METHODS: Deep-targeted sequencing of 24 CHIP mutations (a mean depth of coverage = 1000×) was performed in 1004 patients with AF and 3341 non-AF healthy subjects. Variant allele fraction ≥ 2.0% indicated the presence of CHIP mutations. The association between CHIP and AF was evaluated by the comparison of (i) the prevalence of CHIP mutations between AF and non-AF subjects and (ii) clinical characteristics discriminated by CHIP mutations within AF patients. Furthermore, the risk of clinical outcomes-the composite of heart failure, ischaemic stroke, or death-according to the presence of CHIP mutations in AF was investigated from the UK Biobank cohort.
RESULTS: The mean age was 67.6 ± 6.9 vs. 58.5 ± 6.5 years in AF (paroxysmal, 39.0%; persistent, 61.0%) and non-AF cohorts, respectively. CHIP mutations with a variant allele fraction of ≥2.0% were found in 237 (23.6%) AF patients (DNMT3A, 13.5%; TET2, 6.6%; and ASXL1, 1.5%) and were more prevalent than non-AF subjects [356 (10.7%); P < .001] across the age. After multivariable adjustment (age, sex, smoking, body mass index, diabetes, and hypertension), CHIP mutations were 1.4-fold higher in AF [adjusted odds ratio (OR) 1.38; 95% confidence interval 1.10-1.74, P < .01]. The ORs of CHIP mutations were the highest in the long-standing persistent AF (adjusted OR 1.50; 95% confidence interval 1.14-1.99, P = .004) followed by persistent (adjusted OR 1.44) and paroxysmal (adjusted OR 1.33) AF. In gene-specific analyses, TET2 somatic mutation presented the highest association with AF (adjusted OR 1.65; 95% confidence interval 1.05-2.60, P = .030). AF patients with CHIP mutations were older and had a higher prevalence of diabetes, a longer AF duration, a higher E/E\', and a more severely enlarged left atrium than those without CHIP mutations (all P < .05). In UK Biobank analysis of 21 286 AF subjects (1297 with CHIP and 19 989 without CHIP), the CHIP mutation in AF is associated with a 1.32-fold higher risk of a composite clinical event (heart failure, ischaemic stroke, or death).
CONCLUSIONS: CHIP mutations, primarily DNMT3A or TET2, are more prevalent in patients with AF than non-AF subjects whilst their presence is associated with a more progressive nature of AF and unfavourable clinical outcomes.
方法:对1004例房颤患者和3341例非房颤健康受试者进行了24个CHIP突变(平均覆盖深度=1000倍)的深度靶向测序。变异等位基因分数≥2.0%表明存在CHIP突变。通过比较(i)AF和非AF受试者之间CHIP突变的患病率和(ii)AF患者中CHIP突变的临床特征来评估CHIP和AF之间的关联。此外,临床结果的风险-心力衰竭的复合,缺血性中风,或死亡-根据CHIP突变在AF中的存在,我们从UKBiobank队列进行了调查。
结果:平均年龄为67.6±6.9。房颤患者58.5±6.5年(阵发性,39.0%;持久性,61.0%)和非AF队列,分别。在237例(23.6%)AF患者中发现具有≥2.0%变异等位基因分数的CHIP突变(DNMT3A,13.5%;TET2,6.6%;ASXL1,1.5%),并且比非AF受试者更普遍[356(10.7%);P<.001]。经过多变量调整(年龄,性别,吸烟,身体质量指数,糖尿病,和高血压),CHIP突变在AF中高出1.4倍[校正比值比(OR)1.38;95%置信区间1.10-1.74,P<.01]。CHIP突变的OR在长期持续性AF中最高(调整OR1.50;95%置信区间1.14-1.99,P=.004),其次是持续性AF(调整OR1.44)和阵发性AF(调整OR1.33)。在基因特异性分析中,TET2体细胞突变与房颤的相关性最高(校正OR1.65;95%置信区间1.05-2.60,P=.030)。CHIP突变的AF患者年龄较大,糖尿病患病率较高,较长的AF持续时间,较高的E/E\',与没有CHIP突变的患者相比,左心房扩大更严重(所有P<0.05)。在英国生物银行分析21286例房颤受试者(1297例使用CHIP,19989例不使用CHIP),房颤的CHIP突变与复合临床事件的1.32倍风险相关(心力衰竭,缺血性中风,或死亡)。
结论:CHIP突变,主要是DNMT3A或TET2在房颤患者中比非房颤患者中更普遍,同时它们的存在与房颤的进展性和不利的临床结局相关。