PLEC2021-008194

AtheroClonal

is a public-private collaborative project funded by the Spanish Science Ministry “I+D+I Líneas Estratégicas” 2021 call.

We aim to unveil the connection between somatic mutations, clonal hematopoiesis driven by these mutations, and atherosclerotic cardiovascular disease.

Accumulating evidence suggest that traditional cardiovascular risk factors are incompletely predictive of cardiovascular disease,

as a substantial risk remains even when these factors are apparently managed well. In this context, clonal hematopoiesis has emerged as a new and potent risk factor for atherosclerotic cardiovascular disease, which is completely independent of conventional risk factors and, therefore, may provide the basis for completely new preventive or therapeutic strategies.

Clonal hematopoiesis is a common condition whereby a substantial fraction of an individual’s blood cells is derived from a single dominant hematopoietic stem cell clone.

This condition is frequently driven by the random acquisition of somatic mutations that provide a competitive advantage to the mutant cell, allowing for the mutation to expand throughout the hematopoietic system and its progeny, which includes mature blood and immune cells. Human and mouse studies strongly support a causal and direct contribution of some clonal hematopoiesis-related mutations to accelerated atherosclerosis development through exacerbated inflammatory responses.

The AtheroClonal Consortium assembles a group of clinicians and basic scientists with complementary and multidisciplinary expertise, based at internationally-recognized academic institutions (Centro Nacional de Investigaciones Cardiovasculares, Institut de Recerca Biomèdica de Barcelona, Institut Germans Trias I Pujol), and have leveraged a key commercial partnership with IMEGEN S.L., a private company that is becoming an international reference in the transformation of genomic data into medical knowledge.

Our collaborative project intends to answer these questions and to address major gaps in knowledge and technology that limit the translation of CH data into new strategies for the management of atherosclerotic CVD.

To achieve these objectives, we propose to use an interdisciplinary collaborative approach that combines longitudinal deep sequencing studies in human cohorts that are deeply phenotyped at the cardiovascular level, computational biology approaches to identify new driver genes and mutations, machine learning models to predict CH and atherosclerosis progression and understand the interplay between both conditions, and experimental studies in innovative mouse models to gain insight into observations made in humans.

Findings obtained using these approaches will then be applied to the development of new tools for the detection of CH that are tailored to the clinical setting. Overall, we expect that AtheroClonal will provide unprecedented insight into the role of somatic mutations and CH as new mechanisms of atherosclerosis and will help take this field forward and closer to the development of clinical trials that evaluate precision strategies for the prevention, prediction and treatment of atherosclerosis and associated CVD.