Abstract 4148070: Clonal Hematopoeisis of Indeterminate Potential and Risk of Autopsy-defined Sudden Cardiac Death

Clonal hematopoiesis (CH) of indeterminate potential (CHIP), driven by somatic mutations in leukemia-associated genes, confers increased risk of hematologic malignancies, cardiovascular disease, and all-cause mortality. In blood of healthy individuals, small CH clones can expand over time to reach 2% variant allele frequency (VAF), the current threshold for CHIP. Nevertheless, reliable detection of low-VAF CHIP mutations is challenging, often relying on deep targeted sequencing. Here, we present UNISOM, a streamlined workflow for enhancing CHIP detection from whole-genome and whole-exome sequencing data that are underpowered, especially for low VAFs. UNISOM utilizes a meta-caller for variant detection, in couple with machine learning models which classify variants into CHIP, germline, and artifact. In whole-exome sequencing data, UNISOM recovered nearly 80% of the CHIP mutations identified via deep targeted sequencing in the same cohort. Applied to whole-genome sequencing data from Mayo Clinic Biobank, it recapitulated the patterns previously established in much larger cohorts, including the most frequently mutated CHIP genes and predominant mutation types and signatures, as well as strong associations of CHIP with age and smoking status. Notably, 30% of the identified CHIP mutations had < 5% VAFs, demonstrating its high sensitivity toward small mutant clones. This workflow is applicable to CHIP screening in population genomic studies. The UNISOM pipeline is freely available at https://github.com/shulanmayo/UNISOM and https://ngdc.cncb.ac.cn/biocode/tool/7816.

