# Altered CD4+ T cell function in relation to the AHI1 MS locus

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2021 · $405,000

## Abstract

Project Summary/Abstract
Multiple sclerosis (MS) is both an inflammatory and neurodegenerative disease that has genetic and
environmental components to susceptibility. The identification of susceptibility loci by unbiased genome-wide
association studies (GWAS) is a major step forward in multiple sclerosis (MS), but we do not yet understand
how allelic variation influences immune function. This transition remains a major challenge in the
understanding of MS and of other human autoimmune diseases. Increasing evidence suggests that
autoreactive CD4+ T cells play a central role in MS pathophysiology. Our evaluation of the 110 validated MS
susceptibility loci using a cohort of healthy genotyped adults identified MS variants that alter nearby gene
expression in naïve CD4+ T cells. We quickly focused our attention on the rs6908428 single nucleotide
polymorphism (SNP) located near the transcription start site of the Abelson helper Integration site 1 (AHI1)
gene because (i) this locus is robustly associated with MS susceptibility (p=1.8 x 10-20), (ii) the “credible set” of
SNPs in strong linkage disequilibrium (LD) with the top SNP that may contain the causal variant is small
(n=11), (iii) the susceptibility allele rs6908428A has a strong effect on RNA expression of AHI1 (1.12 x 10-107)
but not on neighboring genes in CD4+ T cells (not a coincidental overlap), (iv) AHI1 expression is induced in
pathogenic interleukin (IL)-17A-producing T cells (Th17) that are implicated in MS pathogenesis and are well
characterized in the laboratory and (v) we have discovered that Ahi1/AHI1 binds phospholipase C (PLC)γ1
and that pharmacological inhibition of PLCγ1 suppresses human Th17 cell proliferation and a mouse model of
MS. Finally, in MS patients, AHI1 RNA expression is elevated in CD4+ T cells from MS patients compared to
healthy subjects, as well as in PBMCs of MS patients with a higher disease activity.
 The principal goals of the proposed project are: (1) Identification as well as in vitro and ex vivo
validation of causal variant(s) involved in the regulation of AHI1 transcription in CD4+ T cells, (2) analysis of
Ahi1 function in murine CD4+ T cells and its influence on encephalitogenicity in a mouse model of MS, and (3)
analysis of AHI1's influence on gene networks in human Th17 cells in genotyped healthy subjects (n=100), and
glatiramer acetate-treated MS patients (n=100). We thus propose a multifaceted approach integrating human
genetic and human functional immunology experiments to understand how the susceptibility loci alter the state
of activation in pathogenic Th17 to modulate susceptibility to MS and aggravate disease severity.

## Key facts

- **NIH application ID:** 10119232
- **Project number:** 5R01AI130547-06
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Wassim Elyaman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $405,000
- **Award type:** 5
- **Project period:** 2017-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10119232

## Citation

> US National Institutes of Health, RePORTER application 10119232, Altered CD4+ T cell function in relation to the AHI1 MS locus (5R01AI130547-06). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10119232. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*