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 inDNMT3A,TET2,ASXL1,JAK2,SRSF2, orPPM1D. Myeloid CH increased by 1.1-fold per annum (myeloid mCA,P = 1.57 x 10(-38); driver mutations,P = 5.89 x 10(-47)). Genome-wide association analysis identified two distinct signals withinTERTthat predisposed to myeloid CH, plus a weaker signal corresponding to theJAK246/1 haplotype. Specific subtypes of myeloid CH were associated with several blood features and clinical phenotypes, includingTET2mutations 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 x 10(-6)), a difference principally due to current (OR = 1.10;P = 6.14 x 10(-6)) rather than past smoking (P = 0.08). Breakdown of CH by specific mutation type revealed thatASXL1loss of function mutations were most strongly associated with current smoking status (OR = 1.07;P = 1.92 x 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 ofASXL1-mutant clones.