Genome-wide analyses of 200,453 individuals yield new insights into the causes and consequences of clonal hematopoiesis.

Autor: Kar SP; MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK. siddhartha.kar@bristol.ac.uk.; Section of Translational Epidemiology, Division of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK. siddhartha.kar@bristol.ac.uk., Quiros PM; Department of Haematology, Wellcome-MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, UK. pmquiros@ispasturias.es.; Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK. pmquiros@ispasturias.es.; Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain. pmquiros@ispasturias.es., Gu M; Department of Haematology, Wellcome-MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, UK.; Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK., Jiang T; BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge, Cambridge, UK., Mitchell J; Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK., Langdon R; MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.; Section of Translational Epidemiology, Division of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK., Iyer V; Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK., Barcena C; Department of Haematology, Wellcome-MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, UK.; Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK., Vijayabaskar MS; Department of Haematology, Wellcome-MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, UK.; Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK., Fabre MA; Department of Haematology, Wellcome-MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, UK.; Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK.; Department of Haematology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK., Carter P; Division of Cardiovascular Medicine, Department of Medicine, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK., Petrovski S; Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK.; Department of Medicine, University of Melbourne, Austin Health, Melbourne, Victoria, Australia., Burgess S; BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge, Cambridge, UK.; MRC Biostatistics Unit, University of Cambridge, Cambridge, UK., Vassiliou GS; Department of Haematology, Wellcome-MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, UK. gsv20@cam.ac.uk.; Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK. gsv20@cam.ac.uk.; Department of Haematology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK. gsv20@cam.ac.uk.
Jazyk: angličtina
Zdroj: Nature genetics [Nat Genet] 2022 Aug; Vol. 54 (8), pp. 1155-1166. Date of Electronic Publication: 2022 Jul 14.
DOI: 10.1038/s41588-022-01121-z
Abstrakt: Clonal hematopoiesis (CH), the clonal expansion of a blood stem cell and its progeny driven by somatic driver mutations, affects over a third of people, yet remains poorly understood. Here we analyze genetic data from 200,453 UK Biobank participants to map the landscape of inherited predisposition to CH, increasing the number of germline associations with CH in European-ancestry populations from 4 to 14. Genes at new loci implicate DNA damage repair (PARP1, ATM, CHEK2), hematopoietic stem cell migration/homing (CD164) and myeloid oncogenesis (SETBP1). Several associations were CH-subtype-specific including variants at TCL1A and CD164 that had opposite associations with DNMT3A- versus TET2-mutant CH, the two most common CH subtypes, proposing key roles for these two loci in CH development. Mendelian randomization analyses showed that smoking and longer leukocyte telomere length are causal risk factors for CH and that genetic predisposition to CH increases risks of myeloproliferative neoplasia, nonhematological malignancies, atrial fibrillation and blood epigenetic ageing.
(© 2022. The Author(s).)
Databáze: MEDLINE
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