our findings provide evidence for shared genetic influences between CCT and keratoconus, and implicate candidate genes acting in collagen and extracellular matrix regulation.

Published
2018

35. PR interval genome-wide association meta-analysis identifies 50 loci associated with atrial and atrioventricular electrical activity

Author

van Setten, Jessica, Brody, Jennifer A, Jamshidi, Yalda, Swenson, Brenton R, Butler, Anne M, Campbell, Harry, Del Greco, Fabiola M, Evans, Daniel S, Gibson, Quince, Gudbjartsson, Daniel F, Kerr, Kathleen F, Krijthe, Bouwe P, Lyytikäinen, Leo-Pekka, Müller, Christian, Müller-Nurasyid, Martina, Nolte, Ilja M, Padmanabhan, Sandosh, Ritchie, Marylyn D, Robino, Antonietta, Smith, Albert V, Steri, Maristella, Tanaka, Toshiko, Teumer, Alexander, Trompet, Stella, Ulivi, Sheila, Verweij, Niek, Yin, Xiaoyan, Arnar, David O, Asselbergs, Folkert W, Bader, Joel S, Barnard, John, Bis, Josh, Blankenberg, Stefan, Boerwinkle, Eric, Bradford, Yuki, Buckley, Brendan M, Chung, Mina K, Crawford, Dana, den Hoed, Marcel, Denny, Josh C, Dominiczak, Anna F, Ehret, Georg B, Eijgelsheim, Mark, Ellinor, Patrick T, Felix, Stephan B, Franco, Oscar H, Franke, Lude, Harris, Tamara B, Holm, Hilma, Ilaria, Gandin, Iorio, Annamaria, Kähönen, Mika, Kolcic, Ivana, Kors, Jan A, Lakatta, Edward G, Launer, Lenore J, Lin, Honghuang, Lin, Henry J, Loos, Ruth JF, Lubitz, Steven A, Macfarlane, Peter W, Magnani, Jared W, Leach, Irene Mateo, Meitinger, Thomas, Mitchell, Braxton D, Munzel, Thomas, Papanicolaou, George J, Peters, Annette, Pfeufer, Arne, Pramstaller, Peter P, Raitakari, Olli T, Rotter, Jerome I, Rudan, Igor, Samani, Nilesh J, Schlessinger, David, Silva Aldana, Claudia T, Sinner, Moritz F, Smith, Jonathan D, Snieder, Harold, Soliman, Elsayed Z, Spector, Timothy D, Stott, David J, Strauch, Konstantin, Tarasov, Kirill V, Thorsteinsdottir, Unnur, Uitterlinden, Andre G, Van Wagoner, David R, Völker, Uwe, Völzke, Henry, Waldenberger, Melanie, Jan Westra, Harm, Wild, Philipp S, Zeller, Tanja, Alonso, Alvaro, Avery, Christy L, Bandinelli, Stefania, Benjamin, Emelia J, Cucca, Francesco, Dörr, Marcus, and Ferrucci, Luigi

Subjects
Biological Sciences, Genetics, Human Genome, Heart Disease, Biotechnology, Cardiovascular, Aetiology, 2.1 Biological and endogenous factors, Atrial Function, Atrioventricular Node, Electrocardiography, Electrophysiological Phenomena, Female, Genome-Wide Association Study, Humans, Linkage Disequilibrium, Male, Mutation, Missense, Risk Factors
Abstract

Electrocardiographic PR interval measures atrio-ventricular depolarization and conduction, and abnormal PR interval is a risk factor for atrial fibrillation and heart block. Our genome-wide association study of over 92,000 European-descent individuals identifies 44 PR interval loci (34 novel). Examination of these loci reveals known and previously not-yet-reported biological processes involved in cardiac atrial electrical activity. Genes in these loci are over-represented in cardiac disease processes including heart block and atrial fibrillation. Variants in over half of the 44 loci were associated with atrial or blood transcript expression levels, or were in high linkage disequilibrium with missense variants. Six additional loci were identified either by meta-analysis of ~105,000 African and European-descent individuals and/or by pleiotropic analyses combining PR interval with heart rate, QRS interval, and atrial fibrillation. These findings implicate developmental pathways, and identify transcription factors, ion-channel genes, and cell-junction/cell-signaling proteins in atrio-ventricular conduction, identifying potential targets for drug development.

