# MHC variation at high resolution in multiple sclerosis

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2021 · $632,927

## Abstract

We proposed to study at high resolution the Major Histocompatibility Complex (MHC) locus in multiple
sclerosis (MS), a chronic inflammatory disease of the central nervous system and common cause of non-
traumatic neurological disability in young adults. Over 200 loci have been firmly associated with susceptibility.
The main association signal genome-wide maps to the major histocompatibility complex (MHC) gene cluster
in chromosome 6p21, and explains up to 10% of the genetic variance underlying risk. This region contains
~165 genes, about half having pivotal roles in the immune system. These include the human leukocyte
antigen (HLA) genes, which have been associated with more than 100 infectious, autoimmune and
inflammatory disease phenotypes, as well as drug reactions and cancers. Despite a sustained research effort
on the HLA region in MS, further studies are needed to generate unifying and testable mechanistic models
connected to disease pathogenesis. By examining large and well-characterized cohorts, we aim to reveal
important aspects of the contribution of immune polymorphism to both, risk and progression. Our
experimental approach involves complete sequencing of the 5 Mb MHC, generating high depth coverage of
exonic and intronic as well intergenic segments, thus identifying all possible variants associated with the
phenotypes, and distinguishing otherwise identical classical HLA alleles that differ in noncoding regions. In
Specific Aim 1 we will sequence the MHC in 2,000 MS cases and 2,000 controls representing European, and
African ancestries for a comprehensive analysis of sequence and structure variation. In Specific Aim 2 we
will implement a systems-level pathway analysis pipeline, leveraging large open access databases to allow
the identification of MHC variants with regulatory potential. Finally, in Specific Aim 3 we will employ genomic
editing technologies to setup a robust cellular platform with the capability to efficiently screen the identified
candidate variants, prioritizing on regulation of gene expression and gene-gene interactions. Full description
of MHC variation in informative, poly-ancestral MS datasets, coupled with state-of the art-bioinformatics and
hypothesis driven molecular approaches promises to yield novel insights into the genetic underpinnings of
disease susceptibility.

## Key facts

- **NIH application ID:** 10133162
- **Project number:** 5R01NS102153-05
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** JILL Allison HOLLENBACH
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $632,927
- **Award type:** 5
- **Project period:** 2017-08-15 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10133162

## Citation

> US National Institutes of Health, RePORTER application 10133162, MHC variation at high resolution in multiple sclerosis (5R01NS102153-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10133162. Licensed CC0.

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