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

Abstract

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=1.57x10 -38 ; driver mutations, P=5.89x10 - 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=3.38x10 -6 ), a difference principally due to current (OR=1.10; P=6.14x10 -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=1.92x10 -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.

Increased CHIP Prevalence Amongst People Living with HIV

“…14 Furthermore, similar to the gene distribution in MDS, we find a greater relative prevalence of ASXL1 mutations among PLWH compared to controls. Of note, while cigarette smoking selects for ASXL1 clonal hematopoiesis 15 , our cohort of PLWH still had an increased prevalence of ASXL1 mutations compared to the control cohort despite being well balanced for smoking status across cohorts.…”

Combination of myeloproliferative neoplasm driver gene activation with mutations of splice factor or epigenetic modifier genes increases risk of rapid blastic progression

“…However, ASXL1 had the lowest hazard ratio (HR) compared with SRSF2 and IDH1 (HR 2.0, HR 3.0, and HR 4.3) in their cohort 28 . A large‐scale cohort analysis of patients with clonal hematopoiesis show that presence of ASXL1 ‐mutant clones is significantly associated with current and past smoking 29 …”

Clonal cytopenia of undetermined significance (CCUS) with dysplasia is enriched for MDS‐type molecular findings compared to CCUS without dysplasia

“…Smoking is a well‐established risk factor for both clonal hematopoiesis and myeloid malignancies 2,12 . Two groups 22,23 recently reported an association between smoking and ASXL1 mutations in clonal hematopoiesis, in individuals unselected for the presence of hematologic malignancies and/or peripheral blood cytopenias. In our study, an association between smoking and ASXL1 variants was not apparent in CCUS or MDS patients, likely due to the small size of our cohorts.…”