tbuckley/cabot-search huggingface dataset:
Effectiveness of ex ante honesty oaths in reducing dishonesty depends on content
Authors: Janis H. Zickfeld, Karolina A. Ścigała, Christian T. Elbæk, John Michael, Mathilde H. Tønnesen, Gabriel Levy, Shahar Ayal, Isabel Thielmann, Laila Nockur, Eyal Peer, Valerio Capraro, Rachel Barkan, Simen Bø, Štěpán Bahník, Daniele Nosenzo, Ralph Hertwig, Nina Mazar, Alexa Weiss, Ann-Kathrin Koessler, Ronit Montal-Rosenberg, Sebastian Hafenbrädl, Yngwie Asbjørn Nielsen, Patricia Kanngiesser, Simon Schindler, Philipp Gerlach, Nils Köbis, Nicolas Jacquemet, Marek Vranka, Dan Ariely, Jareef Bin Martuza, Yuval Feldman, Michał Białek, Jan K. Woike, Zoe Rahwan, Alicia Seidl, Eileen Chou, Agne Kajackaite, Simeon Schudy, Ulrich Glogowsky, Anna Z. Czarna, Stefan Pfattheicher, Panagiotis Mitkidis
Journal: Nature Human Behaviour (2024)
Downregulating human leucocyte antigens on mesenchymal stromal cells by epigenetically repressing a β2-microglobulin super-enhancer
Authors: Fei Wang, Ran Li, Jing Yi Xu, Xiaoxia Bai, Ying Wang, Xu Ri Chen, Chen Pan, Shen Chen, Ke Zhou, Boon Chin Heng, Xuewei Wu, Wei Guo, Zhe Song, Shu Cheng Jin, Jing Zhou, Xiao Hui Zou, Hong Wei Ouyang, Hua Liu
Journal: Nature Biomedical Engineering (2024)
A comprehensive study of genetic regulation and disease associations of plasma circulatory microRNAs using population-level data
Authors: Rima Mustafa, Michelle M. J. Mens, Arno van Hilten, Jian Huang, Gennady Roshchupkin, Tianxiao Huan, Linda Broer, Joyce B. J. van Meurs, Paul Elliott, Daniel Levy, M. Arfan Ikram, Marina Evangelou, Abbas Dehghan, Mohsen Ghanbari
Journal: Genome biology (2024)

Abstract Background MicroRNAs (miRNAs) are small non-coding RNAs that post-transcriptionally regulate gene expression. Perturbations in plasma miRNA levels are known to impact disease risk and have potential as disease biomarkers. Exploring the genetic regulation of miRNAs may yield new insights into their important role in governing gene expression and disease mechanisms. Results We present genome-wide association studies of 2083 plasma circulating miRNAs in 2178 participants of the Rotterdam Study to identify miRNA-expression quantitative trait loci (miR-eQTLs). We identify 3292 associations between 1289 SNPs and 63 miRNAs, of which 65% are replicated in two independent cohorts. We demonstrate that plasma miR-eQTLs co-localise with gene expression, protein, and metabolite-QTLs, which help in identifying miRNA-regulated pathways. We investigate consequences of alteration in circulating miRNA levels on a wide range of clinical conditions in phenome-wide association studies and Mendelian randomisation using the UK Biobank data ( N = 423,419), revealing the pleiotropic and causal effects of several miRNAs on various clinical conditions. In the Mendelian randomisation analysis, we find a protective causal effect of miR-1908-5p on the risk of benign colon neoplasm and show that this effect is independent of its host gene ( FADS1 ). Conclusions This study enriches our understanding of the genetic architecture of plasma miRNAs and explores the signatures of miRNAs across a wide range of clinical conditions. The integration of population-based genomics, other omics layers, and clinical data presents opportunities to unravel potential clinical significance of miRNAs and provides tools for novel miRNA-based therapeutic target discovery.
