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Association between functional variants in BIRC5/survivin gene 3' untranslated region and mRNA expression in lymphoblastoid cell lines.

ABSTRACT: Baculoviral inhibitor of apoptosis repeat-containing 5 (BIRC5)/survivin genetic microRNA (miRNA) binding site variants in the 3' untranslated region (3'UTR) are known to be significantly associated with cancer risk. However, the roles of genetic variants in BIRC5/survivin gene 3'UTRs and post-transcriptional regulation have not been elucidated. In the present study, we revealed that rs1042489, rs1042542, rs17882360, rs2239680, rs2661694 and rs4789560 in the BIRC5/survivin 3'UTR have potential miRNA binding sites using bioinformatics analysis. However, only rs1042489 was significantly associated with BIRC5/survivin mRNA expression in lymphoblastoid cell lines (P=0.030); rs1042489 may be a putative variant mediating the post-transcriptional regulation of the target BIRC5/survivin gene. An in-depth understanding of how 3'UTR variants regulate BIRC5/survivin activity is expected to pave the way to targeting the BIRC5/survivin pathway in cancer therapy.

SUBMITTER: Pu F

PROVIDER: S-EPMC4579978 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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Association between functional variants in BIRC5/survivin gene 3' untranslated region and mRNA expression in lymphoblastoid cell lines.

Pu Feifei F Pu Feifei F Shao Zengwu Z Yang Shuhua S Liu Jianxiang J Lin Song S Ma Xiucai X Yang Haofei H

Oncology letters 20150717 4

Baculoviral inhibitor of apoptosis repeat-containing 5 (BIRC5)/survivin genetic microRNA (miRNA) binding site variants in the 3' untranslated region (3'UTR) are known to be significantly associated with cancer risk. However, the roles of genetic variants in BIRC5/survivin gene 3'UTRs and post-transcriptional regulation have not been elucidated. In the present study, we revealed that rs1042489, rs1042542, rs17882360, rs2239680, rs2661694 and rs4789560 in the BIRC5/survivin 3'UTR have potential mi ...[more]

PMID: 26622842

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Project description:BackgroundStatins are widely prescribed to lower plasma low-density lipoprotein cholesterol levels. Though statins reduce cardiovascular disease risk overall, statin efficacy varies, and some people experience adverse side effects while on statin treatment. Statins also have pleiotropic effects not directly related to their cholesterol-lowering properties, but the mechanisms are not well understood. To identify potential genetic modulators of clinical statin response, we looked for genetic variants associated with statin-induced changes in gene expression (differential eQTLs or deQTLs) in lymphoblastoid cell lines (LCLs) derived from participants of the Cholesterol and Pharmacogenetics (CAP) 40 mg/day 6-week simvastatin clinical trial. We exposed CAP LCLs to 2 μM simvastatin or control buffer for 24 h and performed polyA-selected, strand-specific RNA-seq. Statin-induced changes in gene expression from 259 European ancestry or 153 African American ancestry LCLs were adjusted for potential confounders prior to association with genotyped and imputed genetic variants within 1 Mb of each gene's transcription start site.ResultsFrom the deQTL meta-analysis of the two ancestral populations, we identified significant cis-deQTLs for 15 genes (TBC1D4, MDGA1, CHI3L2, OAS1, GATM, ASNSD1, GLUL, TDRD12, PPIP5K2, OAS3, SERPINB1, ANKDD1A, DTD1, CYFIP2, and GSDME), eight of which were significant in at least one of the ancestry subsets alone. We also conducted eQTL analyses of the endogenous (control-treated), statin-treated, and average of endogenous and statin-treated LCL gene expression levels. We identified eQTLs for approximately 6000 genes in each of the three (endogenous, statin-treated, and average) eQTL meta-analyses, with smaller numbers identified in the ancestral subsets alone.ConclusionsSeveral of the genes in which we identified deQTLs have functions in human health and disease, such as defense from viruses, glucose regulation, and response to chemotherapy drugs. This suggests that DNA variation may play a role in statin effects on various health outcomes. These findings could prove useful to future studies aiming to assess benefit versus risk of statin treatment using individual genetic profiles.

Dataset Information

Association between functional variants in BIRC5/survivin gene 3' untranslated region and mRNA expression in lymphoblastoid cell lines.

Publications

Association between functional variants in BIRC5/survivin gene 3' untranslated region and mRNA expression in lymphoblastoid cell lines.

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