Deleterious genetic variants in ciliopathy genes increase risk of ritodrine-induced cardiac and pulmonary side effects
Abstract 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...
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doaj-cf81a2ded3b245d39344ef3df5fed5e02021-04-02T04:03:34ZengBMCBMC Medical Genomics1755-87942018-01-0111111010.1186/s12920-018-0323-4Deleterious genetic variants in ciliopathy genes increase risk of ritodrine-induced cardiac and pulmonary side effectsHeewon Seo0Eun Jin Kwon1Young-Ah You2Yoomi Park3Byung Joo Min4Kyunghun Yoo5Han-Sung Hwang6Ju Han Kim7Young Ju Kim8Seoul National University Biomedical Informatics (SNUBI), Div. of Biomedical Informatics, Seoul National University College of MedicineMedical Research Institute, College of Medicine, Ewha Womans UniversityMedical Research Institute, College of Medicine, Ewha Womans UniversitySeoul National University Biomedical Informatics (SNUBI), Div. of Biomedical Informatics, Seoul National University College of MedicineSeoul National University Biomedical Informatics (SNUBI), Div. of Biomedical Informatics, Seoul National University College of MedicineSeoul National University Biomedical Informatics (SNUBI), Div. of Biomedical Informatics, Seoul National University College of MedicineDepartment of Obstetrics and Gynecology, Konkuk University Medical Center, Konkuk University School of MedicineSeoul National University Biomedical Informatics (SNUBI), Div. of Biomedical Informatics, Seoul National University College of MedicineDepartment of Obstetrics and Gynecology, College of Medicine, Ewha Womans University Mok Dong HospitalAbstract 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, Ca2+-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.http://link.springer.com/article/10.1186/s12920-018-0323-4RitodrinePulmonary oedemaWhole-exome sequencingCiliopathyJoubert syndrome |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Heewon Seo Eun Jin Kwon Young-Ah You Yoomi Park Byung Joo Min Kyunghun Yoo Han-Sung Hwang Ju Han Kim Young Ju Kim |
spellingShingle |
Heewon Seo Eun Jin Kwon Young-Ah You Yoomi Park Byung Joo Min Kyunghun Yoo Han-Sung Hwang Ju Han Kim Young Ju Kim Deleterious genetic variants in ciliopathy genes increase risk of ritodrine-induced cardiac and pulmonary side effects BMC Medical Genomics Ritodrine Pulmonary oedema Whole-exome sequencing Ciliopathy Joubert syndrome |
author_facet |
Heewon Seo Eun Jin Kwon Young-Ah You Yoomi Park Byung Joo Min Kyunghun Yoo Han-Sung Hwang Ju Han Kim Young Ju Kim |
author_sort |
Heewon Seo |
title |
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_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_sort |
deleterious genetic variants in ciliopathy genes increase risk of ritodrine-induced cardiac and pulmonary side effects |
publisher |
BMC |
series |
BMC Medical Genomics |
issn |
1755-8794 |
publishDate |
2018-01-01 |
description |
Abstract 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, Ca2+-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. |
topic |
Ritodrine Pulmonary oedema Whole-exome sequencing Ciliopathy Joubert syndrome |
url |
http://link.springer.com/article/10.1186/s12920-018-0323-4 |
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