Variant to Gene Mapping to Discover New Targets for Immune Tolerance.

Parul Mehra,Andrew D Wells

doi:10.3389/fimmu.2021.633219

Abstract

The breakdown of immunological tolerance leads to autoimmune disease, and the mechanisms that maintain self-tolerance, especially in humans, are not fully understood. Genome-wide association studies (GWAS) have identified hundreds of human genetic loci statistically linked to autoimmune disease risk, and epigenetic modifications of DNA and chromatin at these loci have been associated with autoimmune disease risk. Because the vast majority of these signals are located far from genes, identifying causal variants, and their functional consequences on the correct effector genes, has been challenging. These limitations have hampered the translation of GWAS findings into novel drug targets and clinical interventions, but recent advances in understanding the spatial organization of the genome in the nucleus have offered mechanistic insights into gene regulation and answers to questions left open by GWAS. Here we discuss the potential for ‘variant-to-gene mapping’ approaches that integrate GWAS with 3D functional genomic data to identify human genes involved in the maintenance of tolerance.

Highlights

Variant to Gene Mapping to Discover New Targets for Immune ToleranceReviewed by: Kristin Tarbell, Amgen, United States Herman Waldmann, University of Oxford, United Kingdom
Immune tolerance is established through clonal deletion during development of the immune repertoire, and is reinforced in the periphery through cell-intrinsic and -extrinsic mechanisms that limit activation and differentiation
To functionally validate the allele specific expression pattern of 3,000 genes identified by genotype data from the Immunochip, an eQTL analysis was performed in B and T cells from healthy donors which leads to the involvement of cis-regulatory SNPs in gene regulation

Summary

Variant to Gene Mapping to Discover New Targets for Immune Tolerance

Reviewed by: Kristin Tarbell, Amgen, United States Herman Waldmann, University of Oxford, United Kingdom. Because the vast majority of these signals are located far from genes, identifying causal variants, and their functional consequences on the correct effector genes, has been challenging. These limitations have hampered the translation of GWAS findings into novel drug targets and clinical interventions, but recent advances in understanding the spatial organization of the genome in the nucleus have offered mechanistic insights into gene regulation and answers to questions left open by GWAS. We discuss the potential for ‘variant-to-gene mapping’ approaches that integrate GWAS with 3D functional genomic data to identify human genes involved in the maintenance of tolerance

INTRODUCTION

MAINTENANCE OF IMMUNOLOGIC TOLERANCE IN HUMANS AND ITS ROLE IN AUTOIMMUNITY

STATISTICAL LINKAGE OF AUTOIMMUNE RISK VARIANTS WITH TOLERANCE GENE EXPRESSION

Findings

CONCLUSION