Comparative analysis of the Mexico City Prospective Study and the UK Biobank identifies ancestry-specific effects on clonal hematopoiesis
Por:
Wen S., Kuri-Morales P., Hu F., Nag A., Tachmazidou I., Deevi S.V.V., Taiy H., Smith K.R., Loesch D.P., Burren O.S., Dhindsa R.S., Wasilewski S., Alegre-Díaz J., Berumen J., Emberson J., Torres J.M., Collins R., Carss K., Wang Q., Petrovski S., Tapia-Conyer R., Fabre M.A., Harper A.R., Vassiliou G.S., Mitchell J.
Publicada:
1 ene 2025
Resumen:
The impact of genetic ancestry on the development of clonal hematopoiesis (CH) remains largely unexplored. Here, we compared CH in 136,401 participants from the Mexico City Prospective Study (MCPS) to 416,118 individuals from the UK Biobank (UKB) and observed CH to be significantly less common in MCPS compared to UKB (adjusted odds ratio = 0.59, 95% confidence interval (CI) = [0.57, 0.61], P = 7.31 × 10-185). Among MCPS participants, CH frequency was positively correlated with the percentage of European ancestry (adjusted beta = 0.84, 95% CI = [0.66, 1.03], P = 7.35 × 10-19). Genome-wide and exome-wide association analyses in MCPS identified ancestry-specific variants in the TCL1B locus with opposing effects on DNMT3A-CH versus non-DNMT3A-CH. Meta-analysis of MCPS and UKB identified five novel loci associated with CH, including polymorphisms at PARP11/CCND2, MEIS1 and MYCN. Our CH study, the largest in a non-European population to date, demonstrates the power of cross-ancestry comparisons to derive novel insights into CH pathogenesis. © The Author(s) 2025.
Filiaciones:
Wen S.:
Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R & D, AstraZeneca, Cambridge, United Kingdom
Department of Haematology, Wellcome-MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, United Kingdom
Kuri-Morales P.:
Instituto Tecnológico y de Estudios Superiores de Monterrey, Monterrey, Mexico
Hu F.:
Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R & D, AstraZeneca, Cambridge, United Kingdom
Nag A.:
Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R & D, AstraZeneca, Cambridge, United Kingdom
Tachmazidou I.:
Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R & D, AstraZeneca, Cambridge, United Kingdom
Deevi S.V.V.:
Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R & D, AstraZeneca, Cambridge, United Kingdom
Taiy H.:
Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R & D, AstraZeneca, Cambridge, United Kingdom
Smith K.R.:
Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R & D, AstraZeneca, Cambridge, United Kingdom
Loesch D.P.:
Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R & D, AstraZeneca, Cambridge, United Kingdom
Burren O.S.:
Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R & D, AstraZeneca, Cambridge, United Kingdom
Dhindsa R.S.:
Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R & D, AstraZeneca, Waltham, MA, United States
Wasilewski S.:
Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R & D, AstraZeneca, Cambridge, United Kingdom
Alegre-Díaz J.:
Faculty of Medicine, National Autonomous University of Mexico, Copilco Universidad, Ciudad de México, Mexico
Berumen J.:
Faculty of Medicine, National Autonomous University of Mexico, Copilco Universidad, Ciudad de México, Mexico
Emberson J.:
Clinical Trial Service Unit & Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom
Torres J.M.:
Clinical Trial Service Unit & Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom
Collins R.:
Clinical Trial Service Unit & Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom
Carss K.:
Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R & D, AstraZeneca, Cambridge, United Kingdom
Wang Q.:
Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R & D, AstraZeneca, Waltham, MA, United States
Petrovski S.:
Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R & D, AstraZeneca, Cambridge, United Kingdom
Tapia-Conyer R.:
Faculty of Medicine, National Autonomous University of Mexico, Copilco Universidad, Ciudad de México, Mexico
Fabre M.A.:
Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R & D, AstraZeneca, Cambridge, United Kingdom
Department of Haematology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom
Harper A.R.:
Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R & D, AstraZeneca, Cambridge, United Kingdom
Clinical Development, Research and Early Development, Respiratory and Immunology (R & I), BioPharmaceuticals R & D, AstraZeneca, Cambridge, United Kingdom
Vassiliou G.S.:
Department of Haematology, Wellcome-MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, United Kingdom
Department of Haematology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom
Mitchell J.:
Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R & D, AstraZeneca, Cambridge, United Kingdom
All Open Access; Hybrid Gold Open Access
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