Deleterious genetic variants in ciliopathy genes increase risk of ritodrine-induced cardiac and pulmonary side effects

Seo, Hiromi; Kwon, Eun Jin; You, Young Ah; Park, Yoomi; Min, Byung Joo; Yoo, Kyunghun; Hwang, Han Sung; Kim, Ju Han; Kim, Young Ju

doi:10.1186/s12920-018-0323-4

Cited by 16 publications

(15 citation statements)

References 36 publications

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“…[17] The GVB score, defined as the geometric mean of the SIFT scores for the set of coding variants in a gene, is applied to estimate the overall impact of all deleterious variants in the gene. [21] This method operates under the hypothesis that variants that potentially change protein function are not assured, but may cause deleterious phenotypes. [22] A lower GVB score represents an increased likelihood of a variant to be more deleterious to the function of the protein encoded by the gene.…”

Section: Methodsmentioning

confidence: 99%

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PG-path: Modeling and personalizing pharmacogenomics-based pathways

Hong

Kim

2020

PLoS ONE

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A pharmacogenomics-based pathway represents a series of reactions that occur between drugs and genes in the human body after drug administration. PG-path is a pharmacogenomics-based pathway that standardizes and visualizes the components (nodes) and actions (edges) involved in pharmacokinetic and pharmacodynamic processes. It provides an intuitive understanding of the drug response in the human body. A pharmacokinetic pathway visualizes the absorption, distribution, metabolism, and excretion (ADME) at the systemic level, and a pharmacodynamic pathway shows the action of the drug in the target cell at the cellular-molecular level. The genes in the pathway are displayed in locations similar to those inside the body. PG-path allows personalized pathways to be created by annotating each gene with the overall impact degree of deleterious variants in the gene. These personalized pathways play a role in assisting tailored individual prescriptions by predicting changes in the drug concentration in the plasma. PG-path also supports counseling for personalized drug therapy by providing visualization and documentation.

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Section: Methodsmentioning

confidence: 99%

“…[22] A lower GVB score represents an increased likelihood of a variant to be more deleterious to the function of the protein encoded by the gene. [21,22]…”

Section: Methodsmentioning

confidence: 99%

PG-path: Modeling and personalizing pharmacogenomics-based pathways

Hong

Kim

2020

PLoS ONE

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“…Gene-wise variant burden (GVB) analysis was performed to evaluate the aggregated impact of both common and rare variants [7,11,12]. The GVB of a coding gene for each individual was defined as the geometric mean of the SIFT scores of the coding variants (SIFT score < 0.7) in the coding gene, where GVB G denotes the GVB score of gene G. The powers of GVB NUDT15 , GVB TPMT , and GVB CRIM1 for predicting the last-cycle 6-MP DIP were systematically evaluated by analyzing ROC (receiver operating characteristic) curves across seven DIP cutoffs (i.e., 15%, 25%, 35%, 45%, 60%, 80%, and 100%) in terms of the areas under the ROC curves (AUCs) in the discovery, replication, and combined cohorts before and after controlling for the effects of the other two genes.…”

Section: Single-and Multigene Prediction Accuracies For Thiopurine Tomentioning

confidence: 99%

Homozygote CRIM1 variant is associated with thiopurine-induced neutropenia in leukemic patients with both wildtype NUDT15 and TPMT

