Expression Quantitative Trait Loci Analysis in Rheumatoid Arthritis Identifies Tissue Specific Variants Associated with Severity and Outcome

Katriona Goldmann (Lead Author), Athina Spiliopoulou, Andrii Iakovliev, Darren Plant, Nisha Nair, Cankut Çubuk, The MATURA Consortium, Paul M McKeigue, Michael Barnes, Anne Barton, Costantino Pitzalis, Myles J. Lewis*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

Objective
Genome-wide association studies have successfully identified more than 100 loci associated with susceptibility to rheumatoid arthritis (RA). However, our understanding of the functional effects of genetic variants in causing RA and their effects on disease severity and response to treatment remains limited.

Methods
In this study we conducted expression quantitative trait locus (eQTL) analysis to dissect the link between genetic variants and gene expression comparing the disease tissue against blood using RNA-Sequencing of synovial biopsies (n=85) and blood samples (n=51) from treatment-naïve rheumatoid arthritis patients from the Pathobiology of Early Arthritis Cohort (PEAC).

Results
This identified 898 eQTL genes in synovium and genes loci in blood, with 232 genes in common to both synovium and blood, although notably many eQTL were tissue specific. Examining the HLA region, we uncovered a specific eQTL at HLA-DPB2 with the critical triad of SNP rs3128921 driving synovial HLA-DPB2 expression, and both rs3128921 and HLA-DPB2 gene expression correlating with clinical severity and increasing probability of the lympho-myeloid pathotype.

Conclusions
This analysis highlights the need to explore functional consequences of genetic associations in disease tissue. HLA-DPB2 SNP rs3128921 could potentially be used to stratify patients to more aggressive treatment immediately at diagnosis.
Original languageEnglish
Number of pages12
JournalAnnals of the Rheumatic Diseases
Early online date18 Nov 2023
DOIs
Publication statusE-pub ahead of print - 18 Nov 2023

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