Clonal myelopoiesis in the UK Biobank cohort: ASXL1 mutations are strongly associated with smoking

We sought to determine the significance of myeloid clonal hematopoiesis (CH) in the UK Biobank cohort (n = 502,524, median age = 58 years). Utilizing SNP array (n = 486,941) and whole exome sequencing data (n = 49,956), 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, P = 1.57 × 10−38; driver mutations, P = 5.89 × 10−47). 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 (P = 3.38 × 10−6), a difference principally due to current (OR = 1.10; P = 6.14 × 10−6) rather than past smoking (P = 0.08). Breakdown of CH by specific mutation type revealed that ASXL1 loss of function mutations were most strongly associated with current smoking status (OR = 1.07; P = 1.92 × 10−5), and the only abnormality associated with past smoking (OR = 1.04; P = 0.0026). We suggest that the inflammatory environment induced by smoking may promote the outgrowth of ASXL1-mutant clones.