Clonal hematopoiesis of indeterminate potential (CHIP) is defined by the age-dependent accumulation of somatic leukemia-associated driver mutations in hematopoietic stem cells, in individuals with normal blood counts and with absence of an underlying myeloid neoplasm (MN).1, 2 CHIP is associated with an increased risk of developing MN and an increased all-cause mortality, largely due to cardiovascular disease.3 The presence of CHIP prior to receiving chemotherapy and radiation has been associated with therapy related MN (T-MN), such as myelodysplastic syndromes (MDS) and acute myeloid leukemia.4 Autologous stem cell transplantation (ASCT) is an effective treatment modality for managing higher-risk patients with non-Hodgkin's lymphoma (NHL) and multiple myeloma (MM). In a seminal NHL study, 30% of patients were found to have CHIP at the time of ASCT, with the presence of CHIP being associated with an increased rate of T-MN (10-year cumulative incidence of 14.1% vs 4.3%) and an inferior overall survival (10 year OS 30.4% vs 60.9%).5 In MM, targeted sequencing of 629 patients prior to ASCT detected CHIP in 21.6% of patients, with the presence of CHIP strongly associating with inferior OS (HR 1.34, p = .02) and an inferior progression-free survival (PFS, HR 1.45, p < .001). Interestingly, in this study, adverse CHIP-associations were apparently overcome by lenalidomide maintenance therapy.6 Unlike in NHL, CHIP in MM was not associated with T-MN; while lenalidomide maintenance therapy, independent of the presence or absence of CHIP, was associated with T-MN (p = .047) and second primary malignancies (SPM).6 We carried out this study to assess the prevalence and prognostic impact of CHIP in a relatively uniform cohort of MM patients at the time of ASCT, with all patients going on to receive lenalidomide maintenance therapy. Successive MM patients who consented to have their pre-ASCT bone marrow (BM) sample collected and who underwent first ASCT at Mayo Clinic, followed by lenalidomide maintenance therapy, were included in the study. The BM mononuclear cell DNA from pre-ASCT samples was extracted after excluding CD38/CD138+ (negative selection) plasma cells and then subjected to targeted NGS testing (42-myeloid related genes) by previously described methods.7 All patients were closely followed for the development of T-MN as defined by the 2016 WHO criteria, arterial and venous thromboembolism (VTE) and SPM.8, 9 Response to therapy was assessed using the international myeloma working group (IMWG) consensus criteria 2016.10 Statistical methods are highlighted in the supplemental material. Clonal hematopoiesis was detectable in 23 (23%) of 101 MM patients assessed in the study (Table S1, Figure S1). Clinical characteristics, MM risk stratification, median number of prior therapies, response to therapy, ASCT conditioning regimens, engraftment data, day +100 post ASCT outcomes and median duration of lenalidomide maintenance are outlined in Table 1. Except for a higher median age at MM diagnosis in MM patient with CHIP (p = .002), there were no other significant differences between the two groups (Figure S2). Ten (43.5%) patients in the MM CHIP group and 30 (38.0%) in the MM no CHIP group, received alkylatingagent-based induction therapy prior to ASCT (p = .66). Melphalan 200 mg/m2 conditioning was used in 87.1% of patients (95.7% in the CHIP vs 84.6% in the no CHIP group, p = .45), while the remainder received melphalan 140 mg/m2 conditioning. The median duration of lenalidomide maintenance therapy was 21 months (10–36); 16 months in MM patients with CHIP and 22 months in MM patients without CHIP (p = .76), with the median lenalidomide dose being 15 mg (range 10–15 mg; 10 mg in the CHIP group and 15 mg in the no CHIP group, p = .08). The most frequent CHIP mutations encountered included DNMT3A [52%; median variant allele frequency (VAF) 9.0%, range 2.0%–29.2%], TET2 (26%; median VAF 3.0%, range 2.0%–4.8%), followed by TP53, PPM1D and BRAF (10.0% each), respectively (Figures 1(A) and S1). Sixteen patients (69.6%) had one mutation, while seven (30.4%) had >1 mutation and two patients had four mutations each (Figure 1(B)). Eight (66.6%) of 12 patients with DNMT3A mutations had nonsynonymous missense mutations, while four had deletion variants: with no patient harboring the commonly mutated DNMT3A R882 hot spot. There were no statistically significant differences in CHIP mutation distribution, including TP53 and PPM1D mutations, between MM CHIP patients that received alkylating-agent based induction therapy prior to ASCT, vs MM CHIP patients that did not (Figure 1(C)). At last follow up, 70 (69.3%) relapses after ASCT and 41 (40.6%) deaths were documented. Twenty-nine patients (28.7%) were on salvage therapy whereas 13 (12.9%) were on lenalidomide maintenance and 14 (13.8%) were on observation alone, with no statistically significant differences between MM patients with CHIP vs MM without CHIP. Rates of VTE were similar between MM patients with CHIP (30%) and those without CHIP (24%), with similar rates of provoked thromboses (33% vs 29%, p = .4). Thromboses were diagnosed in typical locations in individuals with CHIP including seven lower extremity deep vein thromboses (DVT) and two pulmonary emboli (PE). In contrast, a variety of VTE locations were diagnosed in those without CHIP, including 10 lower extremity DVT, three PE, one DVT with PE, two upper extremity DVT and one portal vein thrombosis. There was a distinction in VTE timing with regards to lenalidomide use between MM patients with CHIP and those without CHIP. For MM patients with CHIP, 2/9 (22.2%) VTE occurred while on lenalidomide, 2/9 (22.2%) occurred prior to lenalidomide and 4/9 (44.4%) occurred at least 3 months after discontinuation of lenalidomide therapy. For MM patients without CHIP, majority (13/17, 76.5%) of VTE occurred while on lenalidomide, with a minority (11%) occurring either before or at least 3 months after discontinuation of lenalidomide. While lenalidomide is a known risk factor for thrombosis in MM, the fact that 44% of VTE in MM with CHIP occurred >3 months after discontinuing lenalidomide, suggests that CHIP might increase VTE risk in this setting (P = .04). Median OS from the time of diagnosis of the entire cohort was 124.6 months (95%CI 97.5-N/A months) with a corresponding 5 year OS of 82.0% (95% CI 74.8%–89.9%). There was no difference in median OS between MM with CHIP vs those without CHIP (100.2 months; 95%CI 76.2-NA months vs 135.6 months; 95%CI 106.3-N/A months, p = .27) (Figure 1(D)), including assessments with individual CHIP-mutations. The median EFS after ASCT was 36.4 months (95%CI 30.5–48.5 months), with there being no difference in median PFS between MM CHIP (36.4 months, 95%CI 24.1–58.5 months) patients vs MM patients without CHIP (36.4 months, 95%CI 29.9–52.4 months) (p = .34) (Figure 1(E)), including TP53 mutations (Figure S3). There were also no differences between the two groups with regards to non-relapse mortality (Figure S4), cumulative incidence of relapse after ASCT (Figure S5) and time to next treatment. Nineteen (18.8%) SPM were documented, 7 (30.4%) in MM CHIP group vs 12 (15.3%) in the MM no CHIP group (Figure 1(F), p = .13), with corresponding 5-year cumulative incidence rates of 22% and 13%, respectively. These SPM included five (4.9%) hematological malignancies (two in MM CHIP vs three in MM no CHIP), seven (6.9%) skin cancers (three in MM CHIP vs four in MM no CHIP) and seven visceral malignancies (two in MM CHIP vs five in MM no CHIP) (Table S2, Figure S6). The two MM CHIP patients who developed T-MN/MDS had TP53 and PPM1D mutations, respectively. In the MM no CHIP group, there was one patient with B-acute lymphoblastic leukemia and two patients with T-MDS with monosomal karyotypes. In summary, we define the CHIP landscape in MM patients at the time of ASCT, with mutations in epigenetic regulator genes being most common (57%), followed by tumor suppressor genes (17%). Unlike in NHL, presence of CHIP at time of ASCT in MM did not impact OS, PFS and incidence of T-MN; a finding potentially attributable to immunomodulatory properties of lenalidomide, or to the use of maintenance therapy in general.6, 11 While the presence of CHIP and lenalidomide therapy have individually been associated with increased risk of thromboses,1-3, 9 we did not see synergy in MM patients with CHIP, although the timing and patterns of thromboses suggest that CHIP might negatively influence thrombotic risk. While SPM have been well described with lenalidomide maintenance therapy,9 we did not see any differences in SPM and hematological malignancies between the two groups. The findings of this study independently confirm a prior observation on the potential ability of lenalidomide maintenance to mitigate the expected adverse effects of CHIP on OS and PFS in MM patients' post-ASCT6; an important consideration given that approximately 13 000 MM patients undergo ASCT in the US annually, with lenalidomide maintenance considered as standard of care.12, 13 Given the smaller sample size and the inherent flaws of a retrospective analysis, future clinical trials evaluating therapies in MM patients' post-ASCT should consider accounting for the presence of CHIP and its impact on outcomes. The authors would like to acknowledge the “Henry Predolin Leukemia Foundation”, Mayo Clinic, Rochester, MN, USA. Mrinal Patnaik has served on the advisory board of Kura Oncology. A Keith Stewart has served on the advisory board for Celgene. Rafael Fonseca has the following disclosures: Consulting: Amgen, BMS, Celgene, Takeda, Bayer, Janssen, Novartis, Pharmacyclics, Sanofi, Karyopharm, Merck, Juno, Kite, Aduro, OncoTracker, Oncopeptides, GSK, AbbVie. Scientific Advisory Board: Adaptive Biotechnologies, Caris Life Sciences and OncoTracker. Gene mutations annotated in the study have been provided in the supplementary material. Raw sequencing data can be made available on request. Appendix S1 Supporting Information. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Premature menopause is an independent risk factor for cardiovascular disease in women, but mechanisms underlying this association remain unclear. Clonal hematopoiesis of indeterminate potential (CHIP), the age-related expansion of hematopoietic cells with leukemogenic mutations without detectable malignancy, is associated with accelerated atherosclerosis. Whether premature menopause is associated with CHIP is unknown. We included postmenopausal women from the UK Biobank (n=11 495) aged 40 to 70 years with whole exome sequences and from the Women's Health Initiative (n=8111) aged 50 to 79 years with whole genome sequences. Premature menopause was defined as natural or surgical menopause occurring before age 40 years. Co-primary outcomes were the presence of any CHIP and CHIP with variant allele frequency >0.1. Logistic regression tested the association of premature menopause with CHIP, adjusted for age, race, the first 10 principal components of ancestry, smoking, diabetes, and hormone therapy use. Secondary analyses considered natural versus surgical premature menopause and gene-specific CHIP subtypes. Multivariable-adjusted Cox models tested the association between CHIP and incident coronary artery disease. The sample included 19 606 women, including 418 (2.1%) with natural premature menopause and 887 (4.5%) with surgical premature menopause. Across cohorts, CHIP prevalence in postmenopausal women with versus without a history of premature menopause was 8.8% versus 5.5% (P<0.001), respectively. After multivariable adjustment, premature menopause was independently associated with CHIP (all CHIP: odds ratio, 1.36 [95% 1.10-1.68]; P=0.004; CHIP with variant allele frequency >0.1: odds ratio, 1.40 [95% CI, 1.10-1.79]; P=0.007). Associations were larger for natural premature menopause (all CHIP: odds ratio, 1.73 [95% CI, 1.23-2.44]; P=0.001; CHIP with variant allele frequency >0.1: odds ratio, 1.91 [95% CI, 1.30-2.80]; P<0.001) but smaller and nonsignificant for surgical premature menopause. In gene-specific analyses, only DNMT3A CHIP was significantly associated with premature menopause. Among postmenopausal middle-aged women, CHIP was independently associated with incident coronary artery disease (hazard ratio associated with all CHIP: 1.36 [95% CI, 1.07-1.73]; P=0.012; hazard ratio associated with CHIP with variant allele frequency >0.1: 1.48 [95% CI, 1.13-1.94]; P=0.005). Premature menopause, especially natural premature menopause, is independently associated with CHIP among postmenopausal women. Natural premature menopause may serve as a risk signal for predilection to develop CHIP and CHIP-associated cardiovascular disease.

