Long-range genomic regulators of THBS1 and LTBP4 modify disease severity in duchenne muscular dystrophy.
Long-range genomic regulators of THBS1 and LTBP4 modify disease severity in duchenne muscular dystrophy.
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DOI：
10.1002/ana.25283
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发表时间：
2018-08
影响因子：
11.2
通讯作者：
United Dystrophinopathy Project
中科院分区：
文献类型：
--
作者：
Weiss RB;Vieland VJ;Dunn DM;Kaminoh Y;Flanigan KM;United Dystrophinopathy Project
Duchenne muscular dystrophy (DMD) is a severe X-linked recessive disease caused by loss-of-function dystrophin (DMD) mutations in boys, who typically suffer loss of ambulation by age 12. Previously we reported that coding variants in latent transforming growth factor beta-binding protein 4 (LTBP4) were associated with reduced TGFβ signaling and prolonged ambulation (p-value = 1.0 × 10−3) in DMD patients; this result was subsequently replicated by other groups. In this study, we evaluated whether additional DMD modifier genes are observed using whole genome association in the original cohort. We performed a genome-wide association study (GWAS) for SNPs influencing loss of ambulation (LOA) in the same cohort of 253 DMD patients used to detect the candidate association with LTBP4 coding variants. Gene expression and chromatin interaction databases were used to fine map association signals above the threshold for genome-wide significance. Despite the small sample size, two loci associated with prolonged ambulation met genome-wide significance and were tagged by rs2725797 (chr15, p-value = 6.6 × 10−9) and rs710160 (chr19, p-value = 4.7 × 10−8). Gene expression and chromatin interaction data indicated that the latter SNP tags regulatory variants of LTBP4, while the former SNP tags regulatory variants of thrombospondin-1 (THBS1): an activator of TGFβ signaling via direct binding to LTBP4 and an inhibitor of pro-angiogenic nitric oxide signaling. Together with prior evidence implicating LTBP4, the THBS1 modifier locus emphasizes the role that common regulatory variants in gene interaction networks can play in mitigating disease progression in muscular dystrophy.
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影响因子：
11.2
作者：
Flanigan, Kevin M.;Ceco, Ermelinda;Lamar, Kay-Marie;Kaminoh, Yuuki;Dunn, Diane M.;Mendell, Jerry R.;King, Wendy M.;Pestronk, Alan;Florence, Julaine M.;Mathews, Katherine D.;Finkel, Richard S.;Swoboda, Kathryn J.;Gappmaier, Eduard;Howard, Michael T.;Day, John W.;McDonald, Craig;McNally, Elizabeth M.;Weiss, Robert B.
通讯作者：
Weiss, Robert B.
遗传对人体组织基因表达的影响。
影响因子：
64.8
作者：
GTEx Consortium;Laboratory, Data Analysis &Coordinating Center (LDACC)—Analysis Working Group;Statistical Methods groups—Analysis Working Group;Enhancing GTEx (eGTEx) groups;NIH Common Fund;NIH/NCI;NIH/NHGRI;NIH/NIMH;NIH/NIDA;Biospecimen Collection Source Site—NDRI;Biospecimen Collection Source Site—RPCI;Biospecimen Core Resource—VARI;Brain Bank Repository—University of Miami Brain Endowment Bank;Leidos Biomedical—Project Management;ELSI Study;Genome Browser Data Integration &Visualization—EBI;Genome Browser Data Integration &Visualization—UCSC Genomics Institute, University of California Santa Cruz;Lead analysts:;Laboratory, Data Analysis &Coordinating Center (LDACC):;NIH program management:;Biospecimen collection:;Pathology:;eQTL manuscript working group:;Battle A;Brown CD;Engelhardt BE;Montgomery SB
通讯作者：
Montgomery SB
影响因子：
64.5
作者：
Hnisz D;Abraham BJ;Lee TI;Lau A;Saint-André V;Sigova AA;Hoke HA;Young RA
通讯作者：
Young RA
影响因子：
15.9
作者：
Heydemann, Ahlke;Ceco, Ermelinda;McNally, Elizabeth M.
通讯作者：
McNally, Elizabeth M.
影响因子：
82.9
作者：
Cohn, Ronald D.;van Erp, Christel;Dietz, Harry C.
通讯作者：
Dietz, Harry C.