Clonal Hematopoiesis of Indeterminate Potential and Kidney Function Decline in the General Population
Year: 2022
Type: article
Study design: Observational Study
Abstract: Rationale & Objective 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. Study Design Cohort study. Setting & Participants 12,004 individuals from 3 community-based cohorts in the TOPMed Consortium. Exposure CHIP status from whole-genome sequences obtained from DNA extracted from peripheral blood. Outcome Risk of 30% decline in estimated glomerular filtration rate (eGFR) and percent eGFR decline per year during the follow-up period. Analytical Approach 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. Results The median baseline eGFR was 84mL/min/1.73m 2 . 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/1.73m 2 , of age above or below 60 years, or with or without diabetes. Limitations Small number of participants with moderate-to-advanced kidney disease and restricted set of CHIP driver variants. Conclusions 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.
Institutions: University of Washington, Vanderbilt University, Queen's University, Population Health Research Institute, St. Joseph’s Healthcare Hamilton, McMaster University, University of North Carolina at Chapel Hill, Vanderbilt University Medical Center, United States Department of Veterans Affairs, Johns Hopkins University, University of Freiburg, Broad Institute, Harvard University, Massachusetts General Hospital
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $3,200
Funders: U.S. Department of Veterans Affairs, Massachusetts General Hospital, Fondation Leducq, National Institutes of Health, National Heart, Lung, and Blood Institute, National Human Genome Research Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Environmental Health Sciences
Awards: Large Scale Sequencing and Analysis of Genomes, Rare variants and NHLBI traits in deeply phenotyped cohorts, G232264632, Clonal hematopoiesis in humans: determinants of development and progression, Targeting Clonal Hematopoiesis of Indeterminate Potential using Human Genetics, G3256118428, Polygenic Risk Scores for Diverse Populations - Bridging Research and Clinical Care, G3755096522, Impact of Clonal Hematopoiesis on the Progression of Kidney Disease, G4252985639, The Human Genome Sequencing Center, G5484742928, Clonal hematopoiesis of indeterminate potential and HIV in the REPRIEVE trial, CHARGE consortium: omics discovery for CVD and aging phenotypes, G603018768, G6556565091, Stress-rest calf muscle perfusion: a functional diagnostic test for peripheral arterial disease (PAD), Studies of Rare Genetic Variation in the Isolated Population of Sardinia, Whole genome sequences in ethnically diverse individuals to comprehensively characterize the genetic mechanisms of dyslipidemias, IDENTIFICATION OF COMMON GENETIC VARIANTS FOR ATRIAL FIBRILLATION AND PR INTERVAL, Clonal Hematopoiesis of Indeterminate Potential in Chronic Kidney Disease Patients, Role of the innate immune system in acute kidney injury, Clonal Hematopoiesis in the Women's Health Initiative
OpenAlex ID: W4304182925