Precisionsmedicin vid SLE nefrit med hjälp av spatial genexpressionsanalys och genetisk- samt epigenetisk riskstratifiering i relation till behandlingssvar.

Elisabeth Skoglund, Uppsala Universitet, 75000

Bakgrund och motivering

Systemic Lupus Erythematosus (SLE) is an autoimmune disease that can be mild to life-threatening. Genes (≈ 200 known loci) and environmental factors (which can influence gene expression through epigenetic changes) interact in the development of SLE. Lupus nephritis (LN) is a severe manifestation affecting up to 50% of patients. Despite aggressive treatment, up to 25% of patients develop end-stage renal disease (ESRD). Better tools are needed to identify these patients at an early stage of the disease.

Syfte och mål

We aim to investigate 1) whether patients with high combined genetic and epigenetic risk for SLE (high-risk group) are less likely to respond to standard LN treatment. 2) Whether the pathophysiological mechanisms in renal tissue are different in the high-risk group compared to the low risk group using spatial transcriptomics. Our hypothesis is that patients with high combined genetic and epigenetic risk are more likely not to respond to standard treatment and that the pathophysiological mechanisms in renal tissue differ between groups.

Metod

llumina Global Screening Array and methylation data are available for a subset of patients with LN. A combined polygenic and epigenetic risk score will be developed in these patients. Patients will be divided into high- and low genetic/epigenetic risk groups and then related to LN treatment response. Kidney biopsies from patients at high genetic/epigenetic risk (top 10%, n=4) and patients at low genetic/epigenetic risk (bottom 10%, n=4) will also be examined. Spatial transcriptomics will be performed using a custom gene module and the NanoString GeoMx platform (NanoString Technologies). The analysis will be performed within the rheumatology research group in collaboration with our bioinformatician and researchers in the group.

Betydelse för patienten

There is an unmet need for individualized LN treatment. The great strength and uniqueness of this project is that we combine three different approaches: Genetics, Epigenetics, and Transcriptomics to get a comprehensive picture of the disease mechanisms involved in LN and relate this to treatment response. Our goal is to develop a genetic and epigenetic tool to be used at the time of diagnosis to individualize treatment and minimize the risk of permanent kidney damage. Further, we will investigate the pathophysiological mechanisms affecting renal tissue to find new drug targets for LN.