Search PubMed⌕ Search
Home/Archive/PubMed

PubMed · 42387303

Identification of a Functional CYP2C8 Variant Allele that Alters Splicing, Reduces Protein Expression, and Increases Drug Exposure.

Anssi J H Mykkänen·Päivi Hirvensalo·Kathrin Klein·Dorota Kaminska·Markus Grube·Tuija Tapaninen·Johanna I Kiiski·Mikko Neuvonen·Ville T Männistö·Jussi Pihlajamäki·Mladen Tzvetkov·Matthias Schwab·Aleksi Tornio·Janne T Backman·Mikko Niemi
View original source ↗Export metadata ↓

Abstract

This study investigated genetic determinants of the pharmacokinetics of the CYP2C8 index drugs repaglinide and gemfibrozil, and their interaction in healthy participants. Sequencing data from a study with montelukast revealed a novel functional CYP2C8 allele (rs2071426, CYP2C8*19), predicted to create an intronic splice donor site. In human liver samples, CYP2C8*19 associated with transcript-specific changes in CYP2C8 mRNA expression, reduced CYP2C8 protein expression, and decreased enzyme activity. Consistently, participants with the CYP2C8*19/*19 genotype had 45% greater area under the plasma repaglinide concentration-time curve from time zero to infinity (AUC0-&#x221e;) than participants with CYP2C8*1/*1 (P&#x2009;=&#x2009;1.6&#x2009;&#xd7;&#x2009;10-4). Participants with CYP2C8*1/*3 had 26% smaller AUC0-&#x221e; (P&#x2009;=&#x2009;0.0033) and those with CYP2C8*1/*4 had 51% greater AUC0-&#x221e; (P&#x2009;=&#x2009;8.2&#x2009;&#xd7;&#x2009;10-4). The fold increase in repaglinide AUC0-&#x221e; caused by gemfibrozil was 36% (P&#x2009;=&#x2009;1.3&#x2009;&#xd7;&#x2009;10-4) smaller in CYP2C8*19/*19 participants than in CYP2C8*1/*1 participants. In a genome-wide association study (GWAS), SLCO1B1 c.521&#x2009;T>C (rs4149056) associated with increased repaglinide AUC0-&#x221e; (P&#x2009;=&#x2009;4.5&#x2009;&#xd7;&#x2009;10-15; n&#x2009;=&#x2009;172) and SLCO1A2 variants associated with decreased AUC0-&#x221e; (P&#x2009;<&#x2009;10-8). In a GWAS of repaglinide after gemfibrozil pretreatment, SLCO1C1 variants associated with decreased AUC0-&#x221e; (P&#x2009;<&#x2009;1.6&#x2009;&#xd7;&#x2009;10-8; n&#x2009;=&#x2009;66). Participants with the poor function SLCO1B1 genotype showed a 32% smaller fold increase in repaglinide AUC0-&#x221e; following gemfibrozil than participants with the normal function SLCO1B1 genotype (P&#x2009;=&#x2009;0.0045). This study characterizes CYP2C8*19 as a novel decreased function allele and shows that CYP2C8 and SLCO1B1 genotypes affect the gemfibrozil-repaglinide interaction.

Explore related subjects

HumansCytochrome P-450 CYP2C8GemfibrozilMalePiperidinesAllelesCarbamatesFemaleAdultArea Under CurveGenotypeRNA SplicingLiver-Specific Organic Anion Transporter 1Cytochrome P-450 CYP2C8 InhibitorsCyclopropanesYoung AdultPolymorphism, Single NucleotideLiverHypoglycemic AgentsDrug InteractionsJournal ArticleResearch Support, Non-U.S. Gov't

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Anssi J H Mykk&#xe4;nen, P&#xe4;ivi Hirvensalo, Kathrin Klein, Dorota Kaminska, Markus Grube, Tuija Tapaninen, Johanna I Kiiski, Mikko Neuvonen, Ville T M&#xe4;nnist&#xf6;, Jussi Pihlajam&#xe4;ki, Mladen Tzvetkov, Matthias Schwab, Aleksi Tornio, Janne T Backman, Mikko Niemi. 2026-07-01. Identification of a Functional CYP2C8 Variant Allele that Alters Splicing, Reduces Protein Expression, and Increases Drug Exposure.. https://doi.org/10.1002/cpt.70376

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related citations

PubMed2027

Global Genomic Surveillance.

Global genomic surveillance has emerged as a foundational pillar of public health in the twenty-first century, enabling real-time tracking of pathogen evolution and informing outbreak response. This chapter examines the strategic architecture of global genomic surveillance, focusing on its application to arboviruses such as chikungunya virus (CHIKV). It explores the integration of genomic data with epidemiological, clinical, and environmental information within a One Health framework, while addressing critical challenges in governance, equity, and interoperability. The discussion covers the entire genomic surveillance workflow, from sample collection and sequencing to bioinformatic analysis and phylogenetic inference, and highlights the transformative role of artificial intelligence (AI) in predictive surveillance. By analyzing global initiatives, operational barriers, and emerging technologies, this chapter underscores the necessity of sustainable, equitable, and interoperable genomic systems to proactively address current and future infectious disease threats.

Humans↗
PubMed2027

Systematic Dissection of Key Driver Perturbation Signatures in Single Cells via ECCITE-seq.

CRISPR screens, such as expanded CRISPR-compatible cellular indexing of transcriptomes and epitopes by sequencing (ECCITE-seq), enable the simultaneous measurement of transcriptomes, gRNA identity, and cell-surface protein expression at single-cell resolution to systematically interrogate gene function. This platform provides a powerful and scalable experimental approach for validating disease-associated regulators identified by large-scale association studies and other computational methods, including network-based analyses of multi-omics data. Here, as an example application, we describe an ECCITE-seq framework to characterize the transcriptomic consequences of perturbing multiple neuronal key driver genes associated with Alzheimer's disease (AD) in human-induced pluripotent stem cell (hiPSC)-derived neurons. More broadly, by integrating customized pooled gRNA libraries with different CRISPR effectors across multiple cell types, this approach allows for the assessment of the regulatory impact of candidate genes implicated in development and disease processes.

Humans↗
PubMed2027

Identification of Genome-Wide Chromatin Structural Aberration in Cancer by Hi-C Analysis.

Aberrant three-dimensional genome organization is a hallmark of cancer, often driving oncogene activation through mechanisms such as enhancer hijacking. High-throughput chromosome conformation capture (Hi-C) maps these interactions on a genome-wide scale. Unlike earlier dilution-based methods, in situ Hi-C performs proximity ligation within intact nuclei, minimizing random ligation noise and enabling fine-scale structure detection. This chapter describes an optimized in situ Hi-C protocol tailored for cancer cell lines using MboI digestion and biotin-mediated pull-down to generate high-complexity libraries. We further outline a computational workflow that extends beyond standard topological mapping of compartments and topologically associating domains to identify cancer-specific aberrations. Specifically, we focus on detecting chromosomal rearrangements (structural variants) and characterizing the distinct circular topology of extrachromosomal DNA. This integrated experimental and analytical framework provides the necessary tools to dissect the spatial dysregulation underlying tumor evolution.

Humans↗