Pushing the boundaries of rare disease diagnostics with the help of the first Undiagnosed Hackathon
Authors: Angelica Maria Delgado-Vega, Helene Cederroth, Fulya Taylan, Katja Ekholm, Marlene Ek, Håkan Thonberg, Anders Jemt, Daniel Nilsson, Jesper Eisfeldt, Kristine Bilgrav Saether, Ida Höijer, Ozlem Akgun-Dogan, Yui Asano, Tahsin Stefan Barakat, Dominyka Batkovskyte, Gareth Baynam, Olaf Bodamer, Wanna Chetruengchai, Pádraic Corcoran, Madeline Couse, Daniel Danis, German Demidov, Eisuke Dohi, Mattias Erhardsson, Luis Fernandez-Luna, Toyofumi Fujiwara, Neha Garg, Roberto Giugliani, Claudia Gonzaga-Jauregui, Giedre Grigelioniene, Tudor Groza, Cecilia Gunnarsson, Anna Hammarsjö, Charles Kumi Hammond, Özden Hatirnaz Ng, Sirisha Hesketh, Dineshani Hettiarachchi, Maria Johansson Soller, Umn Ahmed Kirmani, Martin Kjellberg, Malin Kvarnung, Oleg Kvlividze, Kristina Lagerstedt-Robinson, Paul Lasko, Timo Lassmann, Lynette Y. S. Lau, Steven Laurie, Weng Khong Lim, Zhandong Liu, Mariya Lysenkova Wiklander, Prince Makay, Alassane Baneye Maiga, Carolina Maya-González, M. Stephen Meyn, Ramprasad Neethiraj, Vincenzo Nigro, Felix Nordgren, Jessica Nordlund, Sara Orrsjö, Jesper Ottosson, Ugur Ozbek, Özkan Özdemir, Clyde Partin, David A. Pearce, Raquel Peck, Annie Pedersen, Maria Pettersson, Monnat Pongpanich, Manuel Posada de la Paz, Arun Ramani, Juan Andres Romero, Vanessa I. Romero, Richard Rosenquist, Aung Min Saw, Matthew Spencer, Eva-Lena Stattin, Chalurmpon Srichomthong, Isabel Tapia-Paez, Domenica Taruscio, Julie P. Taylor, Tinatin Tkemaladze, Ian Tully, Zeynep Tümer, Wendy A. G. van Zelst-Stams, Alain Verloes, Emma Västerviga, Sailan Wang, Rachel Yang, Shinya Yamamoto, Vicente A. Yépez, Qing Zhang, Vorasuk Shotelersuk, Samuel Agyei Wiafe, Yasemin Alanay, Lorenzo D. Botto, Salman Kirmani, Aimé Lumaka, Elizabeth Emma Palmer, Ratna Dua Puri, Valtteri Wirta, Anna Lindstrand, Orion J. Buske, Mikk Cederroth, Ann Nordgren
Journal: Nature Genetics (2024)
Pathological mechanisms and candidate therapeutic approaches in the hearing loss of mice carrying human MIR96 mutations
Authors: Morag A. Lewis, Maria Lachgar-Ruiz, Francesca Di Domenico, Graham Duddy, Jing Chen, Sergio Fernandez, Matias Morin, Gareth Williams, Miguel Angel Moreno Pelayo, Karen P. Steel
Journal: Genome Medicine (2024)

Abstract Background Progressive hearing loss is a common problem in the human population with no effective therapeutics currently available. However, it has a strong genetic contribution, and investigating the genes and regulatory interactions underlying hearing loss offers the possibility of identifying therapeutic candidates. Mutations in regulatory genes are particularly useful for this, and an example is the microRNA miR-96, a post-transcriptional regulator which controls hair cell maturation. Mice and humans carrying mutations in miR-96 all exhibit hearing impairment, in homozygosis if not in heterozygosis, but different mutations result in different physiological, structural and transcriptional phenotypes. Methods Here we present our characterisation of two lines of mice carrying different human mutations knocked-in to Mir96 . We have carried out auditory brainstem response tests to examine their hearing with age and after noise exposure and have used confocal and scanning electron microscopy to examine the ultrastructure of the organ of Corti and hair cell synapses. Bulk RNA-seq was carried out on the organs of Corti of postnatal mice, followed by bioinformatic analyses to identify candidate targets. Results While mice homozygous for either mutation are profoundly deaf from 2 weeks old, the heterozygous phenotypes differ markedly, with only one mutation resulting in hearing impairment in heterozygosis. Investigations of the structural phenotype showed that one mutation appears to lead to synaptic defects, while the other has a much more severe effect on the hair cell stereociliary bundles. Transcriptome analyses revealed a wide range of misregulated genes in both mutants which were notably dissimilar. We used the transcriptome analyses to investigate candidate therapeutics, and tested one, finding that it delayed the progression of hearing loss in heterozygous mice. Conclusions Our work adds further support for the importance of the gain of novel targets in microRNA mutants and offers a proof of concept for the identification of pharmacological interventions to maintain hearing.
