Rare genetic variability in human drug target genes modulates drug response and can guide precision medicine

Zhou, Yitian; Arribas, Gabriel Herras; Turku, Ainoleena; Jürgenson, Tuuli; Mkrtchian, Souren; Krebs, Kristi; Wáng, Yì; Svobodová, Barbora; Milani, Lili; Schulte, Gunnar; Korábečný, Jan; Gastaldello, Stefano; Lauschke, Volker M.

doi:10.1126/sciadv.abi6856

Cited by 20 publications

(13 citation statements)

References 54 publications

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“…In G‐protein coupled receptors (GPCRs), which constitute the targets of 34% of approved drugs, sequencing has identified 14 192 missense variants, covering approximately 25% of all nucleotide positions across the entire GPCRome 40 . Further drug target sequencing projects showed that rare variants are predominant also in other PD genes with around 800 000 genetic variants being identified across all FDA‐approved drug targets (98.1% of which were rare with MAF < 1%) 41,42,45 …”

Section: Pharmacogenomic Variability Beyond Well‐characterized Polymo...mentioning

confidence: 99%

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A paradigm shift in pharmacogenomics: From candidate polymorphisms to comprehensive sequencing

Zhou

Koutsilieri

Eliasson

et al. 2022

Basic Clin Pharma Tox

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Genetic factors have long been recognized as important determinants of interindividual variability in drug efficacy and toxicity. However, despite the increasing number of established gene-drug associations, candidate polymorphisms can only explain a fraction of the genetically encoded functional variability in drug disposition. Advancements in genetic profiling methods now allow to analyse the landscape of human pharmacogenetic variations comprehensively, which opens new opportunities to identify novel factors that could explain the "missing heritability." Here, we provide an updated overview of the landscape of pharmacogenomic variability based on recent analyses of population-scale sequencing projects. We then summarize the current state-of-the-art how the functional consequences of variants with unknown effects can be quantitatively estimated while discussing challenges and peculiarities that are specific to pharmacogenes. In the last sections, we discuss the importance of considering ethnogeographic diversity to provide equitable benefits of pharmacogenomics and summarize current roadblocks for the implementation of sequencing-based guidance of clinical decision-making.Based on the current state of the field, we conclude that testing is likely to gradually shift from the interrogation of selected candidate polymorphisms to comprehensive sequencing, which allows to consider the full spectrum of pharmacogenomic variations for a true personalization of genomic prescribing.

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Section: Pharmacogenomic Variability Beyond Well‐characterized Polymo...mentioning

confidence: 99%

“… 40 Further drug target sequencing projects showed that rare variants are predominant also in other PD genes with around 800 000 genetic variants being identified across all FDA‐approved drug targets (98.1% of which were rare with MAF < 1%). 41 , 42 , 45 …”

Section: Pharmacogenomic Variability Beyond Well‐characterized Polymo...mentioning

confidence: 99%

A paradigm shift in pharmacogenomics: From candidate polymorphisms to comprehensive sequencing

Zhou

Koutsilieri

Eliasson

et al. 2022

Basic Clin Pharma Tox

Self Cite

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“…[ 31 ] Specifically, the mutation in the drug‐binding pocket directly influences drug‐target interactions by modifying pocket geometry, topology, or physiochemical interactions. [ 32 ]…”

Section: Discussionmentioning

confidence: 99%

“…[31] Specifically, the mutation in the drug-binding pocket directly influences drug-target interactions by modifying pocket geometry, topology, or physiochemical interactions. [32] For 044, currently undergoing phase II clinical trials, holds great promise as the first anti-metastatic drug. [26] However, the emergence of resistance is a likely eventuality.…”

Section: The Prediction Of Drug Resistance Mutationmentioning

confidence: 99%

Prediction of The Binding Mode of NP‐G2‐044 Targeting Fascin and Its Drug Resistance Mutations

