Pershad Yash, Uddin Md Mesbah, Xue Liying, Haessler Jeffrey, Collins Jason M, Mack Taralynn M, Glick Elena, Glaser Veronica, Zhao Kun, Jaiswal Siddhartha, Manson JoAnn E, Pandey Urvashi, Desai Pinkal, Natarajan Pradeep, Honigberg Michael C, Kooperberg Charles, Whitsel Eric A, Kitzman Jacob O, Bick Alexander G, Reiner Alexander P
Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN.
Cardiovascular Research Center and Center for Genomic Medicine, Department of Medicine, Massachusetts General Hospital, Boston, MA.
Blood. 2025 Aug 28;146(9):1078-1087. doi: 10.1182/blood.2025028417.
Clonal hematopoiesis of indeterminate potential (CHIP) is associated with increased mortality and malignancy risk, yet the determinants of clonal expansion remain poorly understood. We performed sequencing at a depth of coverage of >4000× for CHIP mutations in 6976 postmenopausal women from the Women's Health Initiative (WHI) at 2 time points: the WHI baseline examination and ∼16 years later at the Long Life Study (LLS) visit. Among 3685 CH mutations detected at baseline (variant allele fraction [VAF] of ≥0.5%), 24% were not detected at LLS, 26% were micro-CH at LLS (0.5% ≤ VAF < 2%), and 50% were CHIP (VAF ≥ 2%). We confirmed that clonal expansion is highly dependent on initial clone size and CHIP driver gene, with SF3B1 and JAK2 mutations exhibiting the fastest growth rate. We identified germ line variants in TERT, IL6R, TCL1A, and MSI2 that modulate clonal expansion rate. Measured baseline leukocyte telomere length showed differential effects on incident CHIP risk, with shorter baseline leukocyte telomere length predisposing to incident PPM1D mutations and longer baseline leukocyte telomere length favoring incident DNMT3A mutations. We discovered that the IL6R missense variant p.Asp358Ala specifically impairs TET2 clonal expansion, supported by direct measurements of soluble interleukin-6 receptor and interleukin-6. Faster clonal growth rate was associated with increased risk of cytopenia, leukemia, and all-cause mortality. Notably, CHIP clonal expansion rate mediated 34.4% and 43.7% of the clonal hematopoiesis risk score's predictive value for leukemia and all-cause mortality, respectively. These findings reveal key biological determinants of CHIP progression and suggest that incorporating growth rate measurements could enhance risk stratification.
不确定潜能的克隆性造血（CHIP）与死亡率和恶性肿瘤风险增加相关，但克隆性扩增的决定因素仍知之甚少。我们对来自女性健康倡议（WHI）的6976名绝经后女性在两个时间点进行了深度覆盖>4000×的CHIP突变测序：WHI基线检查时以及约16年后的长寿研究（LLS）访视时。在基线时检测到的3685个CH突变（变异等位基因频率[VAF]≥0.5%）中，24%在LLS时未检测到，26%在LLS时为微小CH（0.5%≤VAF<2%），50%为CHIP（VAF≥2%）。我们证实克隆性扩增高度依赖于初始克隆大小和CHIP驱动基因，SF3B1和JAK2突变表现出最快的生长速度。我们在TERT、IL6R、TCL1A和MSI2中鉴定出调节克隆性扩增速率的种系变异。测量的基线白细胞端粒长度对CHIP发病风险有不同影响，基线白细胞端粒长度较短易患PPM1D突变，而基线白细胞端粒长度较长则有利于DNMT3A突变的发生。我们发现IL6R错义变异p.Asp358Ala特异性损害TET2克隆性扩增，可溶性白细胞介素-6受体和白细胞介素-6的直接测量结果支持了这一点。更快的克隆生长速度与血细胞减少、白血病和全因死亡率风险增加相关。值得注意的是，CHIP克隆性扩增速率分别介导了克隆性造血风险评分对白血病和全因死亡率预测价值的34.4%和43.7%。这些发现揭示了CHIP进展的关键生物学决定因素，并表明纳入生长速率测量可以增强风险分层。
