Genetic, genomic and epigenetic studies as tools for elucidating disease pathogenesis in primary Sjögren’s syndrome

Abstract

Primary Sjögren’s syndrome (pSS) is characterized by lymphoid infiltration of lacrimal and salivary glands leading to xerophthalmia and xerostomia. pSS is a complex disease involving both genetic and environmental risk factors. Technological advances over the past 10 years have revolutionized genetics and genomics research enabling high-throughput characterization and analysis of DNA and RNA in patient samples on a genome-wide scale. Further, application of high-throughput methods for characterization of epigenetic variation, such as DNA methylation status, is increasingly being applied to AID populations and will likely further define additional risk factors for disease risk and outcome. Main results obtain in pSS through these various approaches are reviewed here.

Keywords::

• epigenetics
• genetics
• genomics
• microRNAs
• Sjögren’s syndrome

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• A characteristic type I interferon (IFN) signature has been observed in peripheral blood mononuclear cells (PBMCs) and salivary glands from primary Sjögren’s syndrome (pSS) patients and may reflect viral infection as a triggering factor, with further amplification by genetic susceptibility factors that increase sensitivity to type I IFN pathway induction.

• The IFN regulatory factor 5 (IRF5) insertion-deletion (in/del) polymorphism has been consistently associated with pSS.

• Functional studies of the IRF5 in/del polymorphism have demonstrated that IRF5 mRNA levels in PBMCs from pSS patients are associated with in/del genotype.

• Several studies have demonstrated that a STAT4 variant (rs7582694) is associated with pSS.

• Functional studies have demonstrated strong association of STAT4 mRNA levels with mRNA levels of three type 1 IFN-induced genes in PBMCs of pSS patients.

• Recent evidence supports genetic association of TNF-α-induced protein 3 with SS and both germline and somatic mutations of TNF-α-induced protein 3 has been associated with pSS-associated lymphoma.

• B-lymphoid tyrosine kinase is involved in the adaptive immune response and has been identified as a susceptibility gene for pSS.

• Two genome-wide association studies performed on pSS case and control individuals of European ancestry and in the Han Chinese population confirmed several previously identified SS risk genes, such as MHC, IRF5, STAT4 and B-lymphoid tyrosine kinase. Several novel risk genes, CXCR5, TNIP1 and IL12A in the European population, and GTF2I in the Chinese population, were associated with genome-wide levels of significance in these studies.

• Preliminary results suggest that certain miRNAs may be differentially expressed in PBMCs or salivary glands from pSS patients, thus contributing to disease pathogenesis through altered control of inflammatory cytokine expression and/or altered response to pathogen-associated molecular patterns.