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Epistatic Interaction Linked to Multiple Sclerosis Risk

NEW YORK (GenomeWeb) – Researchers have uncovered an epistatic interaction that contributes to multiple sclerosis risk.

In multiple sclerosis, people's own immune system attacks nerve cells in their brains and spines, which leads to problems with vision, muscle control, balance, and other issues, including possible disability.

Investigators had previously linked a SNP in exon 6 of the IL7R gene to MS risk, and a Duke University-led team used this as a jumping-off point to find other possible MS risk genes. As they reported in Cell today, the researchers used a multidisciplinary approach to find that the RNA helicase DDX39B activates the IL7R exon. In addition, they reported that a DDX39B gene variant is also associated with MS risk and exhibited genetic and functional epistasis with the IL7R variant.

"Our study identifies an interaction with a known MS risk gene to unlock a new MS candidate gene, and in doing so, open up a novel mechanism that is associated with the risk of multiple sclerosis and other autoimmune diseases," co-senior author and Duke researcher Simon Gregory said in a statement.

He and his colleagues performed a proteomic screen to uncover trans-acting factors that affect IL7R exon 6 splicing, and identified 89 possible candidates in two cell lines. One of the top candidates was DDX39B, a DEAD-box protein with a role in constitutive pre-mRNA splicing.

In cell-based studies, they noted that knocking down DDX39B increased exon 6 skipping and that the effect could be rescued by adding in wild-type DDX39B on a silencing-resistant vector. They also found that DDX39B depletion led to an increase of IL7R transcripts.

At the same time, Gregory and his colleagues conducted a genetic association study of the genes that encoded the candidate trans-acting factors they identified through their proteomic screen. In a cohort of 4,088 MS cases and 7,444 controls of European descent, 58 SNPs reached genome-wide significance. All of these SNPs were within the DDX39B gene, the researchers noted. After controlling for DDX39B being in high linkage disequilibrium with HLA genes, 15 DDX39B variants remained associated with MS risk.

None of these variants, however, fell in coding regions, suggesting to the researchers that any functional SNPs might act by regulating DDX39B expression. Indeed, in lymphoblastoid cell lines, the researchers found that one DDX39B risk allele appeared to reduce DDX39B protein expression, but not mRNA levels. Still, through a western blot analysis, they noted a dose-dependent effect of the risk allele on DDX39B protein levels, indicating that it reduces DDX39B mRNA translation, a supposition they confirmed.

Gregory and his colleagues also reported that the DDX39B risk allele and the IL7R risk allele work in cahoots. They found an increased MS risk only among carriers of risk alleles at both loci that worked in a dose-dependent way. In particular, the researchers noted that risk alleles at both loci work together to increase skipping of the IL7R exon 6, which leads to the production of soluble IL7R, which has been shown to exacerbate disease symptoms in a mouse model of MS.

"We can use this information at hand to craft tests that could allow earlier and more accurate diagnoses of multiple sclerosis, and uncover new avenues to expand the therapeutic toolkit to fight MS, and perhaps other autoimmune disorders," added first author Gaddiel Galarza-Muñoz from Duke and the University of Texas Medical Branch at Galveston.