Kidney Week

Abstract: SA-OR28

Clonal Hematopoiesis of Indeterminate Potential and Somatic Mutation Role in CKD: The First Study

Session Information

• Kidneyomics: From Cysts to Populations
  October 24, 2020 | Location: Simulive
  Abstract Time: 05:00 PM - 07:00 PM

Category: Genetic Diseases of the Kidneys

• 1002 Genetic Diseases of the Kidneys: Non-Cystic

Authors

• Cocchi, Enrico, Division of Nephrology and Center for Precision Medicine and Genomics, Department of Medicine, Columbia University, New York, New York, United States

Enrico Cocchi, MD



Enrico Cocchi is a pediatric nephrologist that currently work as a Postdoc in Ali Gharavi's laboratory, Columbia University, New York. As a researcher, he specialized in bioinformatics and genetic analysis and is currently working on several kidney genetic projects. He especially focused on new methods of structural variants and somatic mutations analysis, to explore their role in kidney disease.

• Gharavi, Ali G., Division of Nephrology and Center for Precision Medicine and Genomics, Department of Medicine, Columbia University, New York, New York, United States

Ali G. Gharavi,

Group or Team Name

• Gharavi lab

Background

Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related somatic mutagenesis associated with inflammation and increased risk of death due to cardiovascular disease. Chronic kidney disease (CKD) is strongly associated with cardiovascular disease, suggesting shared pathophysiologic mechanisms. Inflammation is a well-established component of CKD but CHIP has never been investigated in CKD.

Methods

We analyzed whole-exome sequencing data to determine CHIP prevalence and variant allele frequency (VAF) in a cohort of 2,187 CKD patients and 1,686 age-matched controls. Somatic variants were called using Mutect2 and filtered using strict standard criteria. The presence of CHIP mutations was evaluated for associations with demographic and clinical variables, including age, sex, CKD etiology, treatment with immunosuppressive therapies, end-stage renal disease (ESRD), and history of renal transplant.

Results

In a multivariate logistic regression model focused on the most frequently mutated CHIP genes (DNMT3A, TET2, ASXL1, JAK2), we observed an age-independent association between CHIP and CKD, where both prevalence (p=0.04, OR: 1.62) and VAF (3.48% vs. 1.89%, p=0.004) were higher in CKD cases than in controls. Among CKD cases, CHIP was independently associated with history of renal transplant >10 years (p<0.01, OR: 5.8) and treatment with immunosuppressive therapies (p<0.01, OR: 2.6). Differences were primarily driven by TP53, DNMT3A, ASXL1, ATM, and JAK2. In univariate analysis, we also found a higher prevalence of CHIP in patients with lupus nephritis and other autoimmune glomerulonephritis than in patients with other diagnoses (p=0.04), but this association did not persist in multivariate analyses.

Conclusion

Our analysis of a large case-control cohort suggests an independent association between CHIP and CKD. This association was most evident in patients with ongoing inflammation due to renal transplantation or immune-mediated conditions. These data will require replication in larger human cohorts and validation in animal models.