Published
2018

36. Blood-based cardiometabolic phenotypes in atrial fibrillation and their associated risk: EAST-AFNET 4 biomolecule study

Author

Fabritz, Larissa, primary, Chua, Winnie, additional, Cardoso, Victor R, additional, Al-Taie, Christoph, additional, Borof, Katrin, additional, Suling, Anna, additional, Krause, Linda, additional, Kany, Shino, additional, Magnussen, Christina, additional, Wegscheider, Karl, additional, Breithardt, Guenter, additional, Crijns, Harry J G M, additional, Camm, A John, additional, Gkoutos, George, additional, Ellinor, Patrick T, additional, Goette, Andreas, additional, Schotten, Ulrich, additional, Wienhues-Thelen, Ursula-Henrike, additional, Zeller, Tanja, additional, Schnabel, Renate B, additional, Zapf, Antonia, additional, and Kirchhof, Paulus, additional

Published
2024
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37. A latent clinical-anatomical dimension relating metabolic syndrome to brain structure and cognition

Author

Petersen, Marvin, primary, Hoffstaedter, Felix, additional, Nägele, Felix L, additional, Mayer, Carola, additional, Schell, Maximilian, additional, Rimmele, D Leander, additional, Zyriax, Birgit-Christiane, additional, Zeller, Tanja, additional, Kühn, Simone, additional, Gallinat, Jürgen, additional, Fiehler, Jens, additional, Twerenbold, Raphael, additional, Omidvarnia, Amir, additional, Patil, Kaustubh R, additional, Eickhoff, Simon B, additional, Thomalla, Goetz, additional, and Cheng, Bastian, additional

Published
2024
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38. Metabolic Communication by SGLT2 Inhibition

Author

Billing, Anja M., primary, Kim, Young Chul, additional, Gullaksen, Søren, additional, Schrage, Benedikt, additional, Raabe, Janice, additional, Hutzfeldt, Arvid, additional, Demir, Fatih, additional, Kovalenko, Elina, additional, Lassé, Moritz, additional, Dugourd, Aurelien, additional, Fallegger, Robin, additional, Klampe, Birgit, additional, Jaegers, Johannes, additional, Li, Qing, additional, Kravtsova, Olha, additional, Crespo-Masip, Maria, additional, Palermo, Amelia, additional, Fenton, Robert A., additional, Hoxha, Elion, additional, Blankenberg, Stefan, additional, Kirchhof, Paulus, additional, Huber, Tobias B., additional, Laugesen, Esben, additional, Zeller, Tanja, additional, Chrysopoulou, Maria, additional, Saez-Rodriguez, Julio, additional, Magnussen, Christina, additional, Eschenhagen, Thomas, additional, Staruschenko, Alexander, additional, Siuzdak, Gary, additional, Poulsen, Per L., additional, Schwab, Clarissa, additional, Cuello, Friederike, additional, Vallon, Volker, additional, and Rinschen, Markus M., additional

Published
2024
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41. Rationale and Design of the Hamburg City Health Study