Sir William Osler reportedly once said, “Varicose veins are the result of an improper selection of grandparents.” Indeed, our family history strongly influences many aspects of our cardiovascular system, with the magnitude of effect ranging from very strong for autosomal dominant genetic disorders to more subtle in the setting of complex multigenic diseases like coronary atherosclerosis and hypertension. Accordingly, the standard evaluation of any new patient who presents to a physician includes assessment of their family history. Unfortunately, the family history may sometimes be discounted as noncontributory without detailed review. This can be exacerbated by busy office schedules with declining amounts of time available for comprehensive evaluations. A few minutes saved might seem to justify the lack of focus on an aspect of history that is sometimes deemed not to be particularly useful. However, a thorough assessment of family history also may provide the key diagnostic information to determine the cause of an illness, to determine who else is at risk of disease within the family, to add useful prognostic information, and to help for family planning and reproductive decisions. A family history of sudden death should prompt consideration of a wide range of heritable cardiovascular conditions, including many monogenic disorders (Table). However, the terms used by the lay public to describe sudden death may not adequately explain the cause of death on initial consideration. For instance, the phrase “heart attack” may be used to describe sudden death of any etiology. Further questioning may help one to discern whether there was a history of heart failure, cardiomyopathy, coronary artery disease (or its risk factors), aortic aneurysm, or features of syndromic disorders that are associated with sudden death. View this table: Table. Monogenic Disorders Associated With Sudden Death A 40-year-old man presents to a physician for evaluation of palpitations. These occur briefly about once per …

