Journal of the American College of Cardiology

2023

DOI: 10.1016/j.jacc.2023.03.401

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

Esra D. Gümüşer

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,

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,

So Mi Jemma Cho

³

et al.

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Clonal Hematopoiesis Of Undetermined Significance In Cardiov...2

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Ascertainment Of Exposures and Outcomes1

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Cited by 47 publications

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“…Second, we provided substantial evidence that supported the impact of the 2 most frequently mutated genes, DNMT3A and TET2 , on CHD development in East Asian individuals. Of note, the association of DNMT3A -CHIP with CHD remains controversial in previous studies, although TET2 has demonstrated consistent associations . It is plausible that this disparity in the findings of DNMT3A could arise from differences in sequencing depth.…”

Section: Discussionmentioning

confidence: 93%

Somatic and Germline Variants and Coronary Heart Disease in a Chinese Population

Zhao,

Shen,

Liu

et al. 2024

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ImportanceThe genetic basis of coronary heart disease (CHD) has expanded from a germline to somatic genome, including clonal hematopoiesis of indeterminate potential (CHIP). How CHIP confers CHD risk in East Asian individuals, especially those with small clones (variant allele fraction [VAF] 0.5%-2%) and different genetic backgrounds, was completely unknown.ObjectiveTo investigate the CHIP profile in a general Chinese cohort by deep sequencing and further explore the association between CHIP and incident CHD considering germline predisposition.Design, Setting, and ParticipantsThis cohort study used data from 3 prospective cohorts in the project Prediction for Atherosclerotic Cardiovascular Disease Risk in China. Participants without cardiovascular disease or cancer at baseline were enrolled in 2001 and 2008 and had a median follow-up of 12.17 years extending into 2021.ExposuresCHIP mutations were detected by targeted sequencing (mean depth, 916×). A predefined CHD polygenic risk score (PRS) comprising 531 variants was used to evaluate germline predisposition.Main Outcomes and MeasuresThe main outcome was first incident CHD.ResultsAmong 6181 participants, the median (IQR) age was 53.83 years (45.35-62.39 years); 3082 participants (49.9%) were female, and 3099 (50.1%) were male. A total of 1100 individuals (17.80%) harbored 1372 CHIP mutations at baseline. CHIP was independently associated with incident CHD (hazard ratio [HR], 1.42; 95% CI, 1.18-1.72; P = 2.82 × 10−4) and presented a risk gradient with increasing VAF (P = 3.98 × 10−3 for trend). Notably, individuals with small clones, nearly half of CHIP carriers, also demonstrated a higher CHD risk compared with non-CHIP carriers (HR, 1.33; 95% CI, 1.02-1.74; P = .03) and were 4 years younger than those with VAF of 2% or greater (median age, 58.52 vs 62.70 years). Heightened CHD risk was not observed among CHIP carriers with low PRS (HR, 1.02; 95% CI, 0.64-1.64; P = .92), while high PRS and CHIP jointly contributed a 2.23-fold increase in risk (95% CI, 1.51-3.29; P = 6.29 × 10−5) compared with non-CHIP carriers with low PRS. Interestingly, the diversity in CHIP-related CHD risk within each PRS group was substantially diminished when removing variants in the inflammatory pathway from the PRS.ConclusionsThis study revealed that elevated CHD risk attributed to CHIP was nonnegligible even for small clones. Inflammation genes involved in CHD could aggravate or abrogate CHIP-related CHD risk.

“…Second, we provided substantial evidence that supported the impact of the 2 most frequently mutated genes, DNMT3A and TET2 , on CHD development in East Asian individuals. Of note, the association of DNMT3A -CHIP with CHD remains controversial in previous studies, although TET2 has demonstrated consistent associations . It is plausible that this disparity in the findings of DNMT3A could arise from differences in sequencing depth.…”

