Genetic Interleukin 6 Signaling Deficiency Attenuates Cardiovascular Risk in Clonal Hematopoiesis
Alexander G. Bick,James P. Pirruccello,Gabriel K. Griffin,Gabriel K. Griffin,Gabriel K. Griffin,Namrata Gupta,Stacey Gabriel,Danish Saleheen,Peter Libby,Sekar Kathiresan,Pradeep Natarajan +10 more
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TLDR
CHIP is associated with increased risk of incident CVD, and among carriers of large CHIP clones, genetically reduced IL-6 signaling abrogated this risk.Abstract:
Background: Clonal hematopoiesis of indeterminate potential (CHIP) refers to clonal expansion of hematopoietic stem cells attributable to acquired leukemic mutations in genes such as DNMT3A or TET2...read more
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Journal ArticleDOI
Inherited causes of clonal haematopoiesis in 97,691 whole genomes.
Alexander G. Bick,Joshua S. Weinstock,Satish K. Nandakumar,Satish K. Nandakumar,Charles P. Fulco,Charles P. Fulco,Erik L. Bao,Erik L. Bao,Seyedeh M. Zekavat,Seyedeh M. Zekavat,Mindy D. Szeto,Xiaotian Liao,Xiaotian Liao,Matthew Leventhal,Joseph Nasser,Kyle Chang,Cecelia A. Laurie,Bala Bharathi Burugula,Christopher J. Gibson,Amy E. Lin,Margaret A. Taub,François Aguet,Kristin G. Ardlie,Braxton D. Mitchell,Braxton D. Mitchell,Kathleen C. Barnes,Kathleen C. Barnes,Arden Moscati,Myriam Fornage,Susan Redline,Susan Redline,Susan Redline,Bruce M. Psaty,Edwin K. Silverman,Edwin K. Silverman,Scott T. Weiss,Scott T. Weiss,Nicholette D. Palmer,Ramachandran S. Vasan,Esteban G. Burchard,Sharon L.R. Kardia,Jiang He,Robert C. Kaplan,Robert C. Kaplan,Nicholas L. Smith,Nicholas L. Smith,Nicholas L. Smith,Donna K. Arnett,David A. Schwartz,Adolfo Correa,Mariza de Andrade,Xiuqing Guo,Barbara A. Konkle,Brian Custer,Juan M. Peralta,Hongsheng Gui,Deborah A. Meyers,Stephen T. McGarvey,Ida Yii-Der Chen,M. Benjamin Shoemaker,Patricia A. Peyser,Jai G. Broome,Stephanie M. Gogarten,Fei Fei Wang,Quenna Wong,May E. Montasser,Michelle Daya,Eimear E. Kenny,Kari E. North,Lenore J. Launer,Brian E. Cade,Brian E. Cade,Joshua C. Bis,Michael H. Cho,Michael H. Cho,Jessica Lasky-Su,Jessica Lasky-Su,Donald W. Bowden,L. Adrienne Cupples,Angel C.Y. Mak,Lewis C. Becker,Jennifer A. Smith,Tanika N. Kelly,Stella Aslibekyan,Susan R. Heckbert,Susan R. Heckbert,Hemant K. Tiwari,Ivana V. Yang,John A. Heit,Steven A. Lubitz,Steven A. Lubitz,Jill M. Johnsen,Joanne E. Curran,Sally E. Wenzel,Daniel E. Weeks,Dabeeru C. Rao,Dawood Darbar,Jee-Young Moon,Russell P. Tracy,Erin J Buth,Nicholas Rafaels,Ruth J. F. Loos,Peter Durda,Yongmei Liu,Lifang Hou,Jiwon Lee,Priyadarshini Kachroo,Priyadarshini Kachroo,Barry I. Freedman,Daniel Levy,Lawrence F. Bielak,James E. Hixson,James S. Floyd,Eric A. Whitsel,Patrick T. Ellinor,Patrick T. Ellinor,Marguerite R. Irvin,Tasha E. Fingerlin,Laura M. Raffield,Sebastian M. Armasu,Marsha M. Wheeler,Ester Cerdeira Sabino,John Blangero,L. Keoki Williams,Bruce D. Levy,Bruce D. Levy,Wayne Huey-Herng Sheu,Dan M. Roden,Eric Boerwinkle,Eric Boerwinkle,JoAnn E. Manson,JoAnn E. Manson,Rasika A. Mathias,Pinkal Desai,Kent D. Taylor,Andrew D. Johnson,Paul L. Auer,Charles Kooperberg,Cathy C. Laurie,Thomas W. Blackwell,Albert V. Smith,Hongyu Zhao,Ethan M. Lange,Leslie A. Lange,Stephen S. Rich,Jerome I. Rotter,James G. Wilson,James G. Wilson,Paul Scheet,Jacob O. Kitzman,Eric S. Lander,Eric S. Lander,Eric S. Lander,Jesse M. Engreitz,Jesse M. Engreitz,Benjamin L. Ebert,Alexander P. Reiner,Alexander P. Reiner,Siddhartha Jaiswal,Gonçalo R. Abecasis,Gonçalo R. Abecasis,Vijay G. Sankaran,Vijay G. Sankaran,Sekar Kathiresan,Pradeep Natarajan,Pradeep Natarajan +165 more
TL;DR: Analysis of high-coverage whole-genome sequences from 97,691 participants of diverse ancestries in the National Heart, Lung, and Blood Institute Trans-omics for Precision Medicine programme enables simultaneous identification of germline and somatic mutations that predispose individuals to clonal expansion of haematopoietic stem cells.