Author

Jagodzinski, Annika, Johansen, Christoffer, Koch-Gromus, Uwe, Aarabi, Ghazal, Adam, Gerhard, Anders, Sven, Augustin, Matthias, der Kellen, Ramona B., Beikler, Thomas, Behrendt, Christian-Alexander, Betz, Christian S., Bokemeyer, Carsten, Borof, Katrin, Briken, Peer, Busch, Chia-Jung, Büchel, Christian, Brassen, Stefanie, Debus, Eike S., Eggers, Larissa, Fiehler, Jens, Gallinat, Jürgen, Gellißen, Simone, Gerloff, Christian, Girdauskas, Evaldas, Gosau, Martin, Graefen, Markus, Härter, Martin, Harth, Volker, Heidemann, Christoph, Heydecke, Guido, Huber, Tobias B., Hussein, Yassin, Kampf, Marvin O., von dem Knesebeck, Olaf, Konnopka, Alexander, König, Hans-Helmut, Kromer, Robert, Kubisch, Christian, Kühn, Simone, Loges, Sonja, Löwe, Bernd, Lund, Gunnar, Meyer, Christian, Nagel, Lina, Nienhaus, Albert, Pantel, Klaus, Petersen, Elina, Püschel, Klaus, Reichenspurner, Hermann, Sauter, Guido, Scherer, Martin, Scherschel, Katharina, Schiffner, Ulrich, Schnabel, Renate B., Schulz, Holger, Smeets, Ralf, Sokalskis, Vladislavs, Spitzer, Martin S., Terschüren, Claudia, Thederan, Imke, Thoma, Tom, Thomalla, Götz, Waschki, Benjamin, Wegscheider, Karl, Wenzel, Jan-Per, Wiese, Susanne, Zyriax, Birgit-Christiane, Zeller, Tanja, and Blankenberg, Stefan

Published
2020

44. Transcriptome-Wide Analysis Identifies Novel Associations With Blood Pressure

Author

Zeller, Tanja, Schurmann, Claudia, Schramm, Katharina, Müller, Christian, Kwon, Soonil, Wild, Philipp S, Teumer, Alexander, Herrington, David, Schillert, Arne, Iacoviello, Licia, Kratzer, Adelheid, Jagodzinski, Annika, Karakas, Mahir, Ding, Jingzhong, Neumann, Johannes T, Kuulasmaa, Kari, Gieger, Christian, Kacprowski, Tim, Schnabel, Renate B, Roden, Michael, Wahl, Simone, Rotter, Jerome I, Ojeda, Francisco, Carstensen-Kirberg, Maren, Tregouet, David-Alexandre, Dörr, Marcus, Meitinger, Thomas, Lackner, Karl J, Wolf, Petra, Felix, Stephan B, Landmesser, Ulf, Costanzo, Simona, Ziegler, Andreas, Liu, Yongmei, Völker, Uwe, Palmas, Walter, Prokisch, Holger, Guo, Xiuqing, Herder, Christian, Blankenberg, Stefan, and Homuth, Georg

Subjects
Hypertension, Biotechnology, Human Genome, Cardiovascular, Clinical Research, Heart Disease, Genetics, 2.1 Biological and endogenous factors, Aetiology, Good Health and Well Being, Adult, Blood Pressure, Blood Pressure Determination, CCAAT-Enhancer-Binding Proteins, Carrier Proteins, Female, Gene Expression, Gene Expression Profiling, Genome-Wide Association Study, Humans, LIM Domain Proteins, Male, Myelin and Lymphocyte-Associated Proteolipid Proteins, Nucleoside Transport Proteins, Poly(ADP-ribose) Polymerases, Polymorphism, Single Nucleotide, Risk Factors, Stroke, Transcription Factors, blood pressure, gene expression, genome-wide association study, hypertension, transcriptome, Cardiorespiratory Medicine and Haematology, Clinical Sciences, Public Health and Health Services, Cardiovascular System & Hematology
Abstract

Hypertension represents a major cardiovascular risk factor. The pathophysiology of increased blood pressure (BP) is not yet completely understood. Transcriptome profiling offers possibilities to uncover genetics effects on BP. Based on 2 populations including 2549 individuals, a meta-analyses of monocytic transcriptome-wide profiles were performed to identify transcripts associated with BP. Replication was performed in 2 independent studies of whole-blood transcriptome data including 1990 individuals. For identified candidate genes, a direct link between long-term changes in BP and gene expression over time and by treatment with BP-lowering therapy was assessed. The predictive value of protein levels encoded by candidate genes for subsequent cardiovascular disease was investigated. Eight transcripts (CRIP1, MYADM, TIPARP, TSC22D3, CEBPA, F12, LMNA, and TPPP3) were identified jointly accounting for up to 13% (95% confidence interval, 8.7-16.2) of BP variability. Changes in CRIP1, MYADM, TIPARP, LMNA, TSC22D3, CEBPA, and TPPP3 expression associated with BP changes-among these, CRIP1 gene expression was additionally correlated to measures of cardiac hypertrophy. Assessment of circulating CRIP1 (cystein-rich protein 1) levels as biomarkers showed a strong association with increased risk for incident stroke (hazard ratio, 1.06; 95% confidence interval, 1.03-1.09; P=5.0×10-5). Our comprehensive analysis of global gene expression highlights 8 novel transcripts significantly associated with BP, providing a link between gene expression and BP. Translational approaches further established evidence for the potential use of CRIP1 as emerging disease-related biomarker.