Section: Discussionmentioning

confidence: 93%

Somatic and Germline Variants and Coronary Heart Disease in a Chinese Population

Zhao,

Shen,

Liu

et al. 2024

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ImportanceThe genetic basis of coronary heart disease (CHD) has expanded from a germline to somatic genome, including clonal hematopoiesis of indeterminate potential (CHIP). How CHIP confers CHD risk in East Asian individuals, especially those with small clones (variant allele fraction [VAF] 0.5%-2%) and different genetic backgrounds, was completely unknown.ObjectiveTo investigate the CHIP profile in a general Chinese cohort by deep sequencing and further explore the association between CHIP and incident CHD considering germline predisposition.Design, Setting, and ParticipantsThis cohort study used data from 3 prospective cohorts in the project Prediction for Atherosclerotic Cardiovascular Disease Risk in China. Participants without cardiovascular disease or cancer at baseline were enrolled in 2001 and 2008 and had a median follow-up of 12.17 years extending into 2021.ExposuresCHIP mutations were detected by targeted sequencing (mean depth, 916×). A predefined CHD polygenic risk score (PRS) comprising 531 variants was used to evaluate germline predisposition.Main Outcomes and MeasuresThe main outcome was first incident CHD.ResultsAmong 6181 participants, the median (IQR) age was 53.83 years (45.35-62.39 years); 3082 participants (49.9%) were female, and 3099 (50.1%) were male. A total of 1100 individuals (17.80%) harbored 1372 CHIP mutations at baseline. CHIP was independently associated with incident CHD (hazard ratio [HR], 1.42; 95% CI, 1.18-1.72; P = 2.82 × 10−4) and presented a risk gradient with increasing VAF (P = 3.98 × 10−3 for trend). Notably, individuals with small clones, nearly half of CHIP carriers, also demonstrated a higher CHD risk compared with non-CHIP carriers (HR, 1.33; 95% CI, 1.02-1.74; P = .03) and were 4 years younger than those with VAF of 2% or greater (median age, 58.52 vs 62.70 years). Heightened CHD risk was not observed among CHIP carriers with low PRS (HR, 1.02; 95% CI, 0.64-1.64; P = .92), while high PRS and CHIP jointly contributed a 2.23-fold increase in risk (95% CI, 1.51-3.29; P = 6.29 × 10−5) compared with non-CHIP carriers with low PRS. Interestingly, the diversity in CHIP-related CHD risk within each PRS group was substantially diminished when removing variants in the inflammatory pathway from the PRS.ConclusionsThis study revealed that elevated CHD risk attributed to CHIP was nonnegligible even for small clones. Inflammation genes involved in CHD could aggravate or abrogate CHIP-related CHD risk.

“…Additional details on the TOPMed CHIP calling approach have been described previously . Given previous evidence suggesting important heterogeneity between gene-specific CHIP subtypes, we examined the most common gene-specific CHIP subtypes ( DNMT3A and TET2 ) as the coprimary study exposures. Any CHIP, as well as large (variant allele fraction [VAF] >10%) CHIP, DNMT3A CHIP, and TET2 CHIP, were tested as secondary exposures because previous work suggests that larger clones are more strongly associated with some cardiovascular outcomes …”

Section: Methodsmentioning

confidence: 99%

“…Any CHIP, as well as large (variant allele fraction [VAF] >10%) CHIP, DNMT3A CHIP, and TET2 CHIP, were tested as secondary exposures because previous work suggests that larger clones are more strongly associated with some cardiovascular outcomes. 3,13,15 HF adjudication procedures during follow-up were uniform across the JHS and WHI. 7,8 HF events were classified as HFpEF (left ventricular ejection fraction Ն50%) or HFrEF (ejection fraction <50%) based on imaging data before and/or at the time of HF hospitalization.…”

