Human Epistatic Interaction Controls IL7R Splicing and Increases Multiple Sclerosis Risk

被引：83

作者：

Galarza-Munoz, Gaddiel ^{[1
,2
,3
]}

Briggs, Farren B. S. ^{[4
]}

Evsyukova, Irina ^{[2
]}

Schott-Lerner, Geraldine ^{[3
]}

Kennedy, Edward M. ^{[1
]}

Nyanhete, Tinashe ^{[5
,6
]}

Wang, Liuyang ^{[1
]}

Bergamaschi, Laura ^{[7
]}

Widen, Steven G. ^{[3
]}

Tomaras, Georgia D. ^{[1
,5
,6
]}

Ko, Dennis C. ^{[1
,8
]}

Bradrick, Shelton S. ^{[1
,2
,3
]}

Barcellos, Lisa F. ^{[9
]}

Gregory, Simon G. ^{[7
,10
]}

Garcia-Blanco, Mariano A. ^{[1
,2
,3
]}

机构：

[1] Duke Univ, Dept Mol Genet & Microbiol, Med Ctr, Durham, NC 27710 USA

[2] Duke Univ, Ctr RNA Biol, Durham, NC 27710 USA

[3] Univ Texas Med Branch, Dept Biochem & Mol Biol, Galveston, TX 77555 USA

[4] Case Western Reserve Univ, Sch Med, Dept Epidemiol & Biostat, Cleveland, OH 44106 USA

[5] Duke Univ, Dept Immunol, Durham, NC 27710 USA

[6] Duke Univ, Dept Surg, Durham, NC 27710 USA

[7] Duke Univ, Duke Mol Physiol Inst, Durham, NC 27701 USA

[8] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA

[9] Univ Calif Berkeley, Sch Publ Hlth, Div Epidemiol, Berkeley, CA 94720 USA

[10] Duke Univ, Med Ctr, Dept Neurol, Durham, NC 27710 USA

来源：

CELL | 2017年 / 169卷 / 01期

关键词：

GENOME-WIDE ASSOCIATION; INTERLEUKIN-7; RECEPTOR; MESSENGER-RNA; HAPLOTYPE MAP; IL-7; EXPRESSION; GENE; SUSCEPTIBILITY; TRANSCRIPTION; METAANALYSIS;

D O I：

10.1016/j.cell.2017.03.007

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 50 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.

引用

页码：72 / +

页数：26

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