[No authors listed]
We sought to determine the significance of myeloid clonal hematopoiesis (CH) in the UK Biobank cohort (nâ=â502,524, median ageâ=â58 years). Utilizing SNP array (nâ=â486,941) and whole exome sequencing data (nâ=â49,956), we identified 1166 participants with myeloid CH, defined by myeloid-associated mosaic chromosome abnormalities (mCA) and/or likely somatic driver mutations in DNMT3A, TET2, ASXL1, JAK2, SRSF2, or PPM1D. Myeloid CH increased by 1.1-fold per annum (myeloid mCA, Pâ=â1.57âÃâ10-38; driver mutations, Pâ=â5.89âÃâ10-47). Genome-wide association analysis identified two distinct signals within TERT that predisposed to myeloid CH, plus a weaker signal corresponding to the JAK2 46/1 haplotype. Specific subtypes of myeloid CH were associated with several blood features and clinical phenotypes, including TET2 mutations and chronic obstructive pulmonary disease. Smoking history was significantly associated with myeloid CH: 53% of myeloid CH cases were smokers compared to 44% of controls (Pâ=â3.38âÃâ10-6), a difference principally due to current (ORâ=â1.10; Pâ=â6.14âÃâ10-6) rather than past smoking (Pâ=â0.08). Breakdown of CH by specific mutation type revealed that ASXL1 loss of function mutations were most strongly associated with current smoking status (ORâ=â1.07; Pâ=â1.92âÃâ10-5), and the only abnormality associated with past smoking (ORâ=â1.04; Pâ=â0.0026). We suggest that the inflammatory environment induced by smoking may promote the outgrowth of ASXL1-mutant clones.
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