Published
2017

45. Comparison of HapMap and 1000 Genomes Reference Panels in a Large-Scale Genome-Wide Association Study

Author

de Vries, Paul S, Sabater-Lleal, Maria, Chasman, Daniel I, Trompet, Stella, Ahluwalia, Tarunveer S, Teumer, Alexander, Kleber, Marcus E, Chen, Ming-Huei, Wang, Jie Jin, Attia, John R, Marioni, Riccardo E, Steri, Maristella, Weng, Lu-Chen, Pool, Rene, Grossmann, Vera, Brody, Jennifer A, Venturini, Cristina, Tanaka, Toshiko, Rose, Lynda M, Oldmeadow, Christopher, Mazur, Johanna, Basu, Saonli, Frånberg, Mattias, Yang, Qiong, Ligthart, Symen, Hottenga, Jouke J, Rumley, Ann, Mulas, Antonella, de Craen, Anton JM, Grotevendt, Anne, Taylor, Kent D, Delgado, Graciela E, Kifley, Annette, Lopez, Lorna M, Berentzen, Tina L, Mangino, Massimo, Bandinelli, Stefania, Morrison, Alanna C, Hamsten, Anders, Tofler, Geoffrey, de Maat, Moniek PM, Draisma, Harmen HM, Lowe, Gordon D, Zoledziewska, Magdalena, Sattar, Naveed, Lackner, Karl J, Völker, Uwe, McKnight, Barbara, Huang, Jie, Holliday, Elizabeth G, McEvoy, Mark A, Starr, John M, Hysi, Pirro G, Hernandez, Dena G, Guan, Weihua, Rivadeneira, Fernando, McArdle, Wendy L, Slagboom, P Eline, Zeller, Tanja, Psaty, Bruce M, Uitterlinden, André G, de Geus, Eco JC, Stott, David J, Binder, Harald, Hofman, Albert, Franco, Oscar H, Rotter, Jerome I, Ferrucci, Luigi, Spector, Tim D, Deary, Ian J, März, Winfried, Greinacher, Andreas, Wild, Philipp S, Cucca, Francesco, Boomsma, Dorret I, Watkins, Hugh, Tang, Weihong, Ridker, Paul M, Jukema, Jan W, Scott, Rodney J, Mitchell, Paul, Hansen, Torben, O'Donnell, Christopher J, Smith, Nicholas L, Strachan, David P, and Dehghan, Abbas

Subjects
Epidemiology, Biological Sciences, Health Sciences, Genetics, Human Genome, Genome-Wide Association Study, HapMap Project, Humans, General Science & Technology
Abstract

An increasing number of genome-wide association (GWA) studies are now using the higher resolution 1000 Genomes Project reference panel (1000G) for imputation, with the expectation that 1000G imputation will lead to the discovery of additional associated loci when compared to HapMap imputation. In order to assess the improvement of 1000G over HapMap imputation in identifying associated loci, we compared the results of GWA studies of circulating fibrinogen based on the two reference panels. Using both HapMap and 1000G imputation we performed a meta-analysis of 22 studies comprising the same 91,953 individuals. We identified six additional signals using 1000G imputation, while 29 loci were associated using both HapMap and 1000G imputation. One locus identified using HapMap imputation was not significant using 1000G imputation. The genome-wide significance threshold of 5×10-8 is based on the number of independent statistical tests using HapMap imputation, and 1000G imputation may lead to further independent tests that should be corrected for. When using a stricter Bonferroni correction for the 1000G GWA study (P-value < 2.5×10-8), the number of loci significant only using HapMap imputation increased to 4 while the number of loci significant only using 1000G decreased to 5. In conclusion, 1000G imputation enabled the identification of 20% more loci than HapMap imputation, although the advantage of 1000G imputation became less clear when a stricter Bonferroni correction was used. More generally, our results provide insights that are applicable to the implementation of other dense reference panels that are under development.

