# DNA Binding of Human and Viral Transcription Factors is Associated with Rheumatoid Arthritis Risk Loci

> **NIH VA I01** · CINCINNATI VA MEDICAL CENTER RESEARCH · 2021 · —

## Abstract

This Merit Review application is based on our hypotheses that Fibroblast-Like Synoviocytes (FLS) from
Rheumatoid Arthritis (RA) patients infected with Epstein - Barr virus (EBV) will have unique gene
expression properties that alter the host immune response to EBV, and that these difference influences the risk
for developing RA. These hypotheses is based on the following observations: All 12 of the FLS cell lines that
we have evaluated, six from Rheumatoid Arthritis (RA) patients and six from Osteoarthritis (OA) disease
controls, contained some cells infected with EBV. We discovered that FLS can be superinfected with EBV. We
observed that RA (but not OA) genetic risk loci are enriched for DNA variants that are immunoprecipitated with
Epstein-Barr Nuclear Antigen-2 (EBNA2) (Relative Risk (RR)=4.5, Bonferroni corrected probability
(Pc)=2.4x10-14). Preliminary data showed differences between RA and OA in the expression of the genes
controlled by elements in RA risk loci. These observations and the 792 publications in Pubmed, often
contradictory, present many intriguing relationships between EBV and RA. In our view these observations are
consistent with EBV being involved in the pathogenesis of RA.
 We plan three initiatives with this DVA Merit Award project. First, we will characterize the virus infection in
FLS (Aim 1) by: assessing the frequency of EBV FLS infection, sequencing the EBV DNA in FLS, and
comparing EBV gene expression in RA, OA, & normal (NL) FLS. We will test the hypothesis that FLS infection
is common among the EBV infected human population. Second, we will explore the FLS response to EBV
infection (Aim 2) by determining host gene expression with RNA-seq to assess EBV infected and secondarily
influenced FLS from RA, OA, & NL subjects and by exploring allele specificity at RA loci in RA, OA, and NL
FLS. Once experimental conditions are determined, single cell RNA-seq will characterize the cell population
infected with EBV and the cells responding to EBV infection. These experiments will evaluate the hypotheses
that RA FLS will have a different gene expression profile than the FLS from OA or NL subjects and that the
expression quantitative trait loci (eQTL) will distinguish RA from OA and NL FLS. Third, we will assess the
immune response to EBV infected FLS (Aim 3). Our hypothesis is that the host response to EBV infection of
the FLS will differentiate RA from OA and NL subjects. In specific, our detailed working hypothesis and current
model is: 1. That usually the OA & NL FLS are abortively infected with EBV, 2. That OA & NL EBV infected
FLS exist at a minimal level, perhaps only expressing a few EBV latent genes, as seen in latently infected B
cells, and 3. That EBV infected OA & NL FLS are usually quiescent to immune recognition. In contrast, in RA
there is evidence that the early steps of the EBV lytic program are initiated with the expression of Early-
Immediate EBV antigens. These changes in combination with other factors (e.g.,...

## Key facts

- **NIH application ID:** 10045951
- **Project number:** 5I01BX003850-03
- **Recipient organization:** CINCINNATI VA MEDICAL CENTER RESEARCH
- **Principal Investigator:** KENNETH M KAUFMAN
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2018-10-01 → 2022-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10045951

## Citation

> US National Institutes of Health, RePORTER application 10045951, DNA Binding of Human and Viral Transcription Factors is Associated with Rheumatoid Arthritis Risk Loci (5I01BX003850-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10045951. Licensed CC0.

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