Expression quantitative trait loci analysis in rheumatoid arthritis identifies tissue specific variants associated with severity and outcome

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 patients with RA from the Pathobiology of Early Arthritis Cohort. 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 single-nucleotide polymorphisms (SNPs) 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.

[1]  M. Lewis,et al.  Diversity of NF-κB signalling and inflammatory heterogeneity in Rheumatic Autoimmune Disease. , 2022, Seminars in immunology.

[2]  J. Isaacs,et al.  Interferon-α-mediated therapeutic resistance in early rheumatoid arthritis implicates epigenetic reprogramming , 2022, Annals of the Rheumatic Diseases.

[3]  M. Malaise,et al.  AB0169 EARLY REMISSION AT 6 MONTHS AS A PREDICTOR OF LONGTERM REMISSION IN NEW ONSET RHEUMATOID ARTHRITIS , 2022, Annals of the Rheumatic Diseases.

[4]  Chun Jimmie Ye,et al.  Single-cell eQTL mapping identifies cell type–specific genetic control of autoimmune disease , 2022, Science.

[5]  Yanzhao Liu,et al.  Tumor necrosis factor‐alpha stimulated gene‐6: A biomarker reflecting disease activity in rheumatoid arthritis , 2022, Journal of clinical laboratory analysis.

[6]  H. Tsuchiya,et al.  Multiomics landscape of synovial fibroblasts in rheumatoid arthritis , 2021, Inflammation and regeneration.

[7]  J. Barrett,et al.  Investigation of genetically regulated gene expression and response to treatment in rheumatoid arthritis highlights an association between IL18RAP expression and treatment response , 2020, Annals of the Rheumatic Diseases.

[8]  A. Qian,et al.  The Bone Extracellular Matrix in Bone Formation and Regeneration , 2020, Frontiers in Pharmacology.

[9]  S. Kummerfeld,et al.  Molecular Portraits of Early Rheumatoid Arthritis Identify Clinical and Treatment Response Phenotypes , 2019, Cell reports.

[10]  Nir Hacohen,et al.  Defining inflammatory cell states in rheumatoid arthritis joint synovial tissues by integrating single-cell transcriptomics and mass cytometry , 2019, Nature Immunology.

[11]  Y. Okada,et al.  Genetics of rheumatoid arthritis: 2018 status , 2018, Annals of the rheumatic diseases.

[12]  Helen E. Parkinson,et al.  The NHGRI-EBI GWAS Catalog of published genome-wide association studies, targeted arrays and summary statistics 2019 , 2018, Nucleic Acids Res..

[13]  R. Toes,et al.  Mast cells in early rheumatoid arthritis associate with disease severity and support B cell autoantibody production , 2018, Annals of the rheumatic diseases.

[14]  Stephen Burgess,et al.  Genomic atlas of the human plasma proteome , 2018, Nature.

[15]  Wei Wang,et al.  Comprehensive epigenetic landscape of rheumatoid arthritis fibroblast-like synoviocytes , 2018, Nature Communications.

[16]  A. Barton,et al.  Rheumatoid arthritis , 2018, Nature Reviews Disease Primers.

[17]  A. Barton,et al.  CD4+ and B Lymphocyte Expression Quantitative Traits at Rheumatoid Arthritis Risk Loci in Patients With Untreated Early Arthritis , 2018, Arthritis & rheumatology.

[18]  C. Milner,et al.  TSG-6: A multifunctional protein with anti-inflammatory and tissue-protective properties. , 2018, Matrix biology : journal of the International Society for Matrix Biology.

[19]  M. Leandro,et al.  B cell phenotypes in patients with rheumatoid arthritis relapsing after rituximab: expression of B cell‐activating factor‐binding receptors on B cell subsets , 2017, Clinical and experimental immunology.

[20]  Nicola J. Rinaldi,et al.  Genetic effects on gene expression across human tissues , 2017, Nature.

[21]  T. Furukawa,et al.  Calcification of joints and arteries with novel NT5E mutations with involvement of upper extremity arteries , 2017, Vascular medicine.

