Abstract

Background Clonal hematopoiesis of indeterminate potential (CHIP) is the age-related presence of expanded somatic clones secondary to leukemogenic driver mutations and is associated with cardiovascular (CV) disease and mortality. We sought to evaluate relationships between CHIP with cardiometabolic diseases and incident outcomes in high-risk individuals.

Methods CHIP genotyping was performed in 8469 individuals referred for cardiac catheterization at Duke University (CATHGEN study) to identify variants present at a variant allele fraction (VAF) ≥2%. Associations were tested among any CHIP variant, large CHIP clones (VAF ≥10%) and individual CHIP genes with prevalent cardiometabolic traits. Cox proportional hazard models tested CHIP associations with time-to-overall mortality and Fine-Gray analyses tested CHIP associations with incident cardiovascular outcomes.

Results We identified 463 CHIP variants in 427 individuals (5.0%) of which 268 (3.2%) harbored large CHIP clones. CHIP and large CHIP were associated with lower odds of obesity (OR 0.79 [95% CI 0.65-0.98], p=0.03; OR 0.76 [95% CI 0.57-0.99], p=0.04, respectively). CHIP was associated with prevalent HF (OR 1.25 [95% CI 1.01 - 1.55], p=0.04; especially for non-DNMT3A CHIP (OR 1.38 [95% CI 1.04-1.82], p=0.02). CHIP was also associated with incident events: Non-DNMT3A CHIP was associated with increased risk of time-to-HF hospitalization (HR 1.29 [95% CI 1.02-1.63], p=0.03).

Conclusions In high-risk individuals referred for cardiac catheterization, large CHIP and non-DNTM3A CHIP were associated with obesity, prevalent HF, incident CV events. These findings strengthen the importance of CHIP as a biomarker for CV disease and highlight the contributing risk of large CHIP clones and non-DNMT3A CHIP variants.

Condensed Abstract CHIP, the presence of somatic expanded mutations in myeloid driver genes in hematopoietic cells, is an emerging CVD biomarker. Using whole exome sequencing of peripheral blood derived DNA from participants in the CATHGEN cohort, we identified significant associations with obesity, prevalent HF, incident mortality, HF hospitalization and AF after adjusting for established clinical risk factors. These findings add strength to the growing literature of CHIP as a CVD biomarker, emphasizing large CHIP and non-DNMT3A CHIP variants for driving risk. Future studies should aim to further elucidate gene-specific risk and the inflammatory and metabolic mechanisms possibly mediating these relationships.

What Is New?

In a cohort with high prevalence of CAD, CHIP is inversely associated with obesity and associated with higher odds of prevalent HF and subsequent mortality, even after adjustment for relevant clinical comorbidities. Risk of incident events of mortality, HF hospitalization and AF were driven by large CHIP variants (VAF≥10%) and CHIP variants in genes other than DNMT3A.

What are the Clinical Implications?

Though more research is needed, as the evidence around the risk associated with specific CHIP variants continues to grow, clinicians should be prepared to provide gene- specific counseling for cardiometabolic disease risk.

Competing Interest Statement

P.N. reports research grants from Allelica, Amgen, Apple, Boston Scientific, Genentech / Roche, and Novartis, personal fees from Allelica, Apple, AstraZeneca, Blackstone Life Sciences, Creative Education Concepts, CRISPR Therapeutics, Eli Lilly & Co, Esperion Therapeutics, Foresite Capital, Foresite Labs, Genentech / Roche, GV, HeartFlow, Magnet Biomedicine, Merck, Novartis, Novo Nordisk, TenSixteen Bio, and Tourmaline Bio, equity in Bolt, Candela, Mercury, MyOme, Parameter Health, Preciseli, and TenSixteen Bio, and spousal employment at Vertex Pharmaceuticals, all unrelated to the present work. S.HS. reports research grants from National Institutes of Health, American Heart Association, Verily, AstraZeneca, Lilly and unlicensed patents to Duke University. All other authors report no relevant relationships with industry to disclosure.

Funding Statement

This study was funded by a grant from the National Heart, Lung and Blood Institute (1R38HL143612) and the Edna and Fred L. Mandel Jr. Foundation.

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The Institutional Review Board of Duke University gave ethical approval for this work.

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Data Availability

All data produced in the present study are available upon reasonable request to the authors

AbbreviationsCHIPclonal hematopoiesis of indeterminate potentialVAFvariant allele fractionCATHGENCatheterization GeneticsCADcoronary artery diseaseMImyocardial infarctionCVcardiovascularCVDcardiovascular diseaseHFheart failureAFatrial fibrillation