Journal ArticleDOI
The AIM2 inflammasome exacerbates atherosclerosis in clonal haematopoiesis
Trevor P. Fidler,Chenyi Xue,M. Yalcinkaya,Brian Hardaway,Sandra Abramowicz,Tong Xiao,Wenli Liu,David G. Thomas,Mohammad Ali Hajebrahimi,Joachim Pircher,Carlos Silvestre-Roig,Andriana G. Kotini,Larry Luchsinger,Ying Wei,Marit Westerterp,Marit Westerterp,Hans-Willem Snoeck,Eirini P. Papapetrou,Christian Schulz,Steffen Massberg,Oliver Soehnlein,Oliver Soehnlein,Benjamin L. Ebert,Benjamin L. Ebert,Ross L. Levine,Muredach P. Reilly,Peter Libby,Nan Wang,Alan R. Tall +28 more
TL;DR: This paper showed that increased proliferation and glycolytic metabolism in Jak2VF macrophages lead to DNA replication stress and activation of the AIM2 inflammasome, thereby aggravating atherosclerosis.
Journal ArticleDOI
Interleukin-6 Signaling and Anti-Interleukin-6 Therapeutics in Cardiovascular Disease.
Paul M. Ridker,Manas Rane +1 more
TL;DR: The IL (interleukin)-6 is a pivotal cytokine of innate immunity, which enacts a broad set of physiological functions traditionally associated with host defense, immune cell regulation, proliferation, and proliferation.
Journal ArticleDOI
Ageing and atherosclerosis: vascular intrinsic and extrinsic factors and potential role of IL-6
TL;DR: Ageing-related alterations in the bone marrow increase the phenomenon of clonal haematopoiesis of indeterminate potential and promote a skewing towards myeloid cell differentiation, both of which can accelerate atherosclerosis independently of chronic hyperlipidaemia.
Journal ArticleDOI
Increased stem cell proliferation in atherosclerosis accelerates clonal hematopoiesis
Alexander Heyde,David Rohde,Cameron S. McAlpine,Shuang Zhang,Friedrich Felix Hoyer,Jeffrey M. Gerold,David Cheek,Yoshiko Iwamoto,Maximilian J. Schloss,Katrien Vandoorne,Oriol Iborra-Egea,Christian Muñoz-Guijosa,Antoni Bayes-Genis,Johannes G. Reiter,Morgan Craig,Filip K. Swirski,Matthias Nahrendorf,Martin A. Nowak,Kamila Naxerova +18 more
TL;DR: In this paper, the authors show that hematopoietic stem cell division rates are increased in mice and humans with atherosclerosis, and that increased stem cell proliferation expedites somatic evolution and expansion of clones with driver mutations.
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Age-Related Clonal Hematopoiesis Associated with Adverse Outcomes
Siddhartha Jaiswal,Pierre Fontanillas,Jason Flannick,Jason Flannick,Alisa K. Manning,Peter V. Grauman,Brenton G. Mar,Brenton G. Mar,R. Coleman Lindsley,Craig H. Mermel,Noël P. Burtt,Alejandro Chavez,John M. Higgins,Vladislav Moltchanov,Vladislav Moltchanov,Frank C. Kuo,Michael J. Kluk,Brian E. Henderson,Leena Kinnunen,Heikki A. Koistinen,Heikki A. Koistinen,Claes Ladenvall,Gad Getz,Adolfo Correa,Benjamin F. Banahan,Stacey Gabriel,Stacey Gabriel,Sekar Kathiresan,Heather M. Stringham,Mark I. McCarthy,Michael Boehnke,Jaakko Tuomilehto,Jaakko Tuomilehto,Jaakko Tuomilehto,Christopher A. Haiman,Leif Groop,Gil Atzmon,James G. Wilson,Donna Neuberg,David Altshuler,Benjamin L. Ebert +40 more
TL;DR: Age-related clonal hematopoiesis is a common condition that is associated with increases in the risk of hematologic cancer and in all-cause mortality, with the latter possibly due to an increased risk of cardiovascular disease.
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