# Promoter interactome-aided mapping of unexplored CVID genetic landscapes

> **NIH NIH R01** · CHILDREN'S HOSP OF PHILADELPHIA · 2021 · $570,236

## Abstract

PROJECT SUMMARY/ABSTRACT
Common variable immunodeficiency (CVID) is a primary disease of germinal center (GC) dysfunction, yet most
CVID mechanistic investigations have utilized patient blood samples, which do not contain bona fide GC cells.
Similarly, genome-wide association studies (GWAS) of CVID patients have identified many disease-associated
single nucleotide polymorphisms (SNPs), yet most lie in non-coding DNA and are of unclear relevance to
disease pathogenesis. The long-range goal of the proposed work is to determine the full genetic basis of CVID.
The objective of this grant is to determine which non-coding regions of DNA contribute to GC dysfunction. The
working hypothesis is that CVID GWAS SNPs point to important non-coding genomic regions that interact with
promoters of genes key to GC lymphocyte function. Further, genetic variation altering gene promoter
interactions, or damage to these genes themselves, will lead to GC dysfunction and eventually the symptoms
of CVID. Our rationale is that identifying gene promoter interactions critical to GC homeostasis will provide new
diagnostic and therapeutic opportunities for patients suffering from diseases of GC dysfunction including, but
not limited to, CVID. Our specific aims will test the following hypotheses: (Aim 1) CVID GWAS associated
regions euchromatically interact with gene promoters in T follicular helper cells (Tfh) and/or follicular B cells
(FO B cells); (Aim 2) these interactions influence gene expression; (Aim 3) non-coding variants altering gene
expression or variants damaging coding genes are enriched in CVID patients and that rhese variants alter Tfh
and FO B cell function. The contribution is significant because cataloguing the genes and gene promoter
contacts vital to GC homeostasis/dysfunction will offer new disease discovery opportunities and provide new
molecules to target with personalized therapies. The proposed work is innovative because we are reinterpreting
published GWAS with a suite of interlocking genome-scale technologies capable of annotating individual SNPs
with overlapping layers of cell type-specific epigenetic information including promoter contacts, chromatin
availability and gene expression. Further, we are verifying our findings in CVID exomes and genomes, with
genetically modified cell-lines, with patient lymph nodes and in co-cultures that recapitulate key transcriptional
features of the GC environment.

## Key facts

- **NIH application ID:** 10207385
- **Project number:** 5R01AI146026-03
- **Recipient organization:** CHILDREN'S HOSP OF PHILADELPHIA
- **Principal Investigator:** NEIL DAVID ROMBERG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $570,236
- **Award type:** 5
- **Project period:** 2019-07-16 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10207385

## Citation

> US National Institutes of Health, RePORTER application 10207385, Promoter interactome-aided mapping of unexplored CVID genetic landscapes (5R01AI146026-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10207385. Licensed CC0.

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