Deciphering the Genetic and Genomic Architecture of Systemic Lupus Erythematosus

StrategyThe Department of Research, Development and InnovationMedFUTURE Research CentreBiobaseFaculty Research Centres
Biblioteca „Valeriu Bologa”
Editura „Iuliu Haţieganu”
Revista Medicine and Pharmacy Reports

 

Project title: Deciphering the Genetic and Genomic Architecture of Systemic Lupus Erythematosus

 

Contract no: 760280/26.03.2024

Code: 199/31.07.2023

Total budget: 6.131.326,45 RON, of which the amount of PNNR financing is 5.600.000 RON and the related VAT is 531.326,45 RON.

Duration of project: 28 months (between 26.03.2024-30.06.2026)

Project Director: Prof. dr . George Bertsias, University of Crete School of Medicine, Department of Rheumatology and Clinical Immunology, Crete, Greece.

Postdoctoral researcher (UMF project manager): Asst. Univ. Dr. Pamfil Cristina, e-mail: cristinapamfil.umfcluj@gmail.com

 

The implementation place: University of Medicine and Pharmacy “Iuliu Hațieganu” Cluj- Napoca – Rheumatology Clinic Cluj-Napoca, Clinicilor street no. 2-4 and the Department of Medical Genetics, Pasteur street no. 6, Cluj-Napoca, Romania.

Summary: Systemic Lupus Erythematosus (SLE) is a prototype autoimmune disorder that affects multiple organs. Despite advances in the disease understanding, there are numerous scientific and clinical unmet needs and patients experience substantial morbidity and reduced quality of life. Genetic contribution plays an important role in SLE with currently identified variants explaining <20% of heritability. Moreover, although SLE is characterized by augmented type I interferon (IFN) expression and/or bioactivity, central to disease initiation and progression, the genetic drivers for this perturbation and inter-patient variability remain elusive. Notably, the IFN signature correlates with enhanced efficacy of biological treatments but the underlying molecular explanation is missing. Herein, and capitalizing on our experience with the clinical, genetic, and transcriptomic characterization of SLE, we will gain additional insights first, by integrating genotypes, genome-wide mRNA and alternatively spliced transcriptomes focusing on the IFN pathway, from our existing cohorts of >500 SLE and >300 healthy individuals. Next, we will purify plasmacytoid dendritic cells (main IFN producer) from SLE and healthy subjects, to undergo genotyping and transcriptome analysis at steady state and following activation, thus enabling to call cell-specific expression quantitative trait loci (eQTLs) contributing to IFN deregulation in SLE. Finally, we will analyse our cohort of >100 SLE patients under treatment with the biological agent belimumab (anti-BAFF mAb), in order to characterise in vivo eQTL interactions with the IFN status and BAFF blockade. Our top prioritized results from the aforementioned studies will be functionally confirmed with gene silencing/editing assays in relevant primary immune cells. Collectively, our research will shed light on the genetic causality and aberrant IFN production in SLE, with implications for the molecular and clinical stratification of the disease.

 

General Aim: Our objective is to gain novel insights into the genetic basis of SLE by integrating genome variation with expression.

 

Specific Objectives:

  • Aim 1 – Utilize our existing cohort of over 400 well-characterized SLE patients and more than 200 healthy individuals to correlate genetic polymorphisms with genome- wide expression, including alternatively spliced mRNA isoforms, which represent a significant but underexplored source of biological
  • Aim 2 – Investigate plasmacytoid dendritic cells (pDCs), which are significant producers of interferons, to identify cell-specific expression quantitative trait loci (eQTLs) in systemic lupus erythematosus (SLE) versus healthy individuals, focusing on those associated with interferon
  • Aim 3 – Profile the genotypes and RNA profiles of a large cohort of SLE patients treated with the biological agent This will help characterize in vivo eQTL interactions with IFN status and assess the clinical and immunological effects of BAFF blockade.

 

Expected Results of the Project

  • The project will establish a cohort of over 100 patients with systemic lupus erythematosus (SLE) and over 100 controls, for whom clinical data and biological samples (DNA, RNA, PBMCs, serum) will be Based on these materials, high-resolution genetic and transcriptomic data will be generated, enabling the identification of genetic variants that influence immune responses – particularly the activation of the type I interferon pathway, a central element in lupus pathogenesis.
  • Experimental analyses will focus on ex vivo–stimulated peripheral blood mononuclear cells (PBMCs). Disease-specific molecular signatures will be defined, and links between genetic variants and gene expression (eQTL / splice-QTL) will be
  • In parallel, patients treated with biological therapies (Belimumab and Anifrolumab) will be followed longitudinally to identify genetic and transcriptomic biomarkers that can predict treatment The results will contribute to improved molecular stratification of patients and to potential future recommendations for personalized medicine.
  • The data obtained will be made available to the scientific community, together with standardized bioinformatics The project will support the development of a competitive research team in Romania in the field of multi-omics and translational immunology.

 

Scientific Dissemination:

  • At least two articles in indexed international journals
  • Presentation of results at national and international scientific congresses and conferences

 

The Team

  • George Bertsias -Director proiect, Cercetător cu experiență Leo A.B. Joosten, Cercetător cu experiență
  • Simona Rednic, Cercetător cu experiență
  • Laura Damian, Cercetător cu experiență
  • Cristina Pamfil, Cercetător post-doctorand
  • Tania Crisan, Cercetător post-doctorand
  • Ghib Linda-Jessica – Cercetător post-doctorand
  • Cabău Georgiana – Cercetător post-doctorand
  • Vacant – 1 Cercetător post-doctorand
  • Danci Valentin-Adrian – 1 Student doctorand
  • Ancuta Straton/ Sîrghii Ana, Student doctorand
  • Marian Anamaria, Student doctorand
  • Cabău Georgiana – Asistent de cercetare
  • Badii Oana Medeea – Tehnician 1
  • Moldovan Alin Iulian – Tehnician 2
  • Căprar Sidonia Carmen – Tehnician 3

 

PNRR. Finanțat de Uniunea Europeană – UrmătoareaGenerațieUE
Conținutul acestui material nu reprezintă în mod obligatoriu poziția oficială a Uniunii Europene sau a Guvernului României

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