Integrating metabolomics and proteomics to identify novel drug targets for heart failure and atrial fibrillation
Authors: Marion van Vugt, Chris Finan, Sandesh Chopade, Rui Providencia, Connie R. Bezzina, Folkert W. Asselbergs, Jessica van Setten, A. Floriaan Schmidt
Journal: Genome Medicine (2024)

Abstract Background Altered metabolism plays a role in the pathophysiology of cardiac diseases, such as atrial fibrillation (AF) and heart failure (HF). We aimed to identify novel plasma metabolites and proteins associating with cardiac disease. Methods Mendelian randomisation (MR) was used to assess the association of 174 metabolites measured in up to 86,507 participants with AF, HF, dilated cardiomyopathy (DCM), and non-ischemic cardiomyopathy (NICM). Subsequently, we sourced data on 1567 plasma proteins and performed cis MR to identify proteins affecting the identified metabolites as well as the cardiac diseases. Proteins were prioritised on cardiac expression and druggability, and mapped to biological pathways. Results We identified 35 metabolites associating with cardiac disease. AF was affected by seventeen metabolites, HF by nineteen, DCM by four, and NCIM by taurine. HF was particularly enriched for phosphatidylcholines ( p = 0.029) and DCM for acylcarnitines ( p = 0.001). Metabolite involvement with AF was more uniform, spanning for example phosphatidylcholines, amino acids, and acylcarnitines. We identified 38 druggable proteins expressed in cardiac tissue, with a directionally concordant effect on metabolites and cardiac disease. We recapitulated known associations, for example between the drug target of digoxin (AT1B2), taurine and NICM risk. Additionally, we identified numerous novel findings, such as higher RET values associating with phosphatidylcholines and decreasing AF and HF. RET is targeted by drugs such as regorafenib which has known cardiotoxic side-effects. Pathway analysis implicated involvement of GDF15 signalling through RET, and ghrelin regulation of energy homeostasis in cardiac pathogenesis. Conclusions This study identified 35 plasma metabolites involved with cardiac diseases and linked these to 38 druggable proteins, providing actionable leads for drug development.
Efficacy and Safety of Sodium‐Glucose Co‐Transporter 2 Inhibitors for the Primary Prevention of Cardiovascular, Renal Events and Safety Outcomes in Patients with Systemic Lupus Erythematosus and Comorbid Type 2 Diabetes: A Population‐based Target Trial Emulation
Authors: Kevin Sheng‐Kai Ma, Jui‐En Lo, Vasileios C. Kyttaris, George C. Tsokos, Karen H. Costenbader
Journal: Arthritis & Rheumatology (2024)

Objectives Patients with systemic lupus erythematosus (SLE) were excluded from sodium‐glucose co‐transporter 2 inhibitors (SGLT2i) clinical trials. It is unknown whether the cardiorenal benefits of SGLT2i extend to patients with SLE and comorbid type 2 diabetes (T2D). Methods We performed an emulated clinical trial in an insurance‐based cohort in the U.S., evaluating SGLT2i versus dipeptidyl peptidase 4 inhibitors (DPP4i) for primary prevention of cardiovascular, renal, and other clinical outcomes among patients with both SLE patients and comorbid T2D. SGLT2i initiators were matched to DPP4i initiators using propensity scores (PS) based on clinical and demographic factors. Hazard ratios (HR with 95% confidence intervals) were calculated using Cox models. Results Outcomes among 2,165 patients starting SGLT2i and 2,165 PS‐matched patients starting DPP4i were compared. Over 753.1 (±479.2) mean days, SGLT2i recipients had significantly lower risks of incident acute kidney injury (HR 0.49, 95% CI 0.39‐0.63), chronic kidney disease (HR 0.61, 0.50‐0.76), end‐stage renal disease (HR 0.40, 0.20‐0.80), heart failure (HR 0.72, 0.56‐0.92), and emergency department visits (HR 0.90, 0.82‐0.99). Risks of all‐cause mortality (HR 0.89, 0.65‐1.21), lupus nephritis (HR 0.67, 0.38‐1.15), myocardial infarction (HR 0.81, 0.54‐1.23), stroke (HR 1.03, 0.74‐1.44), and hospitalizations (HR 0.76, 0.51‐1.12) did not differ. Genital infection risk (HR 1.31, 1.07‐1.61) was increased, but urinary tract infection risk (HR 0.90, 0.79‐1.03) did not differ. No significant difference was observed for diabetic ketoacidosis risk (HR 1.065, 0.53‐2.14) and fractures (HR 0.95, 0.66‐1.36). Conclusions In this emulated clinical trial, SGLT2i vs. DPP4i use was associated with significantly reduced risks of several cardiorenal complications among patients with both SLE and T2D.
