Kidney International Reports (Jun 2024)

Prioritization of Kidney Cell Types Highlights Myofibroblast Cells in Regulating Human Blood Pressure

  • Mahboube Ganji-Arjenaki,
  • Zoha Kamali,
  • Soroush Sardari,
  • Martin de Borst,
  • Harold Snieder,
  • Ahmad Vaez,
  • Evangelos Evangelou,
  • Helen R. Warren,
  • He Gao,
  • Georgios Ntritsos,
  • Niki Dimou,
  • Tonu Esko,
  • Reedik Mägi,
  • Lili Milani,
  • Peter Almgren,
  • Thibaud Boutin,
  • Stéphanie Debette,
  • Jun Ding,
  • Franco Giulianini,
  • Elizabeth G. Holliday,
  • Anne U. Jackson,
  • Ruifang Li -Gao,
  • Wei -Yu Lin,
  • Jian'an Luan,
  • Massimo Mangino,
  • Christopher Oldmeadow,
  • Bram Peter Prins,
  • Yong Qian,
  • Muralidharan Sargurupremraj,
  • Nabi Shah,
  • Praveen Surendran,
  • Sébastien Thériault,
  • Niek Verweij,
  • Sara M. Willems,
  • Jing -Hua Zhao,
  • Philippe Amouyel,
  • John Connell,
  • Renée de Mutsert,
  • Alex S.F. Doney,
  • Martin Farrall,
  • Cristina Menni,
  • Andrew D. Morris,
  • Raymond Noordam,
  • Guillaume Paré,
  • Neil R. Poulter,
  • Denis C. Shields,
  • Alice Stanton,
  • Simon Thom,
  • Gonçalo Abecasis,
  • Najaf Amin,
  • Dan E. Arking,
  • Kristin L. Ayers,
  • Caterina M. Barbieri,
  • Chiara Batini,
  • Joshua C. Bis,
  • Tineka Blake,
  • Murielle Bochud,
  • Michael Boehnke,
  • Eric Boerwinkle,
  • Dorret I. Boomsma,
  • Erwin P. Bottinger,
  • Peter S. Braund,
  • Marco Brumat,
  • Archie Campbell,
  • Harry Campbell,
  • Aravinda Chakravarti,
  • John C. Chambers,
  • Ganesh Chauhan,
  • Marina Ciullo,
  • Massimiliano Cocca,
  • Francis Collins,
  • Heather J. Cordell,
  • Gail Davies,
  • Martin H. de Borst,
  • Eco J. de Geus,
  • Ian J. Deary,
  • Joris Deelen,
  • Fabiola Del Greco M,
  • Cumhur Yusuf Demirkale,
  • Marcus Dörr,
  • Georg B. Ehret,
  • Roberto Elosua,
  • Stefan Enroth,
  • A. Mesut Erzurumluoglu,
  • Teresa Ferreira,
  • Mattias Frånberg,
  • Oscar H. Franco,
  • Ilaria Gandin,
  • Paolo Gasparini,
  • Vilmantas Giedraitis,
  • Christian Gieger,
  • Giorgia Girotto,
  • Anuj Goel,
  • Alan J. Gow,
  • Vilmundur Gudnason,
  • Xiuqing Guo,
  • Ulf Gyllensten,
  • Anders Hamsten,
  • Tamara B. Harris,
  • Sarah E. Harris,
  • Catharina A. Hartman,
  • Aki S. Havulinna,
  • Andrew A. Hicks,
  • Edith Hofer,
  • Albert Hofman,
  • Jouke-Jan Hottenga,
  • Jennifer E. Huffman,
  • Shih-Jen Hwang,
  • Erik Ingelsson,
  • Alan James,
  • Rick Jansen,
  • Marjo -Riitta Jarvelin,
  • Roby Joehanes,
  • Åsa Johansson,
  • Andrew D. Johnson,
  • Peter K. Joshi,
  • Pekka Jousilahti,
  • J. Wouter Jukema,
  • Antti Jula,
  • Mika Kähönen,
  • Sekar Kathiresan,
  • Bernard D. Keavney,
  • Kay-Tee Khaw,
  • Paul Knekt,
  • Joanne Knight,
  • Ivana Kolcic,
  • Jaspal S. Kooner,
  • Seppo Koskinen,
  • Kati Kristiansson,
  • Zoltan Kutalik,
  • Maris Laan,
  • Marty Larson,
  • Lenore J. Launer,
  • Benjamin Lehne,
  • Terho Lehtimäki,
  • David C.M. Liewald,
  • Li Lin,
  • Lars Lind,
  • Cecilia M. Lindgren,
  • YongMei Liu,
  • Ruth J.F. Loos,
  • Lorna M. Lopez,
  • Yingchang Lu,
  • Leo-Pekka Lyytikäinen,
  • Anubha Mahajan,
  • Chrysovalanto Mamasoula,
  • Jaume Marrugat,
  • Jonathan Marten,
  • Yuri Milaneschi,
  • Anna Morgan,
  • Andrew P. Morris,
  • Alanna C. Morrison,
  • Peter J. Munson,
  • Mike A. Nalls,
  • Priyanka Nandakumar,
  • Christopher P. Nelson,
  • Teemu Niiranen,
  • Ilja M. Nolte,
  • Teresa Nutile,
  • Albertine J. Oldehinkel,
  • Ben A. Oostra,
  • Paul F. O'Reilly,
  • Elin Org,
  • Sandosh Padmanabhan,
  • Walter Palmas,
  • Aarno Palotie,
  • Alison Pattie,
  • Brenda W.J.H. Penninx,
  • Markus Perola,
  • Annette Peters,
  • Ozren Polasek,
  • Peter P. Pramstaller,
  • Quang Tri Nguyen,
  • Olli T. Raitakari,
  • Rainer Rettig,
  • Kenneth Rice,
  • Paul M. Ridker,
  • Janina S. Ried,
  • Harriëtte Riese,
  • Samuli Ripatti,
  • Antonietta Robino,
  • Lynda M. Rose,
  • Jerome I. Rotter,
  • Igor Rudan,
  • Daniela Ruggiero,
  • Yasaman Saba,
  • Cinzia F. Sala,
  • Veikko Salomaa,
  • Nilesh J. Samani,
  • Antti-Pekka Sarin,
  • Reinhold Schmidt,
  • Helena Schmidt,
  • Nick Shrine,
  • David Siscovick,
  • Albert V. Smith,
  • Harold Snieder,
  • Siim Sõber,
  • Rossella Sorice,
  • John M. Starr,
  • David J. Stott,
  • David P. Strachan,
  • Rona J. Strawbridge,
  • Johan Sundström,
  • Morris A. Swertz,
  • Kent D. Taylor,
  • Alexander Teumer,
  • Martin D. Tobin,
  • Maciej Tomaszewski,
  • Daniela Toniolo,
  • Michela Traglia,
  • Stella Trompet,
  • Jaakko Tuomilehto,
  • Christophe Tzourio,
  • André G. Uitterlinden,
  • Ahmad Vaez,
  • Peter J. van der Most,
  • Cornelia M. van Duijn,
  • Germaine C. Verwoert,
  • Veronique Vitart,
  • Uwe Völker,
  • Peter Vollenweider,
  • Dragana Vuckovic,
  • Hugh Watkins,
  • Sarah H. Wild,
  • Gonneke Willemsen,
  • James F. Wilson,
  • Alan F. Wright,
  • Jie Yao,
  • Tatijana Zemunik,
  • Weihua Zhang,
  • John R. Attia,
  • Adam S. Butterworth,
  • Daniel I. Chasman,
  • David Conen,
  • Francesco Cucca,
  • John Danesh,
  • Caroline Hayward,
  • Joanna M.M. Howson,
  • Markku Laakso,
  • Edward G. Lakatta,
  • Claudia Langenberg,
  • Olle Melander,
  • Dennis O. Mook-Kanamori,
  • Colin N.A. Palmer,
  • Lorenz Risch,
  • Robert A. Scott,
  • Rodney J. Scott,
  • Peter Sever,
  • Tim D. Spector,
  • Pim van der Harst,
  • Nicholas J. Wareham,
  • Eleftheria Zeggini,
  • Daniel Levy,
  • Patricia B. Munroe,
  • Christopher Newton-Cheh,
  • Morris J. Brown,
  • Andres Metspalu,
  • Bruce M. Psaty,
  • Louise V. Wain,
  • Paul Elliott,
  • Mark J. Caulfield