Published
2017

46. Genome-wide Trans-ethnic Meta-analysis Identifies Seven Genetic Loci Influencing Erythrocyte Traits and a Role for RBPMS in Erythropoiesis

Author

van Rooij, Frank JA, Qayyum, Rehan, Smith, Albert V, Zhou, Yi, Trompet, Stella, Tanaka, Toshiko, Keller, Margaux F, Chang, Li-Ching, Schmidt, Helena, Yang, Min-Lee, Chen, Ming-Huei, Hayes, James, Johnson, Andrew D, Yanek, Lisa R, Mueller, Christian, Lange, Leslie, Floyd, James S, Ghanbari, Mohsen, Zonderman, Alan B, Jukema, J Wouter, Hofman, Albert, van Duijn, Cornelia M, Desch, Karl C, Saba, Yasaman, Ozel, Ayse B, Snively, Beverly M, Wu, Jer-Yuarn, Schmidt, Reinhold, Fornage, Myriam, Klein, Robert J, Fox, Caroline S, Matsuda, Koichi, Kamatani, Naoyuki, Wild, Philipp S, Stott, David J, Ford, Ian, Slagboom, P Eline, Yang, Jaden, Chu, Audrey Y, Lambert, Amy J, Uitterlinden, André G, Franco, Oscar H, Hofer, Edith, Ginsburg, David, Hu, Bella, Keating, Brendan, Schick, Ursula M, Brody, Jennifer A, Li, Jun Z, Chen, Zhao, Zeller, Tanja, Guralnik, Jack M, Chasman, Daniel I, Peters, Luanne L, Kubo, Michiaki, Becker, Diane M, Li, Jin, Eiriksdottir, Gudny, Rotter, Jerome I, Levy, Daniel, Grossmann, Vera, Patel, Kushang V, Chen, Chien-Hsiun, Project, The BioBank Japan, Ridker, Paul M, Tang, Hua, Launer, Lenore J, Rice, Kenneth M, Li-Gao, Ruifang, Ferrucci, Luigi, Evans, Michelle K, Choudhuri, Avik, Trompouki, Eirini, Abraham, Brian J, Yang, Song, Takahashi, Atsushi, Kamatani, Yoichiro, Kooperberg, Charles, Harris, Tamara B, Jee, Sun Ha, Coresh, Josef, Tsai, Fuu-Jen, Longo, Dan L, Chen, Yuan-Tsong, Felix, Janine F, Yang, Qiong, Psaty, Bruce M, Boerwinkle, Eric, Becker, Lewis C, Mook-Kanamori, Dennis O, Wilson, James G, Gudnason, Vilmundur, O'Donnell, Christopher J, Dehghan, Abbas, Cupples, L Adrienne, Nalls, Michael A, Morris, Andrew P, Okada, Yukinori, Reiner, Alexander P, and Zon, Leonard I

Subjects
Epidemiology, Biological Sciences, Health Sciences, Genetics, Human Genome, Hematology, Africa, Alleles, Animals, Bayes Theorem, Erythrocytes, Erythropoiesis, Ethnicity, Europe, Asia, Eastern, Female, Genome-Wide Association Study, Humans, Linkage Disequilibrium, Male, RNA-Binding Proteins, Racial Groups, Zebrafish, BioBank Japan Project, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

Genome-wide association studies (GWASs) have identified loci for erythrocyte traits in primarily European ancestry populations. We conducted GWAS meta-analyses of six erythrocyte traits in 71,638 individuals from European, East Asian, and African ancestries using a Bayesian approach to account for heterogeneity in allelic effects and variation in the structure of linkage disequilibrium between ethnicities. We identified seven loci for erythrocyte traits including a locus (RBPMS/GTF2E2) associated with mean corpuscular hemoglobin and mean corpuscular volume. Statistical fine-mapping at this locus pointed to RBPMS at this locus and excluded nearby GTF2E2. Using zebrafish morpholino to evaluate loss of function, we observed a strong in vivo erythropoietic effect for RBPMS but not for GTF2E2, supporting the statistical fine-mapping at this locus and demonstrating that RBPMS is a regulator of erythropoiesis. Our findings show the utility of trans-ethnic GWASs for discovery and characterization of genetic loci influencing hematologic traits.

