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Cell. 2017 Mar 23;169(1):72-84.e13. doi: 10.1016/j.cell.2017.03.007.

Human Epistatic Interaction Controls IL7R Splicing and Increases Multiple Sclerosis Risk.

Author information

1
Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA; Center for RNA Biology, Duke University, Durham, NC 27710, USA; Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555, USA.
2
Department of Epidemiology and Biostatistics, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.
3
Center for RNA Biology, Duke University, Durham, NC 27710, USA.
4
Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555, USA.
5
Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA.
6
Department of Immunology, Duke University Durham, NC 27710, USA; Department of Surgery, Duke University Durham, NC 27710, USA.
7
Duke Molecular Physiology Institute, Duke University, Durham, NC 27701, USA.
8
Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA; Department of Immunology, Duke University Durham, NC 27710, USA; Department of Surgery, Duke University Durham, NC 27710, USA.
9
Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA; Department of Medicine, Duke University Medical Center; Durham, NC 27710, USA.
10
Division of Epidemiology, School of Public Health, University of California Berkeley, Berkeley, CA 94720, USA.
11
Duke Molecular Physiology Institute, Duke University, Durham, NC 27701, USA; Department of Neurology, Duke University Medical Center, Durham, NC 27710, USA. Electronic address: simon.gregory@duke.edu.
12
Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA; Center for RNA Biology, Duke University, Durham, NC 27710, USA; Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555, USA. Electronic address: maragarc@utmb.edu.

Abstract

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.

KEYWORDS:

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

PMID:
28340352
PMCID:
PMC5456452
DOI:
10.1016/j.cell.2017.03.007
[Indexed for MEDLINE]
Free PMC Article

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