Periodic Reporting for period 1 - B-specific (B-specific: B-cell related gene and protein markers with prognostic and therapeutic value for CVD)
Reporting period: 2023-10-01 to 2024-09-30
Atherosclerosis is the major underlying condition of cardiovascular disease (CVD) and one the leading causes of death. Rupture of atherosclerotic lesions can lead to acute cardiovascular events, such as myocardial infarction and stroke, making biomarkers to diagnose patients at risk for these events and develop tailored preventive interventions, an urgent need. Although atherosclerosis is a chronic inflammatory disease, clinical investigation of the adaptive immune system as a potential marker for disease development has been limited. The B-specific consortium aims to classify and mitigate risk of CVD by generating novel types of genetic data and defining novel prognostic and therapeutic targets attained from our recent discovery of a specific subset of a cell of our adaptive immune system, the B cell. We will employ state-of-the-art technology, including single cell RNA sequencing, in CVD patient material. With access to large population-based cohorts (FIMCOD, Rotterdam Study) spanning healthy adults of 40-105 years of age, we aim to assess the prognostic value of circulating B cell subsets and its markers in (sub)clinical atherosclerosis and investigate the contribution of genetic disposition. Using the extensive genomics data of the Rotterdam Study, we will be able to determine causal links between the prognostic indicators and disease progression by applying Mendelian Randomization experiments and confirm these relationships in models of atherosclerosis. Based on these findings, B-specific aims to develop at least 1 proof-of-concept therapy to eliminate pathogenic B cells. B-specific will implement an active open science platform and in combination with a targeted dissemination approach to healthcare professionals, we aim to impact cardiology practice and provide important new means of patient stratification and treatment options.
Since the start of the project on October 1st, 2023, we have been working on the described tasks in the different work packages of this program. We here report the main results we have obtained in the last year. In October 2023, we held the program's kick-off meeting in Leiden, where we discussed the advisory board members, which were then appointed. We created a logo, a website and a dissemination plan. Scientifically, we have analysed datasets from human atherosclerosis, including our own and publicly RNA sequencing datasets, to identify B cell subsets and potential unique markers to measure and analyse these cell subsets. We have found multiple B cell clusters expressing markers of interest, which are shared with partners in other work packages for mechanistic analysis in population databases. In addition, we have been using flow cytometry to identify the B cell subsets on protein levels in human plaque versus matched blood samples. We are currently associating these data with human atherosclerotic plaque stability parameters. These B cell subsets were also measured in patient cohorts in Sweden. We found a circulating B cell subset to predict future first-time cardiovascular event in one of the general population-based cohort, even when accounting for traditional risk factors. This is a very relevant finding for further studies. Finally, we have been optimising methods for specific marker analysis in plasma samples from cardiovascular patients.
We are still in the early phase of the project, where we have identified potential B cell subsets and genetic markers for these B cells. At this moment, we are validating these within the framework of the program. After this validation and further research that is described in the work packages of B-specific, we will be able to elaborate on key needs for potential impact.