DOI
https://doi.org/10.1016/j.ekir.2024.03.001
Journal volume & issue
Vol. 9, no. 6
pp. 1849 – 1859

Abstract

Read online

Introduction: Blood pressure (BP) is a highly heritable trait with over 2000 underlying genomic loci identified to date. Although the kidney plays a key role, little is known about specific cell types involved in the genetic regulation of BP. Methods: Here, we applied stratified linkage disequilibrium score (LDSC) regression to connect BP genome-wide association studies (GWAS) results to specific cell types of the mature human kidney. We used the largest single-stage BP genome-wide analysis to date, including up to 1,028,980 adults of European ancestry, and single-cell transcriptomic data from 14 mature human kidneys, with mean age of 41 years. Results: Our analyses prioritized myofibroblasts and endothelial cells, among the total of 33 annotated cell type, as specifically involved in BP regulation (P < 0.05/33, i.e., 0.001515). Enrichment of heritability for systolic BP (SBP) was observed in myofibroblast cells in mature human kidney cortex, and enrichment of heritability for diastolic BP (DBP) was observed in descending vasa recta and peritubular capillary endothelial cells as well as stromal myofibroblast cells. The new finding of myofibroblast, the significant cell type for both BP traits, was consistent in 8 replication efforts using 7 sets of independent data, including in human fetal kidney, in East-Asian (EAS) ancestry, using mouse single-cell RNA sequencing (scRNA-seq) data, and when using another prioritization method. Conclusion: Our findings provide a solid basis for follow-up studies to further identify genes and mechanisms in myofibroblast cells that underlie the regulation of BP.

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