Introduction: Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related disorder associated with increased risk of atherosclerotic cardiovascular disease (ASCVD). Mechanistic studies of CHIP implicate inflammatory pathways underlying this relationship. Although inflammation is a well-established component of chronic kidney disease (CKD), linked to both CKD progression and ASCVD in CKD patients, CHIP has not been investigated in a CKD setting. Objective: To estimate the prevalence of CHIP in patients with CKD and to examine the cross-sectional associations between CHIP and biomarkers that were previously related to CKD progression and ASCVD among CKD patients. Methods: The current study was conducted among 598 Chronic Renal Insufficiency Cohort (CRIC) study participants with whole-exome sequencing data and baseline measures of fibrinogen, interleukin (IL)-6, serum albumin, and tumor necrosis factor-α. CHIP was detected from sequencing data using MuTect2. CHIP was defined as the presence of a somatic hematologic malignancy-associated mutation with a variant allele frequency (VAF) of at least 2%. CHIP was also categorized ordinally by clone size as no CHIP, small CHIP clone (VAF&lt;10%), and large CHIP clone (VAF ≥10%). Ordinal logistic regression was used to test associations of CHIP with each biomarker in age- and multivariable-adjusted models. Multivariable models adjusted for age, sex, ancestry, body mass index, estimated glomerular filtration rate, systolic blood pressure, low-density lipoprotein cholesterol, fasting plasma glucose, and blood pressure, lipid, and glucose lowering medications. Results: CHIP was detected in a total of 28 individuals from the WES study (4.7%). Among those 70 years of age and older, we detected a CHIP prevalence of nearly 16%. As expected, participants with CHIP were older than those without CHIP (mean age: 67 and 58 years, respectively; P&lt;0.0001). Other demographic and clinical variables were similar between groups . Age-adjusted models showed strong associations between CHIP and both fibrinogen and IL-6 with odds ratios of 2.49 (95% CI: 1.09, 5.71) and 2.45 (95% CI: 1.05, 5.72), respectively. After multivariable adjustment, only fibrinogen remained associated with CHIP with an odds ratio of 4.70 (95% CI: 1.69, 13.0). Consistent with these findings, there was a strong dose-dependent association between CHIP clone size and fibrinogen in multivariable adjusted analyses (P for linear trend=0.009). Compared to those without CHIP, odds ratios for higher fibrinogen tertile were 3.0 (95% CI: 0.84, 11.3) and 4.7 (95% CI: 1.29, 16.7) among those with small and large CHIP clone sizes, respectively. Conclusions: CHIP prevalence was higher among CKD patients in the current study compared to previous estimates from the general population. Furthermore, a strong, dose-dependent association between CHIP and fibrinogen was identified.

