Browsing by Author "Humbert, Marc"

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    Allele-specific control of rodent and human lncRNA KMT2E-AS1 promotes hypoxic endothelial pathology in pulmonary hypertension
    (American Association for the Advancement of Science, 2024) Tai, Yi-Yin; Yu, Qiujun; Tang, Ying; Sun, Wei; Kelly, Neil J.; Okawa, Satoshi; Zhao, Jingsi; Schwantes-An, Tae-Hwi; Lacoux, Caroline; Torrino, Stephanie; Al Aaraj, Yassmin; El Khoury, Wadih; Negi, Vinny; Liu, Mingjun; Corey, Catherine G.; Belmonte, Frances; Vargas, Sara O.; Schwartz, Brian; Bhat, Bal; Chau, B. Nelson; Karnes, Jason H.; Satoh, Taijyu; Barndt, Robert J.; Wu, Haodi; Parikh, Victoria N.; Wang, Jianrong; Zhang, Yingze; McNamara, Dennis; Li, Gang; Speyer, Gil; Wang, Bing; Shiva, Sruti; Kaufman, Brett; Kim, Seungchan; Gomez, Delphine; Mari, Bernard; Cho, Michael H.; Boueiz, Adel; Pauciulo, Michael W.; Southgate, Laura; Trembath, Richard C.; Sitbon, Olivier; Humbert, Marc; Graf, Stefan; Morrell, Nicholas W.; Rhodes, Christopher J.; Wilkins, Martin R.; Nouraie, Mehdi; Nichols, William C.; Desai, Ankit A.; Bertero, Thomas; Chan, Stephen Y.; Medicine, School of Medicine
    Hypoxic reprogramming of vasculature relies on genetic, epigenetic, and metabolic circuitry, but the control points are unknown. In pulmonary arterial hypertension (PAH), a disease driven by hypoxia inducible factor (HIF)-dependent vascular dysfunction, HIF-2α promoted expression of neighboring genes, long noncoding RNA (lncRNA) histone lysine N-methyltransferase 2E-antisense 1 (KMT2E-AS1) and histone lysine N-methyltransferase 2E (KMT2E). KMT2E-AS1 stabilized KMT2E protein to increase epigenetic histone 3 lysine 4 trimethylation (H3K4me3), driving HIF-2α-dependent metabolic and pathogenic endothelial activity. This lncRNA axis also increased HIF-2α expression across epigenetic, transcriptional, and posttranscriptional contexts, thus promoting a positive feedback loop to further augment HIF-2α activity. We identified a genetic association between rs73184087, a single-nucleotide variant (SNV) within a KMT2E intron, and disease risk in PAH discovery and replication patient cohorts and in a global meta-analysis. This SNV displayed allele (G)-specific association with HIF-2α, engaged in long-range chromatin interactions, and induced the lncRNA-KMT2E tandem in hypoxic (G/G) cells. In vivo, KMT2E-AS1 deficiency protected against PAH in mice, as did pharmacologic inhibition of histone methylation in rats. Conversely, forced lncRNA expression promoted more severe PH. Thus, the KMT2E-AS1/KMT2E pair orchestrates across convergent multi-ome landscapes to mediate HIF-2α pathobiology and represents a key clinical target in pulmonary hypertension.
