Clonal myelopoiesis in the UK Biobank cohort: ASXL1 mutations are strongly associated with smoking
Clonal myelopoiesis in the UK Biobank cohort: ASXL1 mutations are strongly associated with smoking
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DOI：
10.1038/s41375-020-0896-8
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发表时间：
2020-06-10
期刊：
影响因子：
11.4
通讯作者：
Cross, Nicholas C. P.
中科院分区：
文献类型：
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作者：
Dawoud, Ahmed A. Z.;Tapper, William J.;Cross, Nicholas C. P.
我们试图确定髓系克隆造血（CH）在英国生物银行队列中的意义（n = 502,524，中位年龄= 58岁）。利用SNP阵列（n = 486,941）和全外显子组测序数据（n = 49,956），我们确定了1166名髓系CH患者，其定义为髓系相关的镶嵌染色体异常（mCA）和/或可能的体细胞驱动突变inDNMT3A，TET2,ASXL1,JAK2，SRSF2或ppm1d。髓细胞CH每年增加1.1倍(髓细胞mCA，P = 1.57 × 10(-38)；驱动突变，P = 5.89 × 10(-47))。全基因组关联分析发现，intert中有两种不同的信号倾向于髓系CH，另外还有一种较弱的信号对应于jak246 /1单倍型。髓系CH的特定亚型与几种血液特征和临床表型相关，包括tet2突变和慢性阻塞性肺疾病。吸烟史与髓性CH显著相关：53%的髓性CH患者为吸烟者，而对照组为44% (P = 3.38 × 10(-6))，这一差异主要是由于当前吸烟（OR = 1.10;P = 6.14 × 10(-6)）而非既往吸烟（P = 0.08）。按特定突变类型对CH的分解显示，asxl1功能突变缺失与当前吸烟状况的相关性最强（OR = 1.07;P = 1.92 × 10(-5)），唯一的异常与过去吸烟有关（OR = 1.04;P = 0.0026）。我们认为吸烟诱导的炎症环境可能促进asxl1突变体克隆的生长。
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.