Human Epistatic Interaction Controls IL7R Splicing and Increases Multiple Sclerosis Risk

Gaddiel Galarza-Muñoz, Farren B.S. Briggs, Irina Evsyukova, Geraldine Schott-Lerner, Edward M. Kennedy, Tinashe Nyanhete, Liuyang Wang, Laura Bergamaschi, Steven G. Widen, Georgia D. Tomaras, Dennis C. Ko, Shelton S. Bradrick, Lisa F. Barcellos, Simon G. Gregory, Mariano A. Garcia-Blanco

Research output: Contribution to journalArticlepeer-review

73 Scopus citations


Multiple sclerosis (MS) is an autoimmune disorder where T cells attack neurons in the central nervous system (CNS) leading to demyelination and neurological deficits. A driver of increased MS risk is the soluble form of the interleukin-7 receptor alpha chain gene (sIL7R) produced by alternative splicing of IL7R exon 6. Here, we identified the RNA helicase DDX39B as a potent activator of this exon and consequently a repressor of sIL7R, and we found strong genetic association of DDX39B with MS risk. Indeed, we showed that a genetic variant in the 5′ UTR of DDX39B reduces translation of DDX39B mRNAs and increases MS risk. Importantly, this DDX39B variant showed strong genetic and functional epistasis with allelic variants in IL7R exon 6. This study establishes the occurrence of biological epistasis in humans and provides mechanistic insight into the regulation of IL7R exon 6 splicing and its impact on MS risk.

Original languageEnglish (US)
Pages (from-to)72-84.e13
Issue number1
StatePublished - Mar 23 2017


  • DDX39B
  • IL7R
  • alternative splicing
  • autoimmune disorders
  • epistasis
  • genetic association
  • multiple sclerosis

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology


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