Clonal Hematopoiesis of Indeterminate Potential Predicts Adverse Outcomes in Patients With Atherosclerotic Cardiovascular Disease

Abstract

Background: Clonal hematopoiesis of indeterminate potential (CHIP)-the age-related clonal expansion of blood stem cells with leukemia-associated mutations-is a novel cardiovascular risk factor. Whether CHIP remains prognostic in individuals with established atherosclerotic cardiovascular disease (ASCVD) is less clear.

Objectives: This study tested whether CHIP predicts adverse outcomes in individuals with established ASCVD.

Methods: Individuals aged 40 to 70 years from the UK Biobank with established ASCVD and available whole-exome sequences were analyzed. The primary outcome was a composite of ASCVD events and all-cause mortality. Associations of any CHIP (variant allele fraction ≥2%), large CHIP clones (variant allele fraction ≥10%), and the most commonly mutated driver genes (DNMT3A, TET2, ASXL1, JAK2, PPM1D/TP53 [DNA damage repair genes], and SF3B1/SRSF2/U2AF1 [spliceosome genes]) with incident outcomes were compared using unadjusted and multivariable-adjusted Cox regression.

Results: Of 13,129 individuals (median age: 63 years) included, 665 (5.1%) had CHIP. Over a median follow-up of 10.8 years, any CHIP and large CHIP at baseline were associated with adjusted HRs of 1.23 (95% CI: 1.10-1.38; P < 0.001) and 1.34 (95% CI: 1.17-1.53; P < 0.001), respectively, for the primary outcome. TET2 and spliceosome CHIP, especially large clones, were most strongly associated with adverse outcomes (large TET2 CHIP: HR: 1.89; 95% CI: 1.40-2.55; P <0.001; large spliceosome CHIP: HR: 3.02; 95% CI: 1.95-4.70; P < 0.001).

Conclusions: CHIP is independently associated with adverse outcomes in individuals with established ASCVD, with especially high risks observed in TET2 and SF3B1/SRSF2/U2AF1 CHIP.

Keywords: aging; coronary artery disease; inflammation; prevention; risk factor.

FIGURE 1. Study Flow Chart

This study included UK Biobank (UKB) participants with a diagnosis of atherosclerotic cardiovascular disease (ASCVD) (ie, coronary artery disease, stroke, and/or peripheral artery disease) before enrollment and available whole-exome sequencing from whole blood-derived DNA. Participants with prevalent hematologic malignancy, unknown/missing history of cancer, and missing key covariates were excluded. BMI = body mass index; CHIP = clonal hematopoiesis of indeterminate potential; HDL = high-density lipoprotein.

FIGURE 2. Cumulative Incidence of ASCVD Events or Death by CHIP Status

Cumulative incidence plots were constructed using the Kaplan-Meier method and represent (A) the primary outcome of ASCVD events or all-cause mortality, (B) ASCVD events, and (C) all-cause mortality during a median follow-up of 10.8 years (IQR: 10.0 to 11.6 years). The shaded area indicates the 95% CI. Multivariable-adjusted models were adjusted for age at the start of follow-up, age², sex, race (White vs non-White), Townsend deprivation index, current or former smoking, systolic blood pressure, antihypertensive medication use, total cholesterol, HDL cholesterol, cholesterol-lowering medication use, diabetes status, and BMI. Individuals without CHIP constituted the reference group in all analyses. No corrections for multiple testing were applied. *P<0.05. **P<0.01. ***P<0.001. Ref = reference; VAF = variant allele fraction; other abbreviations as in Figure 1.

FIGURE 3. Cumulative Incidence of Cardiovascular and Cancer Mortality by CHIP Status

Cumulative incidence plots were constructed using the Kaplan-Meier method and represent (A) cardiovascular mortality and (B) cancer mortality. See Figure 2 legend for details on the cumulative incidence plots and multivariable-adjusted models used. No corrections for multiple testing were applied. *P<0.05. **P<0.01. ***P<0.001. Abbreviations as in Figures 1 and 2.

FIGURE 4. Associations of CHIP Subtypes With Incident ASCVD or Death

See Figure 2 legend for details on the multivariable-adjusted models used. No corrections for multiple testing were applied. Abbreviations as in Figures 1 and 2.

FIGURE 5. Distribution of hsCRP and NLR by CHIP Driver Gene

Violin plots show the distribution of high-sensitivity C-reactive protein (hsCRP) levels and neutrophil-to-leukocyte ratio (NLR) by CHIP driver mutation. The plots represent all (A) hsCRP and (B) NLR values between 0-11.10 mg/L and 0-8, corresponding to 95% and 99% of all measurements, respectively. The upper and lower bounds of the white boxes represent the IQR, whereas the horizontal line in the box represents the median. P values represent comparisons of gene-specific CHIP subtypes vs no CHIP using the Wilcoxon rank-sum test. hsCRP and NLR values were available for n = 13,088 and n = 12,812, respectively. No corrections for multiple testing were applied.

CENTRAL ILLUSTRATION. Clonal Hematopoiesis of Indeterminate Potential Predicts Adverse Outcomes in Patients With Established Atherosclerotic Cardiovascular Disease

Among participants with established atherosclerotic cardiovascular disease (ASCVD), clonal hematopoiesis of indeterminate potential (CHIP) was associated with higher incidence of ASCVD events and all-cause mortality vs those without CHIP, with the highest incidence observed for those carrying large clones. The highest risk was observed in participants with driver mutations in TET2 or spliceosome genes (ie, SF3B1, SRSF2, and U2AF1). VAF = variant allele fraction.