Abstract：
OBJECTIVE: Both clonal haematopoiesis of indeterminate potential (CHIP) and atrial fibrillation (AF) are age-related conditions. This study investigated the potential role of CHIP in the development and progression of AF.
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.
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.
摘要：
目的：不确定电位的克隆造血（CHIP）和心房颤动（AF）均与年龄有关。这项研究调查了CHIP在AF的发生和发展中的潜在作用。
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。
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。