Published
2017

47. Cost-effectiveness of applying high-sensitivity troponin I to a score for cardiovascular risk prediction in asymptomatic population

Author

Jülicher, Paul, Makarova, Nataliya, Ojeda, Francisco, Giusepi, Isabella, Peters, Annette, Thorand, Barbara, Cesana, Giancarlo, Jørgensen, Torben, Linneberg, Allan, Salomaa, Veikko, Iacoviello, Licia, Costanzo, Simona, Söderberg, Stefan, Kee, Frank, Giampaoli, Simona, Palmieri, Luigi, Donfrancesco, Chiara, Zeller, Tanja, Kuulasmaa, Kari, Tuovinen, Tarja, Lamrock, Felicity, Conrads-Frank, Annette, Brambilla, Paolo, Blankenberg, Stefan, Siebert, Uwe, Jülicher, Paul, Makarova, Nataliya, Ojeda, Francisco, Giusepi, Isabella, Peters, Annette, Thorand, Barbara, Cesana, Giancarlo, Jørgensen, Torben, Linneberg, Allan, Salomaa, Veikko, Iacoviello, Licia, Costanzo, Simona, Söderberg, Stefan, Kee, Frank, Giampaoli, Simona, Palmieri, Luigi, Donfrancesco, Chiara, Zeller, Tanja, Kuulasmaa, Kari, Tuovinen, Tarja, Lamrock, Felicity, Conrads-Frank, Annette, Brambilla, Paolo, Blankenberg, Stefan, and Siebert, Uwe

Abstract

Introduction: Risk stratification scores such as the European Systematic COronary Risk Evaluation (SCORE) are used to guide individuals on cardiovascular disease (CVD) prevention. Adding high-sensitivity troponin I (hsTnI) to such risk scores has the potential to improve accuracy of CVD prediction. We investigated how applying hsTnI in addition to SCORE may impact management, outcome, and cost-effectiveness. Methods: Characteristics of 72,190 apparently healthy individuals from the Biomarker for Cardiovascular Risk Assessment in Europe (BiomarCaRE) project were included into a discrete-event simulation comparing two strategies for assessing CVD risk. The standard strategy reflecting current practice employed SCORE (SCORE); the alternative strategy involved adding hsTnI information for further stratifying SCORE risk categories (S-SCORE). Individuals were followed over ten years from baseline examination to CVD event, death or end of follow-up. The model tracked the occurrence of events and calculated direct costs of screening, prevention, and treatment from a European health system perspective. Cost-effectiveness was expressed as incremental cost-effectiveness ratio (ICER) in € per quality-adjusted life year (QALYs) gained during 10 years of follow-up. Outputs were validated against observed rates, and results were tested in deterministic and probabilistic sensitivity analyses. Results: S-SCORE yielded a change in management for 10.0% of individuals, and a reduction in CVD events (4.85% vs. 5.38%, p<0.001) and mortality (6.80% vs. 7.04%, p<0.001). S-SCORE led to 23 (95%CI: 20–26) additional event-free years and 7 (95%CI: 5–9) additional QALYs per 1,000 subjects screened, and resulted in a relative risk reduction for CVD of 9.9% (95%CI: 7.3–13.5%) with a number needed to screen to prevent one event of 183 (95%CI: 172 to 203). S-SCORE increased costs per subject by 187€ (95%CI: 177 € to 196 €), leading to an ICER of 27,440€/QALY gained. Sensitivity analysis was p

Published
2024
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48. C-reactive protein modifies lipoprotein(a)-related risk for coronary heart disease:the BiomarCaRE project

