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Deleterious genetic variants in ciliopathy genes increase risk of ritodrine-induced cardiac and pulmonary side effects
BACKGROUND: Ritodrine is a commonly used tocolytic to prevent preterm labour. However, it can cause unexpected serious adverse reactions, such as pulmonary oedema, pulmonary congestion, and tachycardia. It is unknown whether such adverse reactions are associated with pharmacogenomic variants in pati...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5784607/ https://www.ncbi.nlm.nih.gov/pubmed/29368655 http://dx.doi.org/10.1186/s12920-018-0323-4 |
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author | Seo, Heewon Kwon, Eun Jin You, Young-Ah Park, Yoomi Min, Byung Joo Yoo, Kyunghun Hwang, Han-Sung Kim, Ju Han Kim, Young Ju |
author_facet | Seo, Heewon Kwon, Eun Jin You, Young-Ah Park, Yoomi Min, Byung Joo Yoo, Kyunghun Hwang, Han-Sung Kim, Ju Han Kim, Young Ju |
author_sort | Seo, Heewon |
collection | PubMed |
description | BACKGROUND: Ritodrine is a commonly used tocolytic to prevent preterm labour. However, it can cause unexpected serious adverse reactions, such as pulmonary oedema, pulmonary congestion, and tachycardia. It is unknown whether such adverse reactions are associated with pharmacogenomic variants in patients. METHODS: Whole-exome sequencing of 13 subjects with serious ritodrine-induced cardiac and pulmonary side-effects was performed to identify causal genes and variants. The deleterious impact of nonsynonymous substitutions for all genes was computed and compared between cases (n = 13) and controls (n = 30). The significant genes were annotated with Gene Ontology (GO), and the associated disease terms were categorised into four functional classes for functional enrichment tests. To assess the impact of distributed rare variants in cases with side effects, we carried out rare variant association tests with a minor allele frequency ≤ 1% using the burden test, the sequence Kernel association test (SKAT), and optimised SKAT. RESULTS: We identified 28 genes that showed significantly lower gene-wise deleteriousness scores in cases than in controls. Three of the identified genes—CYP1A1, CYP8B1, and SERPINA7—are pharmacokinetic genes. The significantly identified genes were categorized into four functional classes: ion binding, ATP binding, Ca(2+)-related, and ciliopathies-related. These four classes were significantly enriched with ciliary genes according to SYSCILIA Gold Standard genes (P < 0.01), thus representing ciliary genes. Furthermore, SKAT showed a marginal trend toward significance after Bonferroni correction with Joubert Syndrome ciliopathy genes (P = 0.05). With respect to the pharmacokinetic genes, rs1048943 (CYP1A1) and rs1804495 (SERPINA7) showed a significantly higher frequency in cases than controls, as determined by Fisher’s exact test (P < 0.05 and P < 0.01, respectively). CONCLUSIONS: Ritodrine-induced cardiac and pulmonary side effects may be associated with deleterious genetic variants in ciliary and pharmacokinetic genes. |
format | Online Article Text |
id | pubmed-5784607 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-57846072018-02-07 Deleterious genetic variants in ciliopathy genes increase risk of ritodrine-induced cardiac and pulmonary side effects Seo, Heewon Kwon, Eun Jin You, Young-Ah Park, Yoomi Min, Byung Joo Yoo, Kyunghun Hwang, Han-Sung Kim, Ju Han Kim, Young Ju BMC Med Genomics Research Article BACKGROUND: Ritodrine is a commonly used tocolytic to prevent preterm labour. However, it can cause unexpected serious adverse reactions, such as pulmonary oedema, pulmonary congestion, and tachycardia. It is unknown whether such adverse reactions are associated with pharmacogenomic variants in patients. METHODS: Whole-exome sequencing of 13 subjects with serious ritodrine-induced cardiac and pulmonary side-effects was performed to identify causal genes and variants. The deleterious impact of nonsynonymous substitutions for all genes was computed and compared between cases (n = 13) and controls (n = 30). The significant genes were annotated with Gene Ontology (GO), and the associated disease terms were categorised into four functional classes for functional enrichment tests. To assess the impact of distributed rare variants in cases with side effects, we carried out rare variant association tests with a minor allele frequency ≤ 1% using the burden test, the sequence Kernel association test (SKAT), and optimised SKAT. RESULTS: We identified 28 genes that showed significantly lower gene-wise deleteriousness scores in cases than in controls. Three of the identified genes—CYP1A1, CYP8B1, and SERPINA7—are pharmacokinetic genes. The significantly identified genes were categorized into four functional classes: ion binding, ATP binding, Ca(2+)-related, and ciliopathies-related. These four classes were significantly enriched with ciliary genes according to SYSCILIA Gold Standard genes (P < 0.01), thus representing ciliary genes. Furthermore, SKAT showed a marginal trend toward significance after Bonferroni correction with Joubert Syndrome ciliopathy genes (P = 0.05). With respect to the pharmacokinetic genes, rs1048943 (CYP1A1) and rs1804495 (SERPINA7) showed a significantly higher frequency in cases than controls, as determined by Fisher’s exact test (P < 0.05 and P < 0.01, respectively). CONCLUSIONS: Ritodrine-induced cardiac and pulmonary side effects may be associated with deleterious genetic variants in ciliary and pharmacokinetic genes. BioMed Central 2018-01-24 /pmc/articles/PMC5784607/ /pubmed/29368655 http://dx.doi.org/10.1186/s12920-018-0323-4 Text en © The Author(s). 2018 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Article Seo, Heewon Kwon, Eun Jin You, Young-Ah Park, Yoomi Min, Byung Joo Yoo, Kyunghun Hwang, Han-Sung Kim, Ju Han Kim, Young Ju Deleterious genetic variants in ciliopathy genes increase risk of ritodrine-induced cardiac and pulmonary side effects |
title | Deleterious genetic variants in ciliopathy genes increase risk of ritodrine-induced cardiac and pulmonary side effects |
title_full | Deleterious genetic variants in ciliopathy genes increase risk of ritodrine-induced cardiac and pulmonary side effects |
title_fullStr | Deleterious genetic variants in ciliopathy genes increase risk of ritodrine-induced cardiac and pulmonary side effects |
title_full_unstemmed | Deleterious genetic variants in ciliopathy genes increase risk of ritodrine-induced cardiac and pulmonary side effects |
title_short | Deleterious genetic variants in ciliopathy genes increase risk of ritodrine-induced cardiac and pulmonary side effects |
title_sort | deleterious genetic variants in ciliopathy genes increase risk of ritodrine-induced cardiac and pulmonary side effects |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5784607/ https://www.ncbi.nlm.nih.gov/pubmed/29368655 http://dx.doi.org/10.1186/s12920-018-0323-4 |
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