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Ann Neurol. 2018 Aug;84(2):234-245. doi: 10.1002/ana.25283. Epub 2018 Aug 25.

Long-range genomic regulators of THBS1 and LTBP4 modify disease severity in duchenne muscular dystrophy.

Author information

1
Department of Human Genetics, University of Utah, Salt Lake City, UT.
2
Battelle Center for Mathematical Medicine, Columbus, OH.
3
Department of Pediatrics, The Ohio State University, Columbus, OH.
4
Department of Statistics, The Ohio State University, Columbus, OH.
5
Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, OH.
6
Department of Neurology, The Ohio State University, Columbus, OH.

Abstract

OBJECTIVE:

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 (TGFβ)-binding protein 4 (LTBP4) were associated with reduced TGFβ signaling and prolonged ambulation (p = 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.

METHODS:

We performed a genome-wide association study (GWAS) for single-nucleotide polymorphisms (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.

RESULTS:

Despite the small sample size, two loci associated with prolonged ambulation met genome-wide significance and were tagged by rs2725797 (chr15, p = 6.6 × 10-9 ) and rs710160 (chr19, p = 4.7 × 10-8 ). Gene expression and chromatin interaction data indicated that the latter SNP tags regulatory variants of LTBP4, whereas the former SNP tags regulatory variants of thrombospondin-1 (THBS1): an activator of TGFβ signaling by direct binding to LTBP4 and an inhibitor of proangiogenic nitric oxide signaling.

INTERPRETATION:

Together with previous 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. Ann Neurol 2018;84:234-245.

PMID:
30014611
PMCID:
PMC6168392
DOI:
10.1002/ana.25283
[Indexed for MEDLINE]
Free PMC Article

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