Unraveling the Epigenetic Landscape of Multiple Sclerosis: How Genetic Susceptibility Shapes T Cell Function
Multiple sclerosis (MS) is a complex inflammatory disease of the central nervous system, where genetic susceptibility plays a crucial role in disease onset and progression. A recent study published in Nature Communications delves into how genetic variants associated with MS influence the epigenome, particularly in CD4+ T cells, a key immune cell type implicated in MS pathogenesis. This research not only provides a genome-wide map of DNA methylation quantitative trait loci (mQTLs) in these cells but also reveals novel insights into how these genetic variants may contribute to disease development through proximal and distal effects on DNA methylation.
Mapping DNA Methylation in MS-Relevant Cells
The study utilized the Illumina MethylationEPIC array to generate genome-wide DNA methylation profiles from CD4+ T cells isolated from 156 MS patients. These profiles were then used to create a comprehensive mQTL map, revealing how genetic variants affect methylation at specific CpG sites across the genome. The focus on CD4+ T cells is particularly important as these cells are believed to play a major role in MS and other inflammatory diseases. The researchers identified 107,922 CpGs where methylation was influenced by cis-acting genetic variants, providing a valuable resource for future studies investigating the molecular mechanisms underlying MS and other related conditions.
Colocalization of MS Susceptibility Loci with DNA Methylation
One of the significant findings of the study was the identification of 19 loci where the same haplotype appears to drive both MS susceptibility and local DNA methylation. This was determined through colocalization analysis, which helps distinguish whether the association between genetic variants and methylation changes is due to a shared causal variant or coincidental linkage. For example, the study found strong evidence of colocalization at a locus on chromosome 5, where the rs7731626 variant affects methylation in and around the ANKRD55 and IL6ST genes, both of which are implicated in immune responses. This suggests that these loci could play a direct role in modulating immune function in MS.
Distal Effects of MS-Associated Variants
Beyond local effects, the study also uncovered two notable distal effects of MS-associated genetic variants on DNA methylation. The first involves a locus on chromosome 16, which influences methylation at a distant CpG island on chromosome 4, near the PRDM8 gene. PRDM8 is a gene involved in histone modification and is thought to play a role in T cell differentiation. The second distal effect was observed with variants in the major histocompatibility complex (MHC) region, which were found to affect methylation at an enhancer region near the PRKCA gene on chromosome 17. PRKCA encodes protein kinase C alpha, a key enzyme in T cell signaling, which further implicates this pathway in MS.
Implications for Understanding MS Pathogenesis
The findings from this study highlight the complexity of the genetic architecture underlying MS and provide new targets for understanding how genetic susceptibility translates into molecular changes that drive disease. The identification of both proximal and distal methylation effects underscores the importance of considering both local and distant regulatory mechanisms when studying the genetic basis of complex diseases like MS.
Moreover, the study's approach of integrating mQTL mapping with colocalization analysis sets a precedent for future research in the field, where similar methods can be applied to other cell types and diseases. The new mQTL map created for CD4+ T cells in MS patients is expected to be a valuable resource for researchers investigating not only MS but also other inflammatory diseases where T cells play a critical role.
References:
Roostaei, T., Klein, HU., Ma, Y. et al. Proximal and distal effects of genetic susceptibility to multiple sclerosis on the T cell epigenome. Nat Commun 12, 7078 (2021).