The Growth Kinetics of Clonal Hematopoiesis Inform Risk of Blood Cancer Progression

INTRO: Clonal hematopoiesis (CH) of indeterminate potential (CHIP) is associated with poor outcomes in those with non-hematologic cancers. CH mutated macrophages and neutrophils have increased capacity to home to peripheral tissues, driving local inflammation; they are also implicated in immunotherapy related toxicity. The relationship between CH and the microbiome in those treated with immunotherapy is not well understood. RESULTS: 35 patients with stage IV melanoma treated with upfront immunotherapy; treatment and cohort characteristics are below (Table 1). We performed error corrected duplex sequencing on peripheral blood mononuclear cells using a panel previously validated for CH mutations. With a cutoff of 0.5% variant allele frequency (VAF), among 10 CHIP positive patients, we found mutations in TET2 (8/10), DNMT3A (7/10), PPM1D (2/10), and JAK2 (1/10). There was no difference in either survival or response based on CHIP status (Log-Rank Chi-Square p=0.44); however, CHIP positivity was associated with greater microbiome richness as measured by alpha diversity (p=0.0012 Shannon diversity) and distinct structural/compositional diversity vs CHIP negative patients as measured by beta diversity (p=0.032, R Squared= 0.045). We inferred KEGG pathway activity from whole genome sequencing and identified that CHIP positive patients were enriched for exopolysaccharide biosynthesis while CHIP negative patients had higher expression of nucleotide sugars biosynthesis and amino acid metabolism pathways. DISCUSSION: In patients treated with immunotherapy for melanoma, microbiome diversity signatures correlate with presence of CHIP. The analysis suggests that there are distinct taxonomic and functional features defining CHIP positivity. The effect of these cells in the tumor microenvironment and their role in immunotherapy response requires further exploration. Citation Format: Eleanor A. Fallon, Samuel Urrutia, Reed Ayabe, Manoj Chelvanambi, Ashish Damania, Sarah Johnson, Tomoyuki Tanaka, Zongrui Li, Yongwoo David Seo, Samuel Cass, Matthew C. Wong, Nadim Ajami, Jennifer Wargo, Koichi Takahashi. Identifying gut microbial determinants of clonal hematopoiesis of indeterminate potential (CHIP) in immunotherapy treated melanoma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2801.

Clonal Hematopoiesis Is Associated with Non-Myeloid Subsequent Malignant Neoplasms after Autologous Hematopoietic Cell Transplantation

Clonal Hematopoiesis Is Associated with Cardiovascular Disease Risk and Worse Survival after Autologous Hematopoietic Cell Transplantation for Lymphoma

RNA-Seq Analysis of Clonal Hematopoiesis (CHIP) Blood Leukocytes Shows Dysregulation of Neutrophil / Innate Immunity-Related Genes

