Premature Menopause, Clonal Hematopoiesis, and Coronary Artery Disease in Postmenopausal Women

Honigberg, Michael C.; Zekavat, Seyedeh M.; Niroula, Abhishek; Griffin, Gabriel K.; Bick, Alexander; Pirruccello, James P.; Nakao, Tetsushi; Whitsel, Eric A.; Farland, Leslie V.; Laurie, Cecelia; Kooperberg, Charles; Manson, JoAnn E.; Gabriel, Stacey; Libby, Peter; Reiner, Alexander P.; Ebert, Benjamin L.; Natarajan, Pradeep

doi:10.1161/circulationaha.120.051775

Cited by 100 publications

(86 citation statements)

References 60 publications

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“…This may be partly explained by an association between CHIP and CVD. On a population level, CHIP has been linked to a greater burden of atherosclerotic vessel disease and a heightened risk of myocardial infarction 50 – 52 as well as to higher blood levels of the inflammatory marker C-reactive protein 53 . Mouse models of CHIP have demonstrated mechanistic ties between certain common CHIP mutations and accelerated atherosclerosis 50 , 54 , 55 as well as heart failure 56 , 57 .…”

Section: Clonal Haematopoiesismentioning

confidence: 99%

Germline risk of clonal haematopoiesis

2021

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Clonal haematopoiesis (CH) is a common, age-related expansion of blood cells with somatic mutations that is associated with an increased risk of haematological malignancies, cardiovascular disease and all-cause mortality. CH may be caused by point mutations in genes associated with myeloid neoplasms, chromosomal copy number changes and loss of heterozygosity events. How inherited and environmental factors shape the incidence of CH is incompletely understood. Even though the several varieties of CH may have distinct phenotypic consequences, recent research points to an underlying genetic architecture that is highly overlapping. Moreover, there are numerous commonalities between the inherited variation associated with CH and that which has been linked to age-associated biomarkers and diseases. In this Review, we synthesize what is currently known about how inherited variation shapes the risk of CH and how this genetic architecture intersects with the biology of diseases that occur with ageing.

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Section: Clonal Haematopoiesismentioning

confidence: 99%

Germline risk of clonal haematopoiesis

2021

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“…After 6.9 years of the follow-up period, they identified increased CVD risk (hazard ratio (HR) − 1.27%) in subjects with CHIP mutations (Bick et al [ 20 ]). The other study was performed on postmenopausal women by Honigberg et al [ 21 ]; 11,495 samples (40–70 years) were obtained from UK BioBank and 8111 samples (50–79 years) were obtained from Women’s Health Initiative (WHI). The study reported that among postmenopausal middle-aged women, CHIP was independently associated with incident coronary artery disease (HR associated with all CHIP: 1.36).…”

Section: Resultsmentioning

confidence: 99%

Clonal hematopoiesis of indeterminate potential (CHIP) and cardiovascular diseases—an updated systematic review

Senguttuvan

Subramanian

Venkatesan

et al. 2021

Journal of Genetic Engineering and Biotechnology

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Background Cardiovascular diseases (CVDs) are the leading cause of mortality in India. Residual risk exists in patients receiving optimal guideline-directed medical therapy. Possession of certain somatic mutations, at a variant allele frequency of ≥ 2% in peripheral blood, driving clonal expansion in the absence of cytopenias and dysplastic hematopoiesis is defined as clonal hematopoiesis of indeterminate potential (CHIP). Recently, it was found that carriers of CHIP had a higher risk to have coronary artery disease (CAD) and early-onset myocardial infarction. Association of CHIP with heart failure and valvular heart diseases is increasingly being considered. The common link that connects CHIP mutations and CVDs is inflammation leading to increased expression of cytokines and chemokines. We intended to do a systematic review about the association of CHIP mutations and CVD along with identifying specific CHIP mutations involved in increasing the risk of having CVDs. The main body of the abstract We performed an extensive literature search in PubMed and Google Scholar databases. Out of 302 articles, we narrowed it down to 10 studies based on our pre-specified criteria. The methodology adopted for the identification of CHIP mutations in the selected studies included – whole-exome sequencing (n = 3), whole-genome analysis (n = 1), transcriptome profiling analysis (n = 1), whole-genome analysis (n = 1), and single-cell RNA-sequencing (n = 1). We found that the available literature suggested an association between CHIP and CVD. The most commonly described CHIP mutations in patients with CVD are DNMT3A, TET2, ASXL1, TP53, JAK2, and SF3B. We further analyzed the commonly mutated CHIP genes using bioinformatics tools. Protein function and interaction analysis were performed using the g: Profiler and GeneMANIA online tools. The results revealed significant bio grid interactions for molecular functions, biological processes, and biological pathways. Interaction analysis showed significant physical and co-expression interactions. Short conclusion We conclude that there exists a significant association between CHIP mutations and CVD with DNMT3A, TET2, ASXL1, TP53, JAK2, and SF3B as the commonly implicated genes. The recognition of the link between CHIP and cardiovascular events will expand our understanding of residual risk and will open up new avenues of investigation and therapeutic modalities in the management of patients with CVD.

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“…Furthermore, systemic markers of inflammation, including CRP, are higher in post-menopausal women than they are in those who are pre-menopausal [ 150 , 151 ]. It is of note that, in women included in the U.K. Biobank and Womens Health Initiative, the prevalence of CHIP was 60% higher in women with premature menopause compared with those without and the presence of CHIP was independently associated with incident coronary artery disease [ 152 ]. Whether or not the presence of CHIP and early-onset menopause increases the risk of developing HFpEF is unknown.…”

Section: Interplay Between Chip Ageing Inflammation and Hfpefmentioning

confidence: 99%

Clonal haematopoiesis of indeterminate potential: intersections between inflammation, vascular disease and heart failure

et al. 2021

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Ageing is a major risk factor for the development of cardiovascular disease (CVD) and cancer. Whilst the cumulative effect of exposure to conventional cardiovascular risk factors is important, recent evidence highlights clonal haematopoiesis of indeterminant potential (CHIP) as a further key risk factor. CHIP reflects the accumulation of somatic, potentially pro-leukaemic gene mutations within haematopoietic stem cells over time. The most common mutations associated with CHIP and CVD occur in genes that also play central roles in the regulation of inflammation. While CHIP carriers have a low risk of haematological malignant transformation (<1% per year), their relative risk of mortality is increased by 40% and this reflects an excess of cardiovascular events. Evidence linking CHIP, inflammation and atherosclerotic disease has recently become better defined. However, there is a paucity of information about the role of CHIP in the development and progression of heart failure, particularly heart failure with preserved ejection fraction (HFpEF). While systemic inflammation plays a role in the pathophysiology of both heart failure with reduced and preserved ejection fraction (EF), it may be of greater relevance in the pathophysiology of HFpEF, which is also strongly associated with ageing. This review describes CHIP and its pathogenetic links with ageing, inflammation and CVD, while providing insight into its putative role in HFpEF.

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Premature Menopause, Clonal Hematopoiesis, and Coronary Artery Disease in Postmenopausal Women

Cited by 100 publications

References 60 publications

Germline risk of clonal haematopoiesis

Germline risk of clonal haematopoiesis

Clonal hematopoiesis of indeterminate potential (CHIP) and cardiovascular diseases—an updated systematic review

Clonal haematopoiesis of indeterminate potential: intersections between inflammation, vascular disease and heart failure

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