Pan,

Wang,

et al. 2023

Advcd Theory and Sims

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Fascin is a major actin‐binding protein (ABP) in filopodia and is highly expressed in metastatic tumors. To inhibit its function, a potent inhibitor called NP‐G2‐044 is currently in phase II clinical trials. However, the binding mode of this inhibitor remains unclear. In this study, the binding mode of NP‐G2‐044 in fascin and predicted drug resistance mutations is investigated. The rough binding position and pose can be deduce based on information from its derivant NP‐G2‐029, whose crystal structure with fascin has been solved. Molecular docking, free energy perturbation (FEP) simulation and metadynamics simulation are performed to confirm the binding pose. Based on the molecular docking results, two binding modes of NP‐G2‐044, pose A and B, are obtained, with pose A being more favorable. For pose A, the planar indazole moiety has the same orientation as NP‐G2‐029 in the complex with fascin, while for pose B, it rotates ≈90°. FEP and metadynamics simulations indicate that both binding poses are possible. Relative binding free energies for mutation effects calculated by FEP predict E215A and R217A are drug resistance mutations. These findings are important for further drug development targeting fascin.

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“…1% and 0.1% of analyzed probesets comprising genes, pseudogenes and precursor microRNAs (n = 32,232) were significantly correlated (absolute r S > 0.04) to SLC10A1 mRNA expression (measured by qPCR) and NTCP protein levels, respectively. Then, we investigated whether pharmacogenes (n = 344) [63], target genes (n = 564) [64] or precursor miRNAs (n = 1372) were correlated with NTCP expression. The significantly correlated genes (adjusted p < 0.05, absolute r S > 0.4) predominately belonged to the pharmacogene group (SLC10A1 mRNA = 5.81%; NTCP protein = 1.45%; Figure 6A).…”

Section: Genome-wide Expression Correlation Analysis and Gene Set Enr...mentioning

confidence: 99%

Hepatic Expression of the Na+-Taurocholate Cotransporting Polypeptide Is Independent from Genetic Variation

Tremmel

Nies

Eijck

et al. 2022

IJMS

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The hepatic Na+-taurocholate cotransporting polypeptide NTCP/SLC10A1 is important for the uptake of bile salts and selected drugs. Its inhibition results in increased systemic bile salt concentrations. NTCP is also the entry receptor for the hepatitis B/D virus. We investigated interindividual hepatic SLC10A1/NTCP expression using various omics technologies. SLC10A1/NTCP mRNA expression/protein abundance was quantified in well-characterized 143 human livers by real-time PCR and LC-MS/MS-based targeted proteomics. Genome-wide SNP arrays and SLC10A1 next-generation sequencing were used for genomic analyses. SLC10A1 DNA methylation was assessed through MALDI-TOF MS. Transcriptomics and untargeted metabolomics (UHPLC-Q-TOF-MS) were correlated to identify NTCP-related metabolic pathways. SLC10A1 mRNA and NTCP protein levels varied 44-fold and 10.4-fold, respectively. Non-genetic factors (e.g., smoking, alcohol consumption) influenced significantly NTCP expression. Genetic variants in SLC10A1 or other genes do not explain expression variability which was validated in livers (n = 50) from The Cancer Genome Atlas. The identified two missense SLC10A1 variants did not impair transport function in transfectants. Specific CpG sites in SLC10A1 as well as single metabolic alterations and pathways (e.g., peroxisomal and bile acid synthesis) were significantly associated with expression. Inter-individual variability of NTCP expression is multifactorial with the contribution of clinical factors, DNA methylation, transcriptional regulation as well as hepatic metabolism, but not genetic variation.

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Rare genetic variability in human drug target genes modulates drug response and can guide precision medicine

Cited by 20 publications

References 54 publications

A paradigm shift in pharmacogenomics: From candidate polymorphisms to comprehensive sequencing

A paradigm shift in pharmacogenomics: From candidate polymorphisms to comprehensive sequencing

Prediction of The Binding Mode of NP‐G2‐044 Targeting Fascin and Its Drug Resistance Mutations

Hepatic Expression of the Na+-Taurocholate Cotransporting Polypeptide Is Independent from Genetic Variation

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