Interleukin-6 Receptor Polymorphism Attenuates Clonal Hematopoiesis-Mediated Coronary Artery Disease Risk Among 451 180 Individuals in the UK Biobank.
Interleukin-6 Receptor Polymorphism Attenuates Clonal Hematopoiesis-Mediated Coronary Artery Disease Risk Among 451 180 Individuals in the UK Biobank.
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在英国生物银行的 451 180 名个体中，白细胞介素 6 受体多态性可降低克隆造血介导的冠状动脉疾病风险。
DOI：
10.1161/circulationaha.122.062126
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发表时间：
2023
期刊：
影响因子：
37.8
通讯作者：
Bick,AlexanderG
中科院分区：
文献类型：
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作者：
Vlasschaert,Caitlyn;Heimlich,JBrett;Rauh,MichaelJ;Natarajan,Pradeep;Bick,AlexanderG
不确定潜能克隆造血 (CHIP) 是一种普遍存在的与年龄相关的疾病，其中造血干细胞在血癌驱动基因（最常见的是 DNMT3A 或 TET2）中获得致病性突变，导致克隆扩增。在大型观察队列中，CHIP 与冠状动脉疾病 (CAD) 相关。 1 小鼠模型表明，白细胞介素 (IL) 1β/IL6 信号传导介导 CHIP 中的动脉粥样硬化。 1 CANTOS（卡纳金单抗抗炎性血栓形成结果研究）的回顾性分析发现，使用抗 IL1β 抗体卡纳金单抗治疗与 TET2 CHIP（而非 DNMT3A CHIP）个体继发性心血管事件风险降低相关。 2 此外，我们之前报道过，在 2019 年英国生物库首次发布的 5 万人外显子组测序报告中，携带与 IL6 信号传导减弱相关的常见遗传性遗传变异（IL6R p.Asp358Ala、rs2228145-C）（IL6 受体阻断的遗传代理）的 CHIP 个体，其发生心血管事件的风险较低。 3 更多 最近，完整的 45 万人英国生物银行外显子组数据集已发布。 Kessler 等人最近对该数据集的分析显示，对 CHIP 和 CAD 风险的影响较小，并且未能显示对 rs2228145-C 的保护作用。然而，作者对 CHIP 使用了宽松的遗传变异过滤标准，增加了假阳性 CHIP 识别的可能性，例如测序伪影和种系变异。我们独立检查了 CHIP 的数据集，采用严格的过滤策略来最大限度地减少误报。使用这个高置信度数据集，我们重现了 CHIP 与 CAD 的关联以及 CHIP 和 IL6R p 之间的相互作用。 Asp358Ala。我们基于之前建立的方法，在英国生物银行的 451 180 名个体中识别出 CHIP，这些个体具有可用的外显子组数据，并且在抽血时没有已知的血液癌症。根据申请 43397 提供了对英国生物银行的访问权限，并从范德比尔特大学医学中心机构审查委员会获得了当地对数据二次分析的批准。这些方法在其他地方有详细描述。 5 简而言之，使用 Mutect2 在 74 个典型 CHIP 基因中调用了假定的体细胞 CHIP 突变。那些出现在预先建立的驱动程序变体列表中的内容都包含在候选变体列表中。 1 该候选列表经过测序质量筛选；例如，总测序深度较低（DP < 20）的变体被删除。然后，我们整合了基于群体的新型过滤参数，例如删除与至少 1 个成熟的 CHIP 标记不相关的热点变体（在数据集中出现≥ 20 次）：年龄和遗传性 TERT 启动子变体 (rs7705526)。然后，我们的目标是定义替代等位基因读取计数深度 (minAD) 的最佳下限。之前从外显子组数据确定 CHIP 的研究使用的 minAD 范围在 3 到 6 之间。较低的 minAD 会增加灵敏度，但会引入假阳性。我们测试了 CHIP 调用的关联
Clonal hematopoiesis of indeterminate potential (CHIP) is a prevalent age-related condition wherein hematopoietic stem cells acquire a pathogenic mutation in a blood cancer driver gene (most commonly DNMT3A or TET2), resulting in a clonal expansion. CHIP is associated with incident coronary artery disease (CAD) in large, observational cohorts. 1 Mouse models suggest that interleukin (IL) 1β/IL6 signaling mediates atherosclerosis in CHIP. 1 A retrospective analysis of CANTOS (Canakinumab Anti-Inflammatory Thrombosis Outcome Study) found that treatment with the anti-IL1β antibody canakinumab was associated with a lower risk of secondary cardiovascular events in individuals with TET2 CHIP but not DNMT3A CHIP. 2 In addition, we previously reported that individuals with CHIP who were carriers of a common inherited genetic variant associated with dampened IL6 signaling (IL6R p. Asp358Ala, rs2228145-C)—a genetic proxy of IL6 receptor blockade—had a lower risk of incident cardiovascular events in the initial 50 000–person exome sequencing release of the UK Biobank available in 2019. 3 More recently, the complete 450 000–person UK Biobank exome data set has been made available. A recent analysis of this data set by Kessler et al4 showed a small effect size for CHIP and CAD risk and failed to show a protective effect for rs2228145-C. However, the authors used a relaxed genetic variant filtering criterion for CHIP, increasing the likelihood of false-positive CHIP calls such as sequencing artifacts and germline variants. We independently examined the data set for CHIP, applying a stringent filtering strategy to minimize false positives. Using this high-confidence data set, we reproduced the association of CHIP with CAD and the interaction between CHIP and IL6R p. Asp358Ala.We built on previously established methods to identify CHIP in 451 180 individuals in the UK Biobank with available exome data and without known hematological cancers at the time of blood draw. Access to UK Biobank was provided under application 43397, and local approval for secondary analyses of the data was obtained from the Vanderbilt University Medical Center institutional review board. The methods are described in detail elsewhere. 5 Briefly, putative somatic CHIP mutations were called with Mutect2 in 74 canonical CHIP genes. Those present in a pre-established list of driver variants were included in the candidate variant list. 1 This candidate list was filtered for sequencing quality; for example, variants with low total sequencing depth (DP< 20) were removed. We then integrated novel population-based filtering parameters such as removing hotspot variants (present≥ 20 times in the data set) that were not associated with at least 1 wellestablished marker of CHIP: age and an inherited TERT promoter variant (rs7705526). We then aimed to define the optimal lower threshold for alternative allele read count depth (minAD). Previous studies ascertaining CHIP from exome data have used minAD ranging between 3 and 6. Lower minAD increases sensitivity but introduces false positives. We tested the association of CHIP calls