Clonal Hematopoiesis of Indeterminate Potential and Diabetic Kidney Disease: A Nested Case-Control Study

Denicolò, Sara; Vogi, Verena; Keller, Felix; Thöni, Stefanie; Eder, Susanne; Heerspink, Hiddo J L; Rosivall, László; Wiȩcek, Andrzej; Mark, Patrick B.; Perco, Paul; Leierer, Johannes; Kronbichler, Andreas; Steger, Marion; Schwendinger, Simon; Zschocke, Johannes; Mayer, Gert; Jukic, Emina

doi:10.1016/j.ekir.2022.01.1064

Cited by 17 publications

(11 citation statements)

References 64 publications

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“…By our estimation, 40 of the 127 variants reported by Denicolò et al. 1 would not be considered CHIP driver variants using the cited conventional criteria. 3 , 4 , 5 Inclusion of benign or misclassified variants would increase CHIP prevalence but may bias results toward the null hypothesis because they would be expected to be evenly represented across groups.…”

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confidence: 73%

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Response to: “Clonal Hematopoiesis of Indeterminate Potential and Diabetic Kidney Disease: A Nested Case-Control Study”

Vlasschaert

Rauh²,

Lanktree³

2022

Kidney International Reports

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confidence: 73%

“…To the Editor: We read the work of Denicolò et al 1 with great interest, reporting a lack of association between clonal hematopoiesis of indeterminate potential (CHIP) and incident or progressive diabetic kidney disease published in KI Reports. A major challenge when investigating CHIP is variant interpretation.…”

mentioning

confidence: 99%

Response to: “Clonal Hematopoiesis of Indeterminate Potential and Diabetic Kidney Disease: A Nested Case-Control Study”

Vlasschaert

Rauh²,

Lanktree³

2022

Kidney International Reports

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“…One reasonable explanation was that more small-clone mutations within these genes could be detected in our study (76% for BCORL1 , 77% for SE TD2 ), which would be missed by low-depth sequencing. Actually, BCORL1 has been most frequently identified by previous high-depth sequencing studies . In addition, ethnic heterogeneity may contribute to the disparities in CHIP profile .…”

Section: Discussionmentioning

confidence: 99%

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

Zhao,

Shen,

Liu

et al. 2024

JAMA Cardiol

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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.

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“…Large population studies have also found higher rates of diabetes mellitus type 2 in patients with CH [15]. Investigation into the incidence or progression of diabetic kidney disease have not found an association with CH but there is evidence that CH promotes the development of chronic kidney disease at large, especially in the context of myeloid CH mutations and myeloid mCAs [75,76]. Thus, aggravation of cardiac risk factors like diabetes and chronic kidney disease is an additional mechanism through which CH mutations are able to impact cardiovascular outcomes.…”

Section: Molecular Mechanisms Of Ch-mediated Cardiotoxicitymentioning

confidence: 99%

Clonal Hematopoiesis and the Heart: a Toxic Relationship

Jensen

Easaw²,

Anderson

et al. 2023

Curr Oncol Rep

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Purpose of Review Clonal hematopoiesis (CH) refers to the expansion of hematopoietic stem cell clones and their cellular progeny due to somatic mutations, mosaic chromosomal alterations (mCAs), or copy number variants which naturally accumulate with age. CH has been linked to increased risk of blood cancers, but CH has also been linked to adverse cardiovascular outcomes. Recent Findings A combination of clinical outcome studies and mouse models have offered strong evidence that CH mutations either correlate with or cause atherosclerosis, diabetes mellitus, chronic kidney disease, heart failure, pulmonary hypertension, aortic aneurysm, myocardial infarction, stroke, aortic stenosis, poor outcomes following transcatheter aortic valve replacement (TAVR) or orthotopic heart transplant, death or need of renal replacement therapy secondary to cardiogenic shock, death from cardiovascular causes at large, and enhance anthracycline cardiac toxicity. Mechanistically, some adverse outcomes are caused by macrophage secretion of IL-1β and IL-6, neutrophil invasion of injured myocardium, and T-cell skewing towards inflammatory phenotypes. Summary CH mutations lead to harmful inflammation and arterial wall invasion by bone marrow-derived cells resulting in poor cardiovascular health and outcomes. Blockade of IL-1β or JAK2 signaling are potential avenues for preventing CHcaused cardiovascular morbidity and mortality.

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Clonal Hematopoiesis of Indeterminate Potential and Diabetic Kidney Disease: A Nested Case-Control Study

Cited by 17 publications

References 64 publications

Response to: “Clonal Hematopoiesis of Indeterminate Potential and Diabetic Kidney Disease: A Nested Case-Control Study”

Response to: “Clonal Hematopoiesis of Indeterminate Potential and Diabetic Kidney Disease: A Nested Case-Control Study”

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

Clonal Hematopoiesis and the Heart: a Toxic Relationship

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