Wen Sean, Kuri-Morales Pablo, Hu Fengyuan, Nag Abhishek, Tachmazidou Ioanna, Deevi Sri V V, Taiy Haeyam, Smith Katherine R, Loesch Douglas P, Burren Oliver S, Dhindsa Ryan S, Wasilewski Sebastian, Alegre-Díaz Jesus, Berumen Jaime, Emberson Jonathan, Torres Jason M, Collins Rory, Carss Keren, Wang Quanli, Petrovski Slavé, Tapia-Conyer Roberto, Fabre Margarete A, Harper Andrew R, Vassiliou George S, Mitchell Jonathan
Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK.
Department of Haematology, Wellcome-MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, UK.
Nat Genet. 2025 Mar;57(3):572-582. doi: 10.1038/s41588-025-02085-6. Epub 2025 Feb 13.
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). 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). 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.
遗传血统对克隆性造血（CH）发展的影响在很大程度上仍未得到充分探索。在此，我们将来自墨西哥城前瞻性研究（MCPS）的136,401名参与者的CH情况与来自英国生物银行（UKB）的416,118名个体进行了比较，发现与UKB相比，CH在MCPS中明显不那么常见（调整后的优势比 = 0.59，95%置信区间（CI）= [0.57, 0.61]，P = 7.31×10）。在MCPS参与者中，CH频率与欧洲血统的百分比呈正相关（调整后的β = 0.84，95% CI = [0.66, 1.03]，P = 7.35×10）。在MCPS中进行的全基因组和外显子组关联分析确定了TCL1B基因座中特定血统的变异，这些变异对DNMT3A-CH与非DNMT3A-CH具有相反的影响。对MCPS和UKB的荟萃分析确定了五个与CH相关的新基因座，包括PARP11/CCND2、MEIS1和MYCN处的多态性。我们的CH研究是迄今为止在非欧洲人群中规模最大的，它展示了跨血统比较在深入了解CH发病机制方面的作用。
