Project Summary
Sjögren’s Disease (SjD, previously known as Sjögren’s syndrome) is a chronic, multisystem autoimmune disease
that causes significant morbidity. Experts estimate that 1.3 million individuals have SjD in the United States
alone. Previous research, particularly Mendelian randomization (MR) analyses, has provided strong evidence
for low vitamin D as a risk factor contributing to several autoimmune conditions. Vitamin D is important for dozens
of biological processes. The gene transcription that occurs with the binding of vitamin D to vitamin D receptors
(VDRs) produces downstream effects implicated in immunomodulation, calcium metabolism, cellular growth,
proliferation and apoptosis, and other important immunologic functions. Single nucleotide polymorphisms (SNPs)
associated with genetic variation in VDR binding affinity (VDR-BVs) have been previously identified in
lymphoblastoid cell lines (LCLs); these VDR-BVs are enriched in genomic regions associated with several
autoimmune diseases, cardiovascular disease, osteoporosis, depression, and cancer. To date, available
research on vitamin D in SjD has been limited to small studies of serum vitamin D levels in SjD cases and
controls which observed lower vitamin D levels in cases. There have been no published studies investigating:
1) low vitamin D as a risk factor for SjD using MR analysis, or 2) genetic variation within individual VDR binding
sites as a risk factor for SjD. VDR-BVs are therefore strong candidates to investigate for their genetic contribution
to SjD. The overall objective of this F31 application is to identify VDR-BVs across the genome and
characterize their association with SjD susceptibility, severity, and related clinical outcomes. We
hypothesize that altered VDR binding disrupts downstream gene regulation by vitamin D and increases the risk
of developing SjD or results in more severe disease. Our approach will use an assembled dataset with more
than 1,500 SjD cases and 27,000 controls (for which the data are already available) matched on race/ethnicity,
with whole genome SNP profiles and demographic and clinical data from the Sjögren’s International
Collaborative Clinical Alliance (SICCA) registry. For this project, we will use VDR-BVs previously identified
through ChIP-seq analysis in LCLs and conduct subsequent analyses in primary CD4+ and CD8+ T cells. The
proposed study will: 1) Identify VDR binding sites through ChIP-exo analysis in primary CD4+ and CD8+ T cells
using the SICCA cases and controls; 2) Estimate the association between VDR-BVs and vitamin D-related SNPs
and SjD susceptibility among SICCA study subjects using MR methods; and 3) Estimate the association between
VDR-BVs and vitamin D-related SNPs and clinical SjD phenotypes among SICCA study subjects using MR
methods. Results from the proposed aims will identify genetic risk factors for SjD related to vitamin D
and identify new genes and regulatory pathways involved in the development of SjD. Ultimately, the goal
of this work is to understand the mechanisms by which vitamin D affects this immune-mediated disease.
