Evidence map›Paper›PMID 29793534›Full record

ArticleHuman genomics2018

Integrating rare genetic variants into pharmacogenetic drug response predictions.

Magnus Ingelman-Sundberg, Souren Mkrtchian, Yitian Zhou, Volker M Lauschke

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In one paragraph

Article in Human genomics, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 108 papers, 3 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
108citing papers in PubMed, 3 pooled it
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

108 citing papers in PubMed, 3 syntheses or guidelines pooled it.

  1. Pooled it
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  10. Hereditary spastic paraplegia: from decades of therapy to future innovations.Therapeutic advances in neurological disorders · 2026
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  18. International journal of molecular sciences · 2024
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48 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

4 authors.

Magnus Ingelman-SundbergDepartment of Physiology and Pharmacology, Section of Pharmacogenetics, Karolinska Institutet, SE-171 77, Stockholm, Sweden.
Souren MkrtchianDepartment of Physiology and Pharmacology, Section of Pharmacogenetics, Karolinska Institutet, SE-171 77, Stockholm, Sweden.
Yitian ZhouDepartment of Physiology and Pharmacology, Section of Pharmacogenetics, Karolinska Institutet, SE-171 77, Stockholm, Sweden.
Volker M LauschkeDepartment of Physiology and Pharmacology, Section of Pharmacogenetics, Karolinska Institutet, SE-171 77, Stockholm, Sweden. volker.lauschke@ki.se.ORCID 0000-0002-1140-6204

Funding

H2020 European Research Council 668353Lennart Philipson Foundation 2017Vetenskapsrådet 2015-02760Vetenskapsrådet 2016-01153Vetenskapsrådet 2016-01154
6 · The paper itself

Abstract

backgroundVariability in genes implicated in drug pharmacokinetics or drug response can modulate treatment efficacy or predispose to adverse drug reactions. Besides common genetic polymorphisms, recent sequencing projects revealed a plethora of rare genetic variants in genes encoding proteins involved in drug metabolism, transport, and response.

resultsTo understand the global importance of rare pharmacogenetic gene variants, we mapped the variability in 208 pharmacogenes by analyzing exome sequencing data from 60,706 unrelated individuals and estimated the importance of rare and common genetic variants using a computational prediction framework optimized for pharmacogenetic assessments. Our analyses reveal that rare pharmacogenetic variants were strongly enriched in mutations predicted to cause functional alterations. For more than half of the pharmacogenes, rare variants account for the entire genetic variability. Each individual harbored on average a total of 40.6 putatively functional variants, rare variants accounting for 10.8% of these. Overall, the contribution of rare variants was found to be highly gene- and drug-specific. Using warfarin, simvastatin, voriconazole, olanzapine, and irinotecan as examples, we conclude that rare genetic variants likely account for a substantial part of the unexplained inter-individual differences in drug metabolism phenotypes.

conclusionsCombined, our data reveal high gene and drug specificity in the contributions of rare variants. We provide a proof-of-concept on how this information can be utilized to pinpoint genes for which sequencing-based genotyping can add important information to predict drug response, which provides useful information for the design of clinical trials in drug development and the personalization of pharmacological treatment.

Indexed as

Biomarkers, PharmacologicalExomeGenotypeHumansPharmacogeneticsPharmacogenomic VariantsPhenotypePolymorphism, Single NucleotideBiomarkers, PharmacologicalADME genesDrug responseGenetic variabilityPersonalized medicinePharmacogenetics

Identifiers

PMID29793534
PMCPMC5968569

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.