Abstract
Genome-wide association studies have identified more than 200 genetic variants to be associated with an increased risk of developing multiple sclerosis (MS). Still, little is known about the causal molecular mechanisms that underlie the genetic contribution to disease susceptibility. In this study, we investigated the role of the single-nucleotide polymorphism (SNP) rs1414273, which is located within the microRNA-548ac stem-loop sequence in the first intron of the CD58 gene. We conducted an expression quantitative trait locus (eQTL) analysis based on public RNA-sequencing and microarray data of blood-derived cells of more than 1000 subjects. Additionally, CD58 transcripts and mature hsa-miR-548ac molecules were measured using real-time PCR in peripheral blood samples of 32 MS patients. Cell culture experiments were performed to evaluate the efficiency of Drosha-mediated stem-loop processing dependent on genotype and to determine the target genes of this underexplored microRNA. Across different global populations and data sets, carriers of the MS risk allele showed reduced CD58 mRNA levels but increased hsa-miR-548ac levels. We provide evidence that the SNP rs1414273 might alter Drosha cleavage activity, thereby provoking partial uncoupling of CD58 gene expression and microRNA-548ac production from the shared primary transcript in immune cells. Moreover, the microRNA was found to regulate genes, which participate in inflammatory processes and in controlling the balance of protein folding and degradation. We thus uncovered new regulatory implications of the MS-associated haplotype of the CD58 gene locus, and we remind that paradoxical findings can be encountered in the analysis of eQTLs upon data aggregation. Our study illustrates that a better understanding of RNA processing events might help to establish the functional nature of genetic variants, which predispose to inflammatory and neurological diseases.
Highlights
In the past 10 years, genome-wide association studies (GWAS) assaying hundreds of thousands of single-nucleotide polymorphisms (SNPs) rapidly expanded our knowledge of genetic loci contributing to complex multifactorial diseases
More than 200 genetic loci have been associated with an increased risk of developing multiple sclerosis (MS)
We investigated the role of a single-nucleotide polymorphism (SNP), which is located within the microRNA-548ac stem-loop sequence in the first intron of the CD58 gene
Summary
In the past 10 years, genome-wide association studies (GWAS) assaying hundreds of thousands of single-nucleotide polymorphisms (SNPs) rapidly expanded our knowledge of genetic loci contributing to complex multifactorial diseases. The current GWAS catalog contains already more than 89000 unique SNP-trait associations [1], and shared risk variants between diseases are increasingly recognized. Despite these important insights, timely diagnosis and appropriate treatment of autoimmune diseases remains challenging, because our understanding of pathogenesis is still limited. We have to bear in mind that association does not imply causation. Onset and course of autoimmune diseases are influenced by a combination of different risk factors, including multiple genetic, epigenetic, immunological, and environmental factors. As in chaotic systems related to the n-body problem, all these factors may constantly interact with each other, which provokes unpredictable outcomes [2]
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