Clonal myelopoiesis in the UK Biobank cohort: ASXL1 mutations are strongly associated with smoking.
Leukemia
; 34(10): 2660-2672, 2020 10.
Article
en En
| MEDLINE
| ID: mdl-32518416
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 = 1.57 × 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.
Texto completo:
1
Colección:
01-internacional
Asunto principal:
Proteínas Represoras
/
Fumar
/
Mielopoyesis
/
Mutación
Tipo de estudio:
Etiology_studies
/
Incidence_studies
/
Observational_studies
/
Prognostic_studies
/
Risk_factors_studies
Límite:
Female
/
Humans
/
Male
/
Middle aged
País/Región como asunto:
Europa
Idioma:
En
Revista:
Leukemia
Asunto de la revista:
HEMATOLOGIA
/
NEOPLASIAS
Año:
2020
Tipo del documento:
Article
País de afiliación:
Reino Unido