@article{68161379e6da4b139ee5b3e1cb1dd219,
title = "Human Epistatic Interaction Controls IL7R Splicing and Increases Multiple Sclerosis Risk",
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",
author = "Gaddiel Galarza-Munoz and Briggs, {Farren B.S.} and Irina Evsyukova and Geraldine Schott and Kennedy, {Edward M.} and Tinashe Nyanhete and Liuyang Wang and Laura Bergamaschi and Widen, {Steven G.} and Tomaras, {Georgia D.} and Ko, {Dennis C.} and Shelton Bradrick and Barcellos, {Lisa F.} and Gregory, {Simon G.} and Garcia-Blanco, {Mariano A.}",
note = "Funding Information: We thank Drs. M. Skeen (Duke) and L.K. Newby (Duke MURDOCK study) for providing DNA and RNA samples from patients and healthy individuals, S. Arvai (Duke) for technical assistance with these samples, the IMSGC for sharing imputed whole genome genotype data, Dr. T.G. Wood and the UTMB NGS Facility for RNA-seq data, and Drs. B.R. Cullen and S.M. Horner (Duke) for reagents, advice, and generosity related to experiments with primary CD4+ T cells. Finally, we express our appreciation for individuals participating in the MURDOCK-MS study. This work was supported by NIH grants R01-NS060925 (S.G.G. and M.A.G.-B.) and R01-ES017080 (L.F.B.), National MS Society Pilot Award #PP2299 and Duke University Whitehead Scholarship (D.C.K. and L.W.), National MS Society research grant RG 4083A1/1 (S.G.G.), Ruth and A. Morris Williams Faculty Research Prize funds from Duke University School of Medicine (G.D.T.), start-up funds from UTMB (M.A.G.-B.), funds from Mr. Herman Stone and family for MS research fund (S.G.G.), and NIH F32-NS087899 postdoctoral fellowship (G.G.M.). M.A.G.-B. and S.G.G. have filed invention disclosures with Duke University for matters related to the work described and consultant agreements with Pfizer, Inc. related to the development of animal models indirectly related to the work described. They attest that in no way did these interests influence the planning, execution or interpretation of the results, or the writing of this manuscript. The other authors have no competing interests or other interests that might be perceived to influence the results and/or discussion reported in this paper. Publisher Copyright: {\textcopyright} 2017 Elsevier Inc.",
year = "2017",
month = mar,
day = "23",
doi = "10.1016/j.cell.2017.03.007",
language = "English (US)",
volume = "169",
pages = "72--84.e13",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "1",
}