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    Mendelian randomisation and experimental medicine approaches to interleukin-6 as a drug target in pulmonary arterial hypertension
    (European Respiratory Society, 2022-03-10) Toshner, Mark; Church, Colin; Harbaum, Lars; Rhodes, Christopher; Villar Moreschi, Sofia S.; Liley, James; Jones, Rowena; Arora, Amit; Batai, Ken; Desai, Ankit A.; Coghlan, John G.; Gibbs, J. Simon R.; Gor, Dee; Gräf, Stefan; Harlow, Louise; Hernandez-Sanchez, Jules; Howard, Luke S.; Humbert, Marc; Karnes, Jason; Kiely, David G.; Kittles, Rick; Knightbridge, Emily; Lam, Brian; Lutz, Katie A.; Nichols, William C.; Pauciulo, Michael W.; Pepke-Zaba, Joanna; Suntharalingam, Jay; Soubrier, Florent; Trembath, Richard C.; Schwantes-An, Tae-Hwi L.; Wort, S. John; Wilkins, Martin R.; Gaine, Sean; Morrell, Nicholas W.; Corris, Paul A.; Uniphy Clinical Trials Network; Medicine, School of Medicine
    Background: Inflammation and dysregulated immunity are important in the development of pulmonary arterial hypertension (PAH). Compelling preclinical data supports the therapeutic blockade of interleukin-6 (IL-6) signalling. Methods: We conducted a phase 2 open-label study of intravenous tocilizumab (8 mg·kg-1) over 6 months in patients with group 1 PAH. Co-primary end-points were safety, defined by incidence and severity of adverse events, and change in pulmonary vascular resistance. Separately, a mendelian randomisation study was undertaken on 11 744 individuals with European ancestry including 2085 patients with idiopathic/heritable disease for the IL-6 receptor (IL6R) variant (rs7529229), known to associate with circulating IL-6R levels. Results: We recruited 29 patients (male/female 10/19; mean±sd age 54.9±11.4 years). Of these, 19 had heritable/idiopathic PAH and 10 had connective tissue disease-associated PAH. Six were withdrawn prior to drug administration; 23 patients received at least one dose of tocilizumab. Tocilizumab was discontinued in four patients owing to serious adverse events. There were no deaths. Despite evidence of target engagement in plasma IL-6 and C-reactive protein levels, both intention-to-treat and modified intention-to-treat analyses demonstrated no change in pulmonary vascular resistance. Inflammatory markers did not predict treatment response. Mendelian randomisation did not support an effect of the lead IL6R variant on risk of PAH (OR 0.99, p=0.88). Conclusion: Adverse events were consistent with the known safety profile of tocilizumab. Tocilizumab did not show any consistent treatment effect.
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    Mining the Plasma Proteome for Insights into the Molecular Pathology of Pulmonary Arterial Hypertension
    (American Thoracic Society, 2022) Harbaum, Lars; Rhodes, Christopher J.; Wharton, John; Lawrie, Allan; Karnes, Jason H.; Desai, Ankit A.; Nichols, William C.; Humbert, Marc; Montani, David; Girerd, Barbara; Sitbon, Olivier; Boehm, Mario; Novoyatleva, Tatyana; Schermuly, Ralph T.; Ghofrani, H. Ardeschir; Toshner, Mark; Kiely, David G.; Howard, Luke S.; Swietlik, Emilia M.; Gräf, Stefan; Pietzner, Maik; Morrell, Nicholas W.; Wilkins, Martin R.; U.K. National Institute for Health Research BioResource Rare Diseases Consortium; U.K. Pulmonary Arterial Hypertension Cohort Study Consortium; U.S. Pulmonary Arterial Hypertension Biobank Consortium; Medical and Molecular Genetics, School of Medicine
    Rationale: Pulmonary arterial hypertension (PAH) is characterized by structural remodeling of pulmonary arteries and arterioles. Underlying biological processes are likely reflected in a perturbation of circulating proteins. Objectives: To quantify and analyze the plasma proteome of patients with PAH using inherited genetic variation to inform on underlying molecular drivers. Methods: An aptamer-based assay was used to measure plasma proteins in 357 patients with idiopathic or heritable PAH, 103 healthy volunteers, and 23 relatives of patients with PAH. In discovery and replication subgroups, the plasma proteomes of PAH and healthy individuals were compared, and the relationship to transplantation-free survival in PAH was determined. To examine causal relationships to PAH, protein quantitative trait loci (pQTL) that influenced protein levels in the patient population were used as instruments for Mendelian randomization (MR) analysis. Measurements and Main Results: From 4,152 annotated plasma proteins, levels of 208 differed between patients with PAH and healthy subjects, and 49 predicted long-term survival. MR based on cis-pQTL located in proximity to the encoding gene for proteins that were prognostic and distinguished PAH from health estimated an adverse effect for higher levels of netrin-4 (odds ratio [OR], 1.55; 95% confidence interval [CI], 1.16–2.08) and a protective effect for higher levels of thrombospondin-2 (OR, 0.83; 95% CI, 0.74–0.94) on PAH. Both proteins tracked the development of PAH in previously healthy relatives and changes in thrombospondin-2 associated with pulmonary arterial pressure at disease onset. Conclusions: Integrated analysis of the plasma proteome and genome implicates two secreted matrix-binding proteins, netrin-4 and thrombospondin-2, in the pathobiology of PAH.