Vitamin D in Primary Sjogren's Syndrome (pSS) and the Identification of Novel Single-Nucleotide Polymorphisms Involved in the Development of pSS-Associated Diseases

Abstract

Sjögren's syndrome (SS) is a chronic autoimmune disorder characterised by lymphocytic infiltration of the exocrine glands, which leads to dryness of the eyes and mouth; systemic manifestations such as arthritis, vasculitis, and interstitial lung disease; and increased risks of lymphoma and cardiovascular diseases. SS predominantly affects women, with a strong genetic component linked to sex chromosomes. Genome-wide association studies (GWASs) have identified numerous single-nucleotide polymorphisms (SNPs) associated with primary SS (pSS), revealing insights into its pathogenesis. The adaptive and innate immune systems are crucial to SS's development, with viral infections implicated as environmental triggers that exacerbate autoimmune responses in genetically susceptible individuals. Moreover, recent research has highlighted the role of vitamin D in modulating immune responses in pSS patients, suggesting its potential therapeutic implications. In this review, we focus on the recently identified SNPs in genes like OAS1, NUDT15, LINC00243, TNXB, and THBS1, which have been associated with increased risks of developing more severe symptoms and other diseases such as fatigue, lymphoma, neuromyelitis optica spectrum disorder (NMOSD), dry eye syndrome (DES), and adverse drug reactions. Future studies should focus on larger, multi-ethnic cohorts with standardised protocols to validate findings and identify new associations. Integrating genetic testing into clinical practise holds promise for improving SS management and treatment strategies, enabling personalised interventions based on comprehensive genetic profiles. By focusing on specific SNPs, vitamin D, and their implications, future research can lead to more effective and personalised approaches for managing pSS and its complications.

Keywords: GWASs; Sjögren’s syndrome; autoimmunity; fatigue; lymphoma; single-nucleotide polymorphisms.

Figure 1

Immunomodulatory effects of vitamin D on innate and adaptive immune responses. The figure describes the effect of vitamin D on B lymphocytes and activated T lymphocytes (the adaptive immune system) and macrophages, neutrophils, NKs, and dendritic cells (the innate immune system). Vitamin D drives the phenotype shift from Th17 and Th1 to Treg and Th2, respectively. Accordingly, the production of INFγ and IL-17 by Th17 is decreased, while the production of IL-10 and IL-4/5/10/13 by Treg and Th2, respectively, is increased. The green and magenta arrows represent, respectively, the increase and decrease in the production of designated molecule.

Figure 2

The role of SNPs in the development of Sjogren’s syndrome-associated diseases. Up- and downward arrows represent the increased/decreased risk of the described SNPs with regard to the development of particular pSS-associated diseases or complications. Oligoadenylate synthetase 1 (OAS1); receptor transporter protein 4 (RTP4); Endoplasmic reticulum to nucleus signalling 1 (ERN1); LIM homeobox 1 locus (LHX1); B lymphocyte hyperactivity with B cell activating factor (BAFF); Tenascin XB (TNXB); Nudix Hydrolase 15 (NUDT15); methylene tetrahydrofolate reductase (MTHFR); TNF Alpha-Induced Protein 3 (TNFAIP3); Leukocyte immunoglobulin-like receptor A3 (LILRA3); Thrombospondin 1 (THBS1).