Somatic mutations and the human gut microbiome and their link/association with cardiovascular diseases in Lifelines DEEP

Cardiovascular disease is the leading cause of mortality and morbidity worldwide, despite advances in treatment and recognition of risk factors, both genetic and environmental (GBD 2016 Causes of Death Collaborators, Lancet 2017). Early recognition of risk factors can aid in the identification of individuals with a high risk of cardiovascular disease. Recent studies have provided novel insights into the development of cardiovascular disease, through acquired mutations that increase the risk of developing hematologic malignancies (Jaiswal et al. NEJM 2014; Jaiswal et al. NEJM 2017; Libby et al. Circ 2018). These somatic mutations occur in the DNA of hematopoietic stem cells in the bone marrow and lead to clones of these mutated stem cells in the peripheral blood. The key genes involved in CHIP are DNMT3A, TET2, ASXL1, TP53, and JAK2 (Khetarpal et al., JACC 2019). The majority of mutations are found in DNMT3A, TET2, and ASXL1 (Fuster et al. Circ Res 2018). However, other genes that have been marked as hematologic malignancy genes have been indicated to be involved in CHIP as well (Xie et al. Nat Med 2014; Jaiswal et al., NEJM 2014). These mutations occur more frequently with increasing age, with prevalence estimates of <1% in the population below 40 years old, but 10-20% in the population of 70 years old (Khetarpal et al., JACC 2019). The presence of these clones represents a premalignant state and is termed clonal hematopoiesis of indeterminate potential (CHIP). Although there is a relative increase, the absolute risk is limited and only a small proportion of CHIP carriers develop a full-blown hematologic malignancy (Khetarpal et al., JACC 2019). 

The presence of CHIP has been associated with a 1.9 (95% CI 1.4-2.7) times increased risk of coronary artery diseases, and a 4 (95% CI 2.4-6.7) times higher risk of myocardial infarction (Jaiswal et al. NEJM 2017). These associations support the link between cancer and cardiovascular disease risk. A possible mechanism underlying this association was shown in mice, where the presence of CHIP was associated with accelerated atherosclerosis (Jaiswal et al. NEJM 2017). In mice, CHIP was also associated with increased interleukin-6 (IL-6) signaling (Fuster et al., Science 2017). IL-6 is a major player in the inflammatory processes in the body (Naka et al. Arthritis Res 2002). In-vitro studies using TET2 knockout bone-marrow or peritoneal macrophages showed increased inflammatory gene expression, including IL6, in response to exposure to LDL (Cull et al., Exp Hematol 2017; Zhang et al., Nat 2015; Fuster et al., Science 2017). The group of Pradeep Natarajan has shown that the cardiovascular disease risk induced by CHIP may be attenuated by lowering the inflammatory state through reduction or blockage of IL-6 signaling. In their research, they used genetic variants that reduced IL-6 signaling (Bick et al., Circ 2019). Although these results are yet to be confirmed in human clinical trials using IL-6 receptor blockers, they indicate a link between the immune system or inflammatory state and cardiovascular disease risk induced by CHIP. An important modulator of the inflammatory status is the gut microbiome. The gut microbiome has also been associated with changes in hematopoiesis in previous studies (Manzo et al. Blood 2015). Moreover, in a TET2-deficient murine model, increased IL-6 production and bacterial translocation was associated with increased pre-leukemic myeloprofliferation (PMP). The increased IL-6 production and bacterial translocation was the result of a dysfunction of the integrity of the intestinal barrier or when bacterial stimuli were induced. That this process was related to the induction of PMP was furthermore shown by the reversal of PMP development after antibiotic treatment (Meisel et al., Nat 2018). This research showed a link between the gut microbiome and specific CHIP mutations through changes in the inflammatory state in mice. 

Although links between the gut microbiome, inflammation and CHIP have been shown in murine models and in-vitro cell studies, it remains unclear whether this is also the case in humans. Therefore, we intend to investigate the association between the composition of the gut microbiome and CHIP mutations and how this relates to the incidence of atherosclerotic cardiovascular diseases such as coronary artery disease. In addition, we intend to investigate whether interactions exist in this relationship with the degree of genome-wide methylation (Cypris et al. Front. Gen. 2019).