Author

Arnold, Natalie, Blaum, Christopher, Goßling, Alina, Brunner, Fabian J., Bay, Benjamin, Ferrario, Marco M., Brambilla, Paolo, Cesana, Giancarlo, Leoni, Valerio, Palmieri, Luigi, Donfrancesco, Chiara, Padró, Teresa, Andersson, Jonas, Jousilahti, Pekka, Ojeda, Francisco, Zeller, Tanja, Linneberg, Allan, Söderberg, Stefan, Iacoviello, Licia, Gianfagna, Francesco, Sans, Susana, Veronesi, Giovanni, Thorand, Barbara, Peters, Annette, Tunstall-Pedoe, Hugh, Kee, Frank, Salomaa, Veikko, Schnabel, Renate B., Kuulasmaa, Kari, Blankenberg, Stefan, Koenig, Wolfgang, Waldeyer, Christoph, Arnold, Natalie, Blaum, Christopher, Goßling, Alina, Brunner, Fabian J., Bay, Benjamin, Ferrario, Marco M., Brambilla, Paolo, Cesana, Giancarlo, Leoni, Valerio, Palmieri, Luigi, Donfrancesco, Chiara, Padró, Teresa, Andersson, Jonas, Jousilahti, Pekka, Ojeda, Francisco, Zeller, Tanja, Linneberg, Allan, Söderberg, Stefan, Iacoviello, Licia, Gianfagna, Francesco, Sans, Susana, Veronesi, Giovanni, Thorand, Barbara, Peters, Annette, Tunstall-Pedoe, Hugh, Kee, Frank, Salomaa, Veikko, Schnabel, Renate B., Kuulasmaa, Kari, Blankenberg, Stefan, Koenig, Wolfgang, and Waldeyer, Christoph

Abstract

Background and Aims Recent investigations have suggested an interdependence of lipoprotein(a) [Lp(a)]-related risk for cardiovascular disease with background inflammatory burden. The aim the present analysis was to investigate whether high-sensitive C-reactive protein (hsCRP) modulates the association between Lp(a) and coronary heart disease (CHD) in the general population. Methods Data from 71 678 participants from 8 European prospective population-based cohort studies were used (65 661 without/6017 with established CHD at baseline; median follow-up 9.8/13.8 years, respectively). Fine and Gray competing risk-adjusted models were calculated according to accompanying hsCRP concentration (<2 and ≥2 mg/L). Results Among CHD-free individuals, increased Lp(a) levels were associated with incident CHD irrespective of hsCRP concentration: fully adjusted sub-distribution hazard ratios [sHRs (95% confidence interval)] for the highest vs. lowest fifth of Lp(a) distribution were 1.45 (1.23–1.72) and 1.48 (1.23–1.78) for a hsCRP group of <2 and ≥2 mg/L, respectively, with no interaction found between these two biomarkers on CHD risk (Pinteraction = 0.82). In those with established CHD, similar associations were seen only among individuals with hsCRP ≥ 2 mg/L [1.34 (1.03–1.76)], whereas among participants with a hsCRP concentration <2 mg/L, there was no clear association between Lp(a) and future CHD events [1.29 (0.98–1.71)] (highest vs. lowest fifth, fully adjusted models; Pinteraction = 0.024). Conclusions While among CHD-free individuals Lp(a) was significantly associated with incident CHD regardless of hsCRP, in participants with CHD at baseline, Lp(a) was related to recurrent CHD events only in those with residual inflammatory risk. These findings might guide adequate selection of high-risk patients for forthcoming Lp(a)-targeting compounds., Background and Aims Recent investigations have suggested an interdependence of lipoprotein(a) [Lp(a)]-related risk for cardiovascular disease with background inflammatory burden. The aim the present analysis was to investigate whether high-sensitive C-reactive protein (hsCRP) modulates the association between Lp(a) and coronary heart disease (CHD) in the general population. Methods Data from 71 678 participants from 8 European prospective population-based cohort studies were used (65 661 without/6017 with established CHD at baseline; median follow-up 9.8/13.8 years, respectively). Fine and Gray competing risk-adjusted models were calculated according to accompanying hsCRP concentration (<2 and ≥2 mg/L). Results Among CHD-free individuals, increased Lp(a) levels were associated with incident CHD irrespective of hsCRP concentration: fully adjusted sub-distribution hazard ratios [sHRs (95% confidence interval)] for the highest vs. lowest fifth of Lp(a) distribution were 1.45 (1.23-1.72) and 1.48 (1.23-1.78) for a hsCRP group of <2 and ≥2 mg/L, respectively, with no interaction found between these two biomarkers on CHD risk (Pinteraction = 0.82). In those with established CHD, similar associations were seen only among individuals with hsCRP ≥ 2 mg/L [1.34 (1.03-1.76)], whereas among participants with a hsCRP concentration <2 mg/L, there was no clear association between Lp(a) and future CHD events [1.29 (0.98-1.71)] (highest vs. lowest fifth, fully adjusted models; Pinteraction = 0.024). Conclusions While among CHD-free individuals Lp(a) was significantly associated with incident CHD regardless of hsCRP, in participants with CHD at baseline, Lp(a) was related to recurrent CHD events only in those with residual inflammatory risk. These findings might guide adequate selection of high-risk patients for forthcoming Lp(a)-targeting compounds.