[22]  P. Gaffney,et al.  Identification of a Systemic Lupus Erythematosus Risk Locus Spanning ATG16L2, FCHSD2, and P2RY2 in Koreans , 2015, Arthritis & rheumatology.

[23]  Naoyuki Makita,et al.  Quantitative analysis of cadherin‐11 and β‐catenin signalling during proliferation of rheumatoid arthritis‐derived synovial fibroblast cells , 2015, The Journal of pharmacy and pharmacology.

[24]  Zhenlin Zhang,et al.  Calcification of joints and arteries: second report with novel NT5E mutations and expansion of the phenotype , 2015, Journal of Human Genetics.

[25]  Mary D. Fortune,et al.  Integration of disease association and eQTL data using a Bayesian colocalisation approach highlights six candidate causal genes in immune-mediated diseases , 2015, Human molecular genetics.

[26]  A. Azad,et al.  Coiled-coil domain containing 3 (CCDC3) represses tumor necrosis factor-α/nuclear factor κB-induced endothelial inflammation. , 2014, Cellular signalling.

[27]  D. Rowe,et al.  Induced ablation of Bmp1 and Tll1 produces osteogenesis imperfecta in mice. , 2014, Human molecular genetics.

[28]  Ivan Rusyn,et al.  An empirical Bayes approach for multiple tissue eQTL analysis , 2013, Biostatistics.

[29]  T. Ise,et al.  Human Fc Receptor–Like 5 Binds Intact IgG via Mechanisms Distinct from Those of Fc Receptors , 2013, The Journal of Immunology.

[30]  C. Wallace,et al.  Bayesian Test for Colocalisation between Pairs of Genetic Association Studies Using Summary Statistics , 2013, PLoS genetics.

[31]  K. Siminovitch,et al.  Association of granulomatosis with polyangiitis (Wegener's) with HLA-DPB1*04 and SEMA6A gene variants: evidence from genome-wide analysis. , 2013, Arthritis and rheumatism.

[32]  F. Vannberg,et al.  GENETICS OF GENE EXPRESSION IN PRIMARY IMMUNE CELLS IDENTIFIES CELL-SPECIFIC MASTER REGULATORS AND ROLES OF HLA ALLELES , 2012, Nature Genetics.

[33]  R. Ophoff,et al.  Unraveling the Regulatory Mechanisms Underlying Tissue-Dependent Genetic Variation of Gene Expression , 2012, PLoS genetics.

[34]  Robert M. Plenge,et al.  Five amino acids in three HLA proteins explain most of the association between MHC and seropositive rheumatoid arthritis , 2011, Nature Genetics.

[35]  F. Pessler,et al.  Synovial Infiltration with CD79a-positive B Cells, But Not Other B Cell Lineage Markers, Correlates with Joint Destruction in Rheumatoid Arthritis , 2011, The Journal of Rheumatology.

[36]  Andrey A. Shabalin,et al.  Matrix eQTL: ultra fast eQTL analysis via large matrix operations , 2011, Bioinform..

[37]  R. Civitelli,et al.  N-cadherin and cadherin 11 modulate postnatal bone growth and osteoblast differentiation by distinct mechanisms , 2010, Journal of Cell Science.

[38]  B. Dijkmans,et al.  Regulation of IFN response gene activity during infliximab treatment in rheumatoid arthritis is associated with clinical response to treatment , 2010, Arthritis research & therapy.

[39]  J. Reveille,et al.  HLA-DPB1 and DPB2 are genetic loci for systemic sclerosis: a genome-wide association study in Koreans with replication in North Americans. , 2009, Arthritis and rheumatism.

[40]  H. Lodish,et al.  The N-terminal domain of Janus kinase 2 is required for Golgi processing and cell surface expression of erythropoietin receptor. , 2001, Molecular cell.

[41]  R. Hembry,et al.  The effects of selective inhibitors of matrix metalloproteinases (MMPs) on bone resorption and the identification of MMPs and TIMP-1 in isolated osteoclasts. , 1994, Journal of cell science.

[42]  M. Zylka,et al.  NT5E mutations and arterial calcifications. , 2011, The New England journal of medicine.