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.

Public Health Relevance

Central to immunity and critically important for human health, we hypothesize that allelic variants coded in the human Major Histocompatibility Complex (MHC) control the fine-tuning of homeostatic responses affecting susceptibility to multiple sclerosis and the physiology of the inflammatory and neurodegenerative processes that underlie disease progression. By sequencing the whole MHC in large and well-characterized cohorts, we aim to reveal important aspects of the contribution of immune genetic polymorphism. We will use state of the art laboratory and bioinformatics methodology, and leverage our investigators' multidisciplinary experience to gain insight into the role of MHC variation in multiple sclerosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS102153-04
Application #
9923731
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Utz, Ursula
Project Start
2017-08-15
Project End
2022-04-30
Budget Start
2020-05-01
Budget End
2021-04-30
Support Year
4
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Neurology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94118