目的:不确定潜能克隆造血(CHIP),由表明遗传上不同的克隆白细胞群体的扩展的白血病变异体的年龄相关个体发育定义,与血液系统恶性肿瘤和心血管疾病的风险相关。在实验模型中,CHIP的重述促进肾间质纤维化与供体巨噬细胞的直接组织浸润。我们检验了CHIP与一般人群肾功能下降相关的假设。
方法:队列研究。
方法:来自TOPMed联盟3个社区队列的12,004名个体。
方法:来自从外周血提取的DNA获得的全基因组序列的CHIP状态。
结果:在随访期间,估计的肾小球滤过率(eGFR)和eGFR下降百分比每年下降30%的风险。
方法:30%eGFR下降终点的Cox比例风险模型和eGFR年度相对变化的广义估计方程,并进行荟萃分析。使用固定效应荟萃分析合并研究特定的估计。
结果:基线eGFR中位数为84mL/min/1.73mL。CHIP的患病率为6.6%,9.0%,在50-60岁、60-70岁和>70岁的人群中占12.2%,分别。在8年的平均随访期内,对于30%eGFR结局,1,002例CHIP携带者发生了205起事件(2.1起事件/100人年),无CHIP者发生了2,041起事件(1.7起事件/100人年).在荟萃分析中,CHIP与30%eGFR下降的风险更高(17%[95%CI,1%-36%];P=0.04)。基线eGFR高于或低于60mL/min/1.73m2,年龄高于或低于60岁的人之间未观察到差异,或有或没有糖尿病。
结论:少数患有中度至晚期肾脏疾病且CHIP驱动因子变异组受限的参与者。
结论:我们报告了3个无已知肾脏疾病的普通人群队列中CHIP和eGFR下降之间的关联。需要进一步的研究来调查这种新的情况及其对明显肾脏疾病个体的潜在影响。
Clonal hematopoiesis of indeterminate potential (CHIP), defined by the age-related ontogenesis of expanded leukemogenic variants indicative of a genetically distinct clonal leukocyte population, is associated with risk of hematologic malignancy and cardiovascular disease. In experimental models, recapitulation of CHIP promotes kidney interstitial fibrosis with direct tissue infiltration of donor macrophages. We tested the hypothesis that CHIP is associated with kidney function decline in the general population.
Cohort study.
12,004 individuals from 3 community-based cohorts in the TOPMed Consortium.
CHIP status from whole-genome sequences obtained from DNA extracted from peripheral blood.
Risk of 30% decline in estimated glomerular filtration rate (eGFR) and percent eGFR decline per year during the follow-up period.
Cox proportional hazards models for 30% eGFR decline end point and generalized estimating equations for annualized relative change in eGFR with meta-analysis. Study-specific estimates were combined using fixed-effect meta-analysis.
The median baseline eGFR was 84mL/min/1.73m2. The prevalence of CHIP was 6.6%, 9.0%, and 12.2% in persons aged 50-60, 60-70, and>70 years, respectively. Over a median follow-up period of 8 years, for the 30% eGFR outcome 205 events occurred among 1,002 CHIP carriers (2.1 events per 100 person-years) and 2,041 events in persons without CHIP (1.7 events per 100 person-years). In meta-analysis, CHIP was associated with greater risk of a 30% eGFR decline (17% [95% CI, 1%-36%] higher; P=0.04). Differences were not observed between those with baseline eGFR above or below 60mL/min/1.73m2, of age above or below 60 years, or with or without diabetes.
Small number of participants with moderate-to-advanced kidney disease and restricted set of CHIP driver variants.
We report an association between CHIP and eGFR decline in 3 general population cohorts without known kidney disease. Further studies are needed to investigate this novel condition and its potential impact among individuals with overt kidney disease.