The splice site variant rs11078928 may be associated with a genotype-dependent alteration in expression of GSDMB transcriptsReport as inadecuate




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BMC Genomics

, 14:627

Human and rodent genomics

Abstract

BackgroundMany genetic variants have been associated with susceptibility to complex traits by genome wide association studies GWAS, but for most, causal genes and mechanisms of action have yet to be elucidated. Using bioinformatics, we identified index and proxy variants associated with autoimmune disease susceptibility, with the potential to affect splicing of candidate genes. PCR and sequence analysis of whole blood RNA samples from population controls was then carried out for the 8 most promising variants to determine the effect of genetic variation on splicing of target genes.

ResultsWe identified 31 splice site SNPs with the potential to affect splicing, and prioritised 8 to determine the effect of genotype on candidate gene splicing. We identified that variants rs11078928 and rs2014886 were associated with altered splicing of the GSDMB and TSFM genes respectively. rs11078928, present in the asthma and autoimmune disease susceptibility locus on chromosome 17q12-21, was associated with the production of a novel Δ exon5-8 transcript of the GSDMB gene, and a separate decrease in the percentage of transcripts with inclusion of exon 6, whereas the multiple sclerosis susceptibility variant rs2014886, was associated with an alternative TFSM transcript encompassing a short cryptic exon within intron 2.

ConclusionsOur findings demonstrate the utility of a bioinformatic approach in identification and prioritisation of genetic variants effecting splicing of their host genes, and suggest that rs11078928 and rs2014886 may affect the splicing of the GSDMB and TSFM genes respectively.

KeywordsGSDMB Rs11078928 Asthma Autoimmune disease GWAS SNP Alternative mRNA splicing AbbreviationsSNPSingle nucleotide polymorphism

GWASGenome Wide Association Studies

LDLinkage disequilibrium

GSDMBGasdermin B

TSFMTs translation elongation factor, mitochondrial

WTWild-type

MTMutant

NVNovel variant

LCLLymphoblastoid cell line

Electronic supplementary materialThe online version of this article doi:10.1186-1471-2164-14-627 contains supplementary material, which is available to authorized users.

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