Incidence and genetic risk of juvenile idiopathic arthritis in Norway by latitude
Authors: Sigrid V. Hestetun, Hamid K. Rudsari, Piotr Jaholkowski, Alexey Shadrin, Kristine L. Haftorn, Svend Andersen, Marite Rygg, Ellen Nordal, Oleksandr Frei, Ole A. Andreassen, Anne M. Selvaag, Ketil Størdal, Helga Sanner
Journal: Arthritis & Rheumatology (2024)

Objective We aimed to investigate the incidence of juvenile idiopathic arthritis (JIA) in the three geographic regions of Norway and whether potential regional incidence differences are explained by environmental or genetic factors across regions. Methods We conducted a register‐based cohort study including all Norwegian children born from 2004 to 2019, with follow‐up throughout 2020. The JIA diagnosis, defined by at least two International Classification of Diseases, Tenth Revision codes for JIA, was validated against medical records. The incidence rate (IR) and hazard ratio (HR) for JIA were estimated for all Norway and for the North, Mid, and South regions. In a subsample from the Norwegian Mother, Father, and Child Cohort Study (MoBa), the genetic risk for JIA was assessed in the three regions. Results After median 9.1 (range 0.3–16.0) years of follow‐up, we identified 1,184 patients with JIA and 910,058 controls. The IR for JIA/100,000 person‐years was 14.4 in all of Norway, 25.9 in the North region, 17.9 in the Mid region, and 12.5 in the South region. The HR (95% confidence interval [CI]) of JIA in the North region was 2.07 (1.77–2.43) and in the Mid region HR 1.43 (95% CI 1.23–1.67) compared with the South region. Adjustments for perinatal factors, socioeconomic status, and early antibiotic exposure did not change our estimates substantially. In MoBa (238 patients with JIA, 57,392 controls), the association between JIA and region of birth was no longer significant when adjusting for genetic factors. Conclusion We found a higher incidence of JIA with increasing latitude without evidence for available environmental factors explaining the observed gradient. In contrast, genetic factors modified the association, but further studies are warranted.
Neutrophil activation markers can predict rheumatoid arthritis treatment response to the Janus Kinase 1/2 inhibitor baricitinib
Authors: Runa Kuley, Bhargavi Duvvuri, Sabeeha Hasnain, Ernst R. Dow, Alisa E. Koch, Richard E. Higgs, Venkatesh Krishnan, Christian Lood
Journal: Arthritis & Rheumatology (2024)

Objective Neutrophils play an important role in regulating immune and inflammatory responses in patients with rheumatoid arthritis (RA). We assessed whether baricitinib, a JAK1/JAK2 inhibitor, could reduce neutrophil activation and whether a neutrophil activation score could predict treatment response. Methods Markers of neutrophil activation, calprotectin, and neutrophil extracellular traps (NETs) were analyzed using enzyme‐linked immunosorbent assay in plasma from patients with RA (n = 271) and healthy controls (n = 39). For patients with RA, neutrophil activation markers were measured at baseline, 12 weeks, and 24 weeks after receiving placebo and 2 and 4 mg baricitinib. Whole‐blood RNA analyses from multiple randomized baricitinib RA trials were performed to study neutrophil‐related transcripts (n = 1,651). Results Baseline levels of plasma neutrophil markers were elevated in patients with RA compared to healthy controls ( P &lt; 0.001). Receiving baricitinib reduced levels of soluble calprotectin at 12 and 24 weeks, especially in patients with RA responding to treatment, as determined by American College of Rheumatology 20% improvement criteria. Whole‐blood RNA analysis revealed similar changes in the predominant neutrophil markers calprotectin and Fcα receptor I upon reception of baricitinib in three randomized clinical trials involving patients with at various stages of disease‐modifying therapy. Clustering analysis of plasma activation markers showed elevated levels of calprotectin and NETs (eg, a neutrophil activation score, at baseline, could predict treatment response to baricitinib). In contrast, C‐reactive protein levels could not distinguish between responders and nonresponders. Conclusion Neutrophil activation markers may add clinical value in predicting treatment response to baricitinib and other drugs targeting RA. This study supports personalized medicine in treating patients with RA, not only based on symptoms but also based on immunophenotyping.
