B-specific: B-cell related gene and protein markers with prognostic and therapeutic value for CVD

Introduction

Atherosclerosis is the major underlying condition of cardiovascular disease (CVD) and one of the leading causes of mortality. Rupture or erosion of atherosclerotic lesions can lead to acute cardiovascular events, such as myocardial infarction and stroke. This makes biomarkers to diagnose patients at risk for these events and develop tailored preventive interventions an urgent need.

Background

Although atherosclerosis is a chronic inflammatory disease, clinical investigation of the adaptive immune system as a potential rheostat for disease development has been limited.

Objectives

The B-specific consortium aims to classify and mitigate the risk of CVD by:

1. Generating novel types of genetic data.
2. Defining novel prognostic and therapeutic targets attained from our recent discovery of a specific B-cell subset.

Methodology

We will employ state-of-the-art technology, including:

• Single cell RNA sequencing
• BCR repertoire analysis
• Mass spectrometry-based identification of autoantigens in CVD patient material

With access to large population-based cohorts (FIMCOD, ERGO Study) spanning healthy adults of 40-105 years of age, we aim to:

• Assess the prognostic value of circulating B cell subsets and antibodies in (sub)clinical atherosclerosis.
• Investigate the contribution of genetic disposition.

Analysis

Using the extensive genomics data of the ERGO Study, we will be able to determine causal links between the prognostic indicators and disease progression by applying Mendelian Randomization experiments. We will confirm these relationships in ex vivo and in vivo models of atherosclerosis.

Expected Outcomes

Based on these findings, B-specific aims to develop at least one proof-of-concept therapy targeting specific B cells.

Dissemination

B-specific will implement an active open science platform. 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.