et al. 2020

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Background: NUDT15 and TPMT variants are strong genetic determinants of thiopurine-induced hematological toxicity that results in therapeutic failure in pediatric acute lymphoblastic leukemia (ALL). However, many patients with both wild-type (WT) NUDT15 and TPMT still suffer from thiopurine toxicity and therapeutic failure. Methods: Whole-exome sequencing was done for discovery (N = 244) and replication (N = 76) cohorts. Age-and sex-adjusted multiple regression analyses of both WT patients were performed to identify (p < 0.01, N = 188 for discovery) and validate (p < 0.05, N = 52 for replication) candidate variants for the tolerated last-cycle 6-mercaptopurine (6-MP) dose intensity percentage (DIP). Both independent and additive effects of the candidate variants on wellknown NUDT15 and TPMT were evaluated by multigene prediction models. Results: Among the 12 candidate variants from the discovery phase, the rs3821169 variant of the gene encoding Cysteine-Rich Transmembrane BMP Regulator 1 (CRIM1) was successfully replicated (p < 0.05). It showed high interethnic variability with an impressively high allele frequency in East Asians (T = 0.255) compared to Africans (0.001), Americans (0.02), Europeans (0.009), and South Asians (0.05). Homozygote carriers of the CRIM1 rs3821169 variant (N = 12, 5%) showed significantly lower last-cycle 6-MP DIPs in the discovery, replication, and combined cohorts (p = 0.025, 0.013, and 0.001, respectively). The traditional two-gene model (NUDT15 and TPMT) for predicting 6-MP DIP < 25% was outperformed by the three-gene model that included CRIM1, in terms of the area under the receiver operating characteristic curve (0.734 vs. 0.665), prediction accuracy (0.759 vs. 0.756), sensitivity (0.636 vs. 0.523), positive predictive value (0.315 vs. 0.288), and negative predictive value (0.931 vs. 0.913). Conclusions: The CRIM1 rs3821169 variant is suggested to be an independent and/or additive genetic determinant of thiopurine toxicity beyond NUDT15 and TPMT in pediatric ALL.

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“…In the current study, we examined the genetic variants associated with ritodrine-induced pulmonary edema. Using WES data, we compared gene-wise variant burden (GVB) [9][10][11] for each of the 19,729 protein-coding gene between the 16 patients suffering from ritodrineinduced pulmonary edema and their 16 matched controls without symptoms after drug use under similar gestational conditions. In silico analysis of deleterious variants was performed, producing two putative East Asian population-specific variants, rs2229291 (CPT2) and rs2229126 (ADRA1A), located in genes with roles compatible with tocolytic-associated pulmonary edema.…”

Section: Introductionmentioning

confidence: 99%

Identifying genetic variants associated with ritodrine-induced pulmonary edema

et al. 2020

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Introduction Ritodrine is one of the most commonly used tocolytics in preterm labor, acting as a ß2-adrenergic agonist that reduces intracellular calcium levels and prevents myometrial activation. Ritodrine infusion can result in serious maternal complications, and pulmonary edema is a particular concern among these. The cause of pulmonary edema following ritodrine treatment is multifactorial; however, the contributing genetic factors remain poorly understood. This study investigates the genetic variants associated with ritodrine-induced pulmonary edema. Methods In this case-control study, 16 patients who developed pulmonary edema during ritodrine infusion [case], and 16 pregnant women who were treated with ritodrine and did not develop pulmonary edema [control] were included. The control pregnant women were selected after matching for plurality and gestational age at the time of tocolytic use. Maternal blood was collected during admission for tocolytic treatment, and whole exome sequencing was performed with the stored blood samples. Results Gene-wise variant burden (GVB) analysis resulted in a total of 71 candidate genes by comparing the cumulative effects of multiple coding variants for 19729 protein-coding genes between the patients with pulmonary edema and the matched controls. Subsequent data analysis selected only the statistically significant and deleterious variants compatible with ritodrine-induced pulmonary edema. Two final candidate variants in CPT2 and ADRA1A were confirmed by Sanger sequencing. Conclusions We identified new potential variants in genes that play a role in cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) regulation, which supports their putative involvement in the predisposition to ritodrine-induced pulmonary edema in pregnant women.

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Deleterious genetic variants in ciliopathy genes increase risk of ritodrine-induced cardiac and pulmonary side effects

Cited by 16 publications

References 36 publications

PG-path: Modeling and personalizing pharmacogenomics-based pathways

PG-path: Modeling and personalizing pharmacogenomics-based pathways

Homozygote CRIM1 variant is associated with thiopurine-induced neutropenia in leukemic patients with both wildtype NUDT15 and TPMT

Identifying genetic variants associated with ritodrine-induced pulmonary edema

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