A rare and misleading condition: isolated skeletal involvement of Erdheim‐Chester Disease
Authors: Sara Bindoli, Stefania Vio, Marta Sbaraglia, Fabrizio Vianello, Roberta Ramonda
Journal: Arthritis & Rheumatology (2024)

We are describing an unusual presentation of Erdheim-Chester Disease (ECD), a non -Langerhans histiocytosis provoked by abnormal aggregation of foamy histiocytes in several organs and systems. Our patient, already with osteoporosis, presented severe bilateral ankle pain with functional impairment, clinically mimicking "Complex Regional Pain Syndrome" (CRPS); the radiological images and subsequently the bone biopsy were fundamental for achieving the proper diagnosis. The diagnosis was challenging given the isolated bone localization which is uncommonly seen in ECD.
ANCA-ASSOCIATED VASCULITIS, DIAGNOSIS, PATHOPHYSIOLOGY AND TREATMENTVASCULITIS IN CHILDHOODRELEVANCE OF IGG RECEPTORS (FCγR) FOR PATHOGENESIS AND TREATMENT OF AUTOIMMUNE DISEASES HSP REACTIVE T CELLS AS INFLAMMATION REGULATORSIMMUNOTHERAPY OF RHEUMATIC DISEASESIMMUNODEFICIENCIES AS MODELS FOR AUTOIMMUNITYSLEEPING WITH THE ENEMY: TOLERANCE INDUCTION IN CHILDHOOD AUTOIMMUNE DISEASESMECHANISMS OF JOINT DAMAGE BY T CELLS IN JUVENILE IDIOPATHIC ARTHRITIS: CAN THEY BE BLOCKED?REDUCED PERFORIN …
Authors: C. G. M. Kallenberg, M. J. Dillon, W.-L. van der Pol, W. Van Eden, S. Albani, P. Quartier, B. J. Prakken, L. Wedderburn, Ger T. Rijkers, I. C. Chikanza, J. W. J. Bijlsma, Lightman SL, N. M. Wulffraat, D. A. Isenberg, T. W. J. Huizinga, W. B. van den Berg, F. C. Breedveld, M. Boers, J. Sieper, K. J. Murray, M. F. G. van der Meulen, L. Paul, U. Wendling, P. van Kooten, J. Bos-de Ruijter, R. van der Zee, B. Prakken, Nico M. Wulffraat, Elize Elst, Rik Brooimans, Wietse Kuis, E. A. M. Sanders, A. van Royen, W. Kuis
Journal: Annals of the Rheumatic Diseases (2001)
Clonal hematopoiesis and myeloid skewing in older population‐based individuals
Authors: Maaike G. J. M. van Bergen, Priscilla Kamphuis, Aniek O. de Graaf, Jonas B. Salzbrunn, Theresia N. Koorenhof‐Scheele, Isabelle A. van Zeventer, Avinash G. Dinmohamed, Jan Jacob Schuringa, Bert A. van der Reijden, Gerwin Huls, Joop H. Jansen
Journal: American Journal of Hematology (2024)
Arterial-Lymphatic-Like Endothelial Cells Appear in Hereditary Hemorrhagic Telangiectasia 2 and Contribute to Vascular Leakage and Arteriovenous Malformations
Authors: Yang Yang, Xiuju Wu, Yan Zhao, Daoqin Zhang, Li Zhang, Xinjiang Cai, Jaden Ji, Zheng Jing, Kristina I. Boström, Yucheng Yao
Journal: Circulation (2024)

BACKGROUND: Arteriovenous malformations (AVMs) are characteristic of hereditary hemorrhagic telangiectasia. Loss-of-function mutations in the activin receptor‐like kinase 1 ( Alk1 ) are linked to hemorrhagic telangiectasia type 2. METHODS: Endothelial-specific deletion of Alk1, endothelial lineage tracing, transcriptomics of single-cell analysis, and electron microscopy were performed to examine the vascular phenotype and characteristics of ALK1-deficient endothelial cells (ECs) after EC-specific Alk1 deletion. Ischemia assays were used to examine the cell capacity for vascular malformation. Connectivity Map with transcriptomic analysis was applied to identify chemical compounds. Specific methods for arteriovenous malformations, such as micro–computed tomography, with other molecular and cell biological tools were also performed. RESULTS: We performed endothelial-specific deletion of Alk1 in mice and found severe arteriovenous malformations and vascular leakage. The transcriptomics of single-cell analysis revealed a new distinctive cell cluster formed after Alk1 deletion where the cells coexpressed arterial and lymphatic endothelial markers. The analysis projected that these cells potentially originated from arterial ECs after Alk1 deletion. This new population was referred to as