老年女性的克隆性造血与心血管结局

Clonal Hematopoiesis and Cardiovascular Outcomes in Older Women.

作者信息

Ezzat Daniel, Uddin Md Mesbah, Xue Liying, Pershad Yash, Zhang Shengruo, Collins Jason M, Kitzman Jacob O, Jaiswal Siddhartha, Desai Pinkal, Kooperberg Charles, Bick Alexander G, Natarajan Pradeep, Manson JoAnn E, Whitsel Eric A, Reiner Alexander P, Honigberg Michael C

机构信息

Cardiovascular Disease Initiative and Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA; Cardiovascular Research Center and Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA; Faculty of Medicine, KU Leuven, Leuven, Belgium.

出版信息

J Am Coll Cardiol. 2025 Aug 27. doi: 10.1016/j.jacc.2025.07.058.

DOI:10.1016/j.jacc.2025.07.058

PMID:40864016

Abstract

BACKGROUND

Clonal hematopoiesis of indeterminate potential (CHIP) is an emerging aging-related risk factor for cardiovascular disease (CVD). However, previous studies suggest that CHIP's relevance to CVD may diminish with advancing age.

OBJECTIVES

This study aimed to test the association of CHIP and its key subtypes with incident CVD in an older population.

METHODS

Participants in the Women's Health Initiative Long Life Study completed study assessments in 2012-2013 and underwent high-coverage sequencing (median depth 4,580×). The co-primary exposures were composite CHIP and TET2 CHIP. DNMT3A, ASXL1, JAK2, and non-DNMT3A CHIP were examined as secondary exposures. The primary outcome was incident coronary heart disease. Secondary outcomes were incident heart failure with preserved ejection fraction (HFpEF) and reduced ejection fraction (HFrEF), ischemic stroke, venous thromboembolism, and cardiovascular death. Multivariable-adjusted Cox models tested associations between CHIP and incident CVD.

RESULTS

Among 6,677 women (median age 80 years; median follow-up 10.1 years), 2,176 (32.6%) had any CHIP. TET2 CHIP was independently associated with incident coronary heart disease (aHR: 1.36 [95% CI: 1.05-1.77]; P = 0.02), whereas composite CHIP was not (aHR: 1.07 [95% CI: 0.89-1.28]; P = 0.49). Secondarily, TET2 CHIP was associated with HFpEF (aHR: 1.40 [95% CI: 1.03-1.90]; P = 0.03), ASXL1 CHIP with HFrEF (aHR: 3.16 [95% CI: 1.53-6.55]; P = 0.002), and JAK2 CHIP with ischemic stroke (aHR: 2.49 [95% CI: 1.17-5.30]; P = 0.02), venous thromboembolism (aHR: 2.71 [95% CI: 1.11-6.65]; P = 0.03), and cardiovascular death (aHR: 2.62 [95% CI: 1.68-4.11]; P < 0.001). No other significant associations were observed for composite or DNMT3A CHIP.

CONCLUSIONS

In an older female cohort, key CHIP subtypes (TET2, ASXL1, and JAK2) were associated with incident CVD, with associations that appeared to differ by CVD outcome. These findings suggest that CHIP remains associated with cardiovascular health into later life. (Women's Health Initiative [WHI]; NCT00000611).

摘要

背景

不确定潜能克隆造血（CHIP）是一种新出现的与衰老相关的心血管疾病（CVD）风险因素。然而，既往研究提示CHIP与CVD的相关性可能随年龄增长而减弱。

目的

本研究旨在检验老年人群中CHIP及其关键亚型与新发CVD之间的关联。

方法

女性健康倡议长寿研究的参与者于2012 - 2013年完成研究评估，并接受了高覆盖测序（中位深度4,580×）。共同主要暴露因素为复合CHIP和TET2 CHIP。将DNMT3A、ASXL1、JAK2以及非DNMT3A CHIP作为次要暴露因素进行检测。主要结局为新发冠心病。次要结局为射血分数保留的心力衰竭（HFpEF）和射血分数降低的心力衰竭（HFrEF）、缺血性卒中、静脉血栓栓塞以及心血管死亡。多变量调整的Cox模型用于检验CHIP与新发CVD之间的关联。

结果

在6677名女性（中位年龄80岁；中位随访10.1年）中，2176名（32.6%）存在任何类型的CHIP。TET2 CHIP与新发冠心病独立相关（校正后风险比[aHR]：1.36 [95%置信区间（CI）：1.05 - 1.77]；P = 0.02），而复合CHIP则不然（aHR：1.07 [95% CI：0.89 - 1.28]；P = 0.49）。其次，TET2 CHIP与HFpEF相关（aHR：1.40 [95% CI：1.03 - 1.90]；P = 0.03），ASXL1 CHIP与HFrEF相关（aHR：3.16 [95% CI：1.53 - 6.55]；P = 0.002），JAK2 CHIP与缺血性卒中相关（aHR：2.49 [95% CI：1.17 - 5.30]；P = 0.02）、与静脉血栓栓塞相关（aHR：2.71 [95% CI：1.11 - 6.65]；P = 0.03）以及与心血管死亡相关（aHR：2.62 [95% CI：1.68 - 4.11]；P < 0.001）。未观察到复合CHIP或DNMT3A CHIP有其他显著关联。