scholarly journals An integrative multi-omics approach in Sjögren’s Syndrome identifies novel genetic drivers with regulatory function and disease-specificity

Author(s):  
María Teruel ◽  
Guillermo Barturen ◽  
Manuel Martínez-Bueno ◽  
Miguel Barroso ◽  
Olivia Castelli ◽  
...  

ABSTRACTPrimary Sjögren’s syndrome (SS) is a systemic autoimmune disease characterized by lymphocytic infiltration and damage of exocrine salivary and lacrimal glands. The etiology of SS is complex with environmental triggers and genetic factors involved. By conducting an integrated multi-omics study we identified vast coordinated hypomethylation and overexpression effects, that also exhibit increased variability, in many already known IFN-regulated genes. We report a novel epigenetic signature characterized by increased DNA methylation levels in a large number of novel genes enriched in pathways such as collagen metabolism and extracellular matrix organization. We identified new genetic variants associated with SS that mediate their risk by altering DNA methylation or gene expression patterns, as well as disease-interacting genetic variants that exhibit regulatory function only in the SS population. Our study sheds new light on the interaction between genetics, DNA methylation, gene expression and SS, and contributes to elucidate the genetic architecture of gene regulation in an autoimmune population.

RMD Open ◽  
2020 ◽  
Vol 6 (1) ◽  
pp. e000995 ◽  
Author(s):  
Albin Björk ◽  
Elina Richardsdotter Andersson ◽  
Juliana Imgenberg-Kreuz ◽  
Gudny Ella Thorlacius ◽  
Johannes Mofors ◽  
...  

ObjectiveStandard assessment of interferon (IFN) system activity in systemic rheumatic diseases depends on the availability of RNA samples. In this study, we describe and evaluate alternative methods using plasma, serum and DNA samples, exemplified in the IFN-driven disease primary Sjögren’s syndrome (pSS).MethodsPatients with pSS seropositive or negative for anti-SSA/SSB and controls were included. Protein-based IFN (pIFN) scores were calculated from levels of PD-1, CXCL9 and CXCL10. DNA methylation-based (DNAm) IFN scores were calculated from DNAm levels at RSAD2, IFIT1 and IFI44L. Scores were compared with mRNA-based IFN scores measured by quantitative PCR (qPCR), Nanostring or RNA sequencing (RNAseq).ResultsmRNA-based IFN scores displayed strong correlations between B cells and monocytes (r=0.93 and 0.95, p<0.0001) and between qPCR and Nanostring measurements (r=0.92 and 0.92, p<0.0001). The pIFN score in plasma and serum was higher in patients compared with controls (p<0.0001) and correlated well with mRNA-based IFN scores (r=0.62–0.79, p<0.0001), as well as with each other (r=0.94, p<0.0001). Concordance of classification as ‘high’ or ‘low’ IFN signature between the pIFN score and mRNA-based IFN scores ranged from 79.5% to 88.6%, and the pIFN score was effective at classifying patients and controls (area under the curve, AUC=0.89–0.93, p<0.0001). The DNAm IFN score showed strong correlation to the RNAseq IFN score (r=0.84, p<0.0001) and performed well in classifying patients and controls (AUC=0.96, p<0.0001).ConclusionsWe describe novel methods of assessing IFN system activity in plasma, serum or DNA samples, which may prove particularly valuable in studies where RNA samples are not available.


2020 ◽  
Vol 9 (10) ◽  
pp. 3299
Author(s):  
Katarzyna Błochowiak ◽  
Piotr Celichowski ◽  
Bartosz Kempisty ◽  
Katarzyna Iwanik ◽  
Michał Nowicki

Sjögren’s syndrome (SS) is characterized by xerostomia. We aimed to investigate and compare gene expressions in the labial salivary glands of SS patients with xerostomia SS (sicca) and without xerostomia SS (non-sicca) and of healthy subjects (HS) by means of microarray analysis, and to find genes involved in xerostomia. The study group comprised 11 SS patients (3 SS (sicca) and 8 SS (non-sicca)) and 9 HS. The relative gene expression changes were validated with RT-qPCR in the larger study group. Among the differently expressed genes belonging to the “secretion” ontology group with a fold change >2 and with a p value < 0.05, the Transmembrane P24 Trafficking Protein 10 (TMED10), Protein Disulfide Isomerase Family A Member 4 (PDIA4), Calnexin (CANX), Amyloid Beta Precursor Protein (APP), and Transmembrane BAX Inhibitor Motif Containing 6 (TMBIM6) gene expressions in both SS (sicca) and SS (non-sicca) groups were lower than in HS. Significant correlations were observed between TMED10, PDIA4, and CANX gene expression in SS (sicca) patients compared to the controls. There were no differences between the SS (sicca) and SS (non-sicca) study groups in the expression of the aforementioned genes. Results indicate their role in the endoplasmic reticulum system, their overlapping function and the loss of the APP neuroprotective function in xerostomia. It has a multifactorial origin and can be triggered by disturbances to the various signaling pathways in saliva secretion.


2013 ◽  
Vol 72 (Suppl 3) ◽  
pp. A168.2-A168
Author(s):  
C. P. Mavragani ◽  
A. Nezos ◽  
A. Papageorgiou ◽  
G. E. Fragoulis ◽  
M. Koutsilieris ◽  
...  

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