arterial-lymphatic-like ECs according to its cellular markers, and its appearance was validated in the pulmonary small arteries after Alk1 deletion. Transplantation of these cells caused vascular malformations. Endothelial lineage tracing confirmed that these new arterial-lymphatic-like ECs were derived from ALK1 depleted ECs, potentially arterial ECs. We discovered that SOX17 (SRY-box transcription factor 17) induction was responsible for the derivation of these arterial-lymphatic-like ECs. We showed that direct binding of MDM2 (mouse double minute 2) was required for Sox17 to execute this activity. Inhibition of MDM2 reduced the arteriovenous malformations in the mouse model. CONCLUSIONS: Together, our studies revealed the mechanistic underpinnings of ALK1 signaling in regulating the endothelial phenotype and provided possibilities for new therapeutic strategies in hemorrhagic telangiectasia type 2.
Targeting Sphingosine-1-Phosphate Signaling to Prevent the Progression of Aortic Valve Disease
Authors: Marcel Benkhoff, Maike Barcik, Philipp Mourikis, Jana Dahlmanns, Paulina Kahmann, Philipp Wollnitzke, Moritz Hering, Tim Huckenbeck, Julia Hoppe, Nina Semleit, Jennifer Deister-Jonas, Saif Zako, Jasmin Seel, Cristina Coman, Mareike Barth, Mareike Cramer, Carolin Helten, Laura Wildeis, Hao Hu, Gabrielle Al-Kassis, Daniel Metzen, Julia Hesse, Jessica Weber, Lisa Dannenberg, Payam Akhyari, Artur Lichtenberg, Christine Quast, Norbert Gerdes, Tobias Zeus, Oliver Borst, Malte Kelm, Tobias Petzold, Robert Ahrends, Bodo Levkau, Amin Polzin
Journal: Circulation (2024)

BACKGROUND: Aortic valve disease (AVD) is associated with high mortality and morbidity. To date, there is no pharmacological therapy available to prevent AVD progression. Because valve calcification is the hallmark of AVD and S1P (sphingosine-1-phosphate) plays an important role in osteogenic signaling, we examined the role of S1P signaling in aortic stenosis disease. METHODS: AVD progression and its consequences for cardiac function were examined in a murine wire injury–induced AVD model with and without pharmacological and genetic modulation of S1P production, degradation, and receptor signaling. S1P was measured by LC-MS. Calcification of valvular interstitial cells and their response to biomechanical stress were analyzed in the context of S1P signaling. Human explanted aortic valves from patients undergoing aortic valve replacement and cardiovascular magnetic resonance imaging were analyzed for S1P by LC-MS. RESULTS: Raising S1P concentrations in mice with injury-induced AVD by pharmacological inhibition of its sole degrading enzyme S1P lyase vastly enhanced AVD progression and impaired cardiac function resembling human disease. In contrast, low S1P levels caused by SphK1 (sphingosine kinase 1) deficiency potently attenuated AVD progression. We found S1P/S1PR2 (S1P receptor 2) signaling to be responsible for the adverse S1P effect because S1PR2-deficient mice were protected against AVD progression and its deterioration by high S1P. It is important to note that pharmacological S1PR2 inhibition administered after wire injury successfully prevented AVD development. Mechanistically, biomechanical stretch stimulated S1P production by SphK1 in human valvular interstitial cells as measured by C17-S1P generation, whereas S1P/S1PR2 signaling induced their osteoblastic differentiation and calcification through osteogenic RUNX2/OPG signaling and the GSK3β-Wnt-β-catenin pathway. In patients with AVD, stenotic valves exposed to high wall shear stress had higher S1P content and increased SphK1 expression. CONCLUSIONS: Increased systemic or local S1P levels lead to increased valvular calcification. S1PR2 antagonists and SphK1 inhibitors may offer feasible pharmacological approaches to human AVD in prophylactic, disease-modifying or relapse-preventing manners.