Published
2024

49. Serum Concentrations of Matrix Metalloproteinase-1 and Procollagen Type I Carboxy Terminal Propeptide Discriminate Infarct-Like Myocarditis and Non--ST-Segment--Elevation Myocardial Infarction.

Author

Bacmeister, Lucas, Cavus, Ersin, Bohnen, Sebastian, Tahir, Enver, Wolf, Hanna, Buellesbach, Annette, Heidenreich, Adrian, Haacke, Virginia K., Weber, Susanne, Hilgendorf, Ingo, Zeller, Tanja, Ojeda, Francisco, Radunski, Ulf K., Lund, Gunnar K., Adam, Gerhard, Blankenberg, Stefan, Westermann, Dirk, Muellerleile, Kai, and Lindner, Diana

Published
2024
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50. Biostatistical Aspects of Whole Genome Sequencing Studies: Preprocessing and Quality Control.

Author

Betschart, Raphael O., Riccio, Cristian, Aguilera‐Garcia, Domingo, Blankenberg, Stefan, Guo, Linlin, Moch, Holger, Seidl, Dagmar, Solleder, Hugo, Thalén, Felix, Thiéry, Alexandre, Twerenbold, Raphael, Zeller, Tanja, Zoche, Martin, and Ziegler, Andreas

Abstract

Rapid advances in high‐throughput DNA sequencing technologies have enabled large‐scale whole genome sequencing (WGS) studies. Before performing association analysis between phenotypes and genotypes, preprocessing and quality control (QC) of the raw sequence data need to be performed. Because many biostatisticians have not been working with WGS data so far, we first sketch Illumina's short‐read sequencing technology. Second, we explain the general preprocessing pipeline for WGS studies. Third, we provide an overview of important QC metrics, which are applied to WGS data: on the raw data, after mapping and alignment, after variant calling, and after multisample variant calling. Fourth, we illustrate the QC with the data from the GENEtic SequencIng Study Hamburg–Davos (GENESIS‐HD), a study involving more than 9000 human whole genomes. All samples were sequenced on an Illumina NovaSeq 6000 with an average coverage of 35× using a PCR‐free protocol. For QC, one genome in a bottle (GIAB) trio was sequenced in four replicates, and one GIAB sample was successfully sequenced 70 times in different runs. Fifth, we provide empirical data on the compression of raw data using the DRAGEN original read archive (ORA). The most important quality metrics in the application were genetic similarity, sample cross‐contamination, deviations from the expected Het/Hom ratio, relatedness, and coverage. The compression ratio of the raw files using DRAGEN ORA was 5.6:1, and compression time was linear by genome coverage. In summary, the preprocessing, joint calling, and QC of large WGS studies are feasible within a reasonable time, and efficient QC procedures are readily available. [ABSTRACT FROM AUTHOR]

Published
2024
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