Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
Nutrition Department, Harvard T.H. Chan School of Public Health, Boston, MA.
Diabetes Care. 2023 Nov 1;46(11):1978-1985. doi: 10.2337/dc23-0805.
Clonal hematopoiesis of indeterminate potential (CHIP) is an aging-related accumulation of somatic mutations in hematopoietic stem cells, leading to clonal expansion. CHIP presence has been implicated in atherosclerotic coronary heart disease (CHD) and all-cause mortality, but its association with incident type 2 diabetes (T2D) is unknown. We hypothesized that CHIP is associated with elevated risk of T2D.
CHIP was derived from whole-genome sequencing of blood DNA in the National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine (TOPMed) prospective cohorts. We performed analysis for 17,637 participants from six cohorts, without prior T2D, cardiovascular disease, or cancer. We evaluated baseline CHIP versus no CHIP prevalence with incident T2D, including associations with DNMT3A, TET2, ASXL1, JAK2, and TP53 variants. We estimated multivariable-adjusted hazard ratios (HRs) and 95% CIs with adjustment for age, sex, BMI, smoking, alcohol, education, self-reported race/ethnicity, and combined cohorts' estimates via fixed-effects meta-analysis.
Mean (SD) age was 63.4 (11.5) years, 76% were female, and CHIP prevalence was 6.0% (n = 1,055) at baseline. T2D was diagnosed in n = 2,467 over mean follow-up of 9.8 years. Participants with CHIP had 23% (CI 1.04, 1.45) higher risk of T2D than those with no CHIP. Specifically, higher risk was for TET2 (HR 1.48; CI 1.05, 2.08) and ASXL1 (HR 1.76; CI 1.03, 2.99) mutations; DNMT3A was nonsignificant (HR 1.15; CI 0.93, 1.43). Statistical power was limited for JAK2 and TP53 analyses.
CHIP was associated with higher incidence of T2D. CHIP mutations located on genes implicated in CHD and mortality were also related to T2D, suggesting shared aging-related pathology.
不确定潜能的克隆性造血（CHIP）是造血干细胞中体细胞突变的与衰老相关的积累，导致克隆性扩张。CHIP 的存在与动脉粥样硬化性冠心病（CHD）和全因死亡率有关，但与 2 型糖尿病（T2D）的发病风险相关尚不清楚。我们假设 CHIP 与 T2D 的风险升高相关。
CHIP 源自美国国立心肺血液研究所跨组学精准医学（TOPMed）前瞻性队列的血液 DNA 全基因组测序。我们对来自六个队列的 17637 名无 T2D、心血管疾病或癌症的参与者进行了分析。我们评估了基线 CHIP 与无 CHIP 的 T2D 发病情况，包括与 DNMT3A、TET2、ASXL1、JAK2 和 TP53 变异的关联。我们通过固定效应荟萃分析，用年龄、性别、BMI、吸烟、饮酒、教育、自我报告的种族/民族和联合队列的估计值调整多变量调整后的风险比（HR）和 95%置信区间。
平均（SD）年龄为 63.4（11.5）岁，76%为女性，基线时 CHIP 的患病率为 6.0%（n=1055）。在平均 9.8 年的随访期间，n=2467 名参与者被诊断为 T2D。与无 CHIP 的参与者相比，有 CHIP 的参与者发生 T2D 的风险高 23%（CI 1.04，1.45）。具体而言，TET2（HR 1.48；CI 1.05，2.08）和 ASXL1（HR 1.76；CI 1.03，2.99）突变的风险更高；DNMT3A 无统计学意义（HR 1.15；CI 0.93，1.43）。JAK2 和 TP53 分析的统计效能有限。
CHIP 与 T2D 的发生率较高相关。位于与 CHD 和死亡率相关的基因上的 CHIP 突变也与 T2D 相关，提示存在共同的与衰老相关的病理。