Section: Ascertainment Of Exposures and Outcomesmentioning

confidence: 99%

Clonal Hematopoiesis and Incident Heart Failure With Preserved Ejection Fraction

Schuermans,

Honigberg,

Raffield

et al. 2024

JAMA Netw Open

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ImportanceClonal hematopoiesis of indeterminate potential (CHIP), the age-related clonal expansion of hematopoietic stem cells with leukemogenic acquired genetic variants, is associated with incident heart failure (HF).ObjectiveTo evaluate the associations of CHIP and key gene-specific CHIP subtypes with incident HF with preserved ejection fraction (HFpEF) and reduced ejection fraction (HFrEF).Design, Setting, and ParticipantsThis population-based cohort study included participants from 2 racially diverse prospective cohort studies with uniform HF subtype adjudication: the Jackson Heart Study (JHS) and Women’s Health Initiative (WHI). JHS participants were enrolled during 2000 to 2004 and followed up through 2016. WHI participants were enrolled during 1993 to 1998 and followed up through 2022. Participants who underwent whole-genome sequencing, lacked prevalent HF at baseline, and were followed up for HF adjudication were included. Follow-up occurred over a median (IQR) of 12.0 (11.0-12.0) years in the JHS and 15.3 (9.0-22.0) years in the WHI. Statistical analysis was performed from June to December 2023.ExposuresAny CHIP and the most common gene-specific CHIP subtypes (DNMT3A and TET2 CHIP).Main Outcomes and MeasuresFirst incident hospitalized HF events were adjudicated from hospital records and classified as HFpEF (left ventricular ejection fraction ≥50%) or HFrEF (ejection fraction &lt;50%).ResultsA total of 8090 participants were included; 2927 from the JHS (median [IQR] age, 56 [46-65] years; 1846 [63.1%] female; 2927 [100.0%] Black or African American) and 5163 from the WHI (median [IQR] age, 67 [62-72] years; 5163 [100.0%] female; 29 [0.6%] American Indian or Alaska Native, 37 [0.7%] Asian or Pacific Islander, 1383 [26.8%] Black or African American, 293 [5.7%] Hispanic or Latinx, 3407 [66.0%] non-Hispanic White, and 14 [0.3%] with other race and ethnicity). The multivariable-adjusted hazard ratio (HR) for composite CHIP and HFpEF was 1.28 (95% CI, 0.93-1.76; P = .13), and for CHIP and HFrEF it was 0.79 (95% CI, 0.49-1.25; P = .31). TET2 CHIP was associated with HFpEF in both cohorts (meta-analyzed HR, 2.35 [95% CI, 1.34 to 4.11]; P = .003) independent of cardiovascular risk factors and coronary artery disease. Analyses stratified by C-reactive protein (CRP) in the WHI found an increased risk of incident HFpEF in individuals with CHIP and CRP greater than or equal to 2 mg/L (HR, 1.94 [95% CI, 1.20-3.15]; P = .007), but not in those with CHIP and CRP less than 2 mg/L or those with CRP greater than or equal to 2 mg/L without CHIP, when compared with participants without CHIP and CRP less than 2 mg/L.Conclusions and RelevanceIn this cohort study, TET2 CHIP was an independent risk factor associated with incident HFpEF. This finding may have implications for the prevention and management of HFpEF, including development of targeted therapies.

“…In particular, especially high risks were observed in TET2 and SF3B1/SRSF2/U2AF1 CHIP (spliceosome genes). 45 Finally, in a cohort of 177 individuals with no CAD who presented with chest pain and underwent routine coronary functional angiogram, CHIP was significantly more present in patients with coronary microvascular dysfunction. In particular, nearly one-third of major adverse cardiovascular events were mediated by clonal hematopoiesis.…”

Section: Clonal Hematopoiesis Of Undetermined Significance In Atheros...mentioning

confidence: 97%

“…In a recent cohort study of 13 129 patients aged 40–70 years and with established atherosclerotic CVD, both CHIP and CHIP with VAF at least 10% were independently associated with adjusted hazard ratios of 1.23 [95% confidence interval (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 (composite of atherosclerotic CVD event and all-cause mortality) over a median follow-up of 10.8 years. In particular, especially high risks were observed in TET2 and SF3B1/SRSF2/U2AF1 CHIP (spliceosome genes) 45 …”

Section: Clonal Hematopoiesis Of Undetermined Significance In Cardiov...mentioning

confidence: 99%

Clonal hematopoiesis of indeterminate potential: implications for the cardiologists

Sciatti,

D’Elia,

Gori

et al. 2023

Journal of Cardiovascular Medicine

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Myeloproliferative neoplasms, including polycythemia vera, essential thrombocythemia, and myelofibrosis, are characterized by somatic gene mutations in bone marrow stem cells, which trigger an inflammatory response influencing the development of associated cardiovascular complications. In recent years, the same mutations were found in individuals with cardiovascular diseases even in the absence of hematological alterations. These genetic events allow the identification of a new entity called ‘clonal hematopoiesis of indeterminate potential’ (CHIP), as it was uncertain whether it could evolve toward hematological malignancies. CHIP is age-related and, remarkably, myocardial infarction, stroke, and heart failure were frequently reported in these individuals and attributed to systemic chronic inflammation driven by the genetic mutation. We reviewed the connection between clonal hematopoiesis, inflammation, and cardiovascular diseases, with a practical approach to improve clinical practice and highlight the current unmet needs in this area of knowledge.

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