Clonal hematopoiesis (CH) of indeterminate potential (CHIP) is a risk factor for cardiovascular disease. The relationship between CHIP and coronary microvascular dysfunction (CMD) is unknown. The current study examines the association between CHIP and CH with CMD and the potential relationships in risk for adverse cardiovascular outcomes. In this retrospective observational study, targeted next-generation sequencing was performed for 177 participants with no coronary artery disease who presented with chest pain and underwent routine coronary functional angiogram. Patients with somatic mutations in leukemia-associated driver genes in hematopoietic stem and progenitor cells were examined; CHIP was considered at a variant allele fraction ≥2%; CH was considered at a variant allele fraction ≥1%. CMD was defined as coronary flow reserve to intracoronary adenosine of ≤2. Major adverse cardiovascular events considered were myocardial infarction, coronary revascularization, or stroke. A total of 177 participants were examined. Mean follow-up was 12±7 years. A total of 17 patients had CHIP and 28 had CH. Cases with CMD (n=19) were compared with controls with no CMD (n=158). Cases were 56±9 years, were 68% women, and had more CHIP (27%; P=0.028) and CH (42%; P=0.001) than controls. CMD was associated with independent risk for major adverse cardiovascular events (hazard ratio, 3.89 [95% CI, 1.21-12.56]; P=0.023), and 32% of this risk was mediated by CH. The risk mediated by CH was ≈0.5× as large as the direct effect of CMD on major adverse cardiovascular events. In humans, we observe patients with CMD are more likely to have CHIP, and nearly one-third of major adverse cardiovascular events in CMD are mediated by CH.

Clonal Hematopoiesis of Indeterminate Potential (CHIP) Related to the Etiology of Ischemic Stroke

Lower risk of incident dementia in males but not females with TET2 clonal hematopoiesis - a secondary analysis of the aspriin in reducing events in the elderly (ASPREE) trial

Clonal hematopoiesis of indeterminate potential (CHIP) is the age-related clonal expansion of hematopoietic stem cells with leukemia-associated mutations. Certain CHIP mutations promote atherosclerosis and heart failure through immune-related pathways. To test whether CHIP is associated with the development of myocarditis and pericarditis. This observational population-based cohort study used data from the UK Biobank. Enrollment occurred between 2006 and 2010. Participants with whole-exome sequencing, no prevalent cardiovascular disease or hematological malignancy, and complete covariate data were included. Follow-up occurred for a median of 13.6 (IQR, 12.8-14.2) years. Analyses were conducted from November 2024 to July 2025. Any CHIP (variant allele frequency [VAF] ≥2%) and large CHIP (VAF ≥10%) constituted coprimary study exposures. Secondary analyses considered DNMT3A and TET2 CHIP as separate exposures. The primary outcome was a composite of incident myocarditis and pericarditis. Cox regression tested associations of CHIP with myocarditis and pericarditis, adjusting for age, sex, race and ancestry, and cardiovascular risk factors. Secondary analyses considered myocarditis and pericarditis as separate outcomes. Additional analyses compared associations of CHIP with myocarditis and pericarditis with those with other cardiovascular diseases, and tested the bidirectional associations between CHIP and noncardiac immune-mediated inflammatory diseases. Among 335 426 participants (mean age, 56.1 years; 185 429 female [55.3%] and 149 997 male [44.7%]), 11 057 had any CHIP (3.3%), 7271 had large CHIP (2.2%), and 382 developed myocarditis or pericarditis (0.11%). Any and large CHIP were associated with multivariable-adjusted hazard ratios of 1.75 (95% CI, 1.14-2.68; P = .01) and 2.07 (95% CI, 1.28-3.33; P = .003), respectively, for the primary composite outcome of incident myocarditis and pericarditis. Increased risks were observed for DNMT3A and TET2 CHIP, with hazard ratios of 2.22 (95% CI, 1.17-4.21; P = .01) for DNMT3A with pericarditis and 3.65 (95% CI, 1.16-11.49; P = .03) for TET2 with myocarditis. CHIP associated with myocarditis and pericarditis more strongly than with other cardiovascular diseases (eg, coronary artery disease and heart failure). Any CHIP was also associated with 1.27-fold risk (95% CI, 1.16-1.39; P < .001) of developing noncardiac immune-mediated inflammatory diseases, without evidence for reverse causation. In this study, CHIP was a strong risk factor for myocarditis and pericarditis among middle-aged adults. Targeting CHIP and its downstream pathways may represent a strategy for preventing or treating pericarditis and myocarditis.

Association of Clonal Hematopoiesis of Indeterminate Potential (CHIP) with Incidence of Venous Thromboembolism Varies By Age: The Atherosclerosis Risk in Communities Study