Evidence map›Paper›PMID 26021325›Full record

ArticleDrug metabolism and disposition: the biological fate of chemicals2015

The CYP2C19 Intron 2 Branch Point SNP is the Ancestral Polymorphism Contributing to the Poor Metabolizer Phenotype in Livers with CYP2C19*35 and CYP2C19*2 Alleles.

Amarjit S Chaudhry, Bhagwat Prasad, Yoshiyuki Shirasaka, Alison Fohner, David Finkelstein, Yiping Fan, Shuoguo Wang, Gang Wu, Eleni Aklillu, Sarah C Sim and 2 more

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Article in Drug metabolism and disposition: the biological fate of chemicals, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.

0numbers the graph read from it
0cells of the map it votes in
16citing papers in PubMed
4.0field-weighted citation impact, top 7% of its field
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

16 citing papers in PubMed, 27 citations in OpenAlex.

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  13. The effect ofExperimental and therapeutic medicine · 2018
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  15. Interindividual Variability in Cytochrome P450-Mediated Drug Metabolism.Drug metabolism and disposition: the biological fate of chemicals · 2016
    Review
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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

12 authors at 3 institutions in 2 countries.

Amarjit S ChaudhryDepartment of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee (A.S.C., E.G.S.); Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington (B.P., Y.S., A.F., K.E.T.); Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee (D.F., Y.F., S.W., G.W.); Department of Laboratory Medicine, Division of Clinical Pharmacology, Karolinska Institutet, Stockholm, Sweden (E.A.); and Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden (S.C.S.).
Bhagwat PrasadDepartment of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee (A.S.C., E.G.S.); Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington (B.P., Y.S., A.F., K.E.T.); Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee (D.F., Y.F., S.W., G.W.); Department of Laboratory Medicine, Division of Clinical Pharmacology, Karolinska Institutet, Stockholm, Sweden (E.A.); and Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden (S.C.S.).
Yoshiyuki ShirasakaDepartment of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee (A.S.C., E.G.S.); Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington (B.P., Y.S., A.F., K.E.T.); Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee (D.F., Y.F., S.W., G.W.); Department of Laboratory Medicine, Division of Clinical Pharmacology, Karolinska Institutet, Stockholm, Sweden (E.A.); and Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden (S.C.S.).
Alison FohnerDepartment of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee (A.S.C., E.G.S.); Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington (B.P., Y.S., A.F., K.E.T.); Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee (D.F., Y.F., S.W., G.W.); Department of Laboratory Medicine, Division of Clinical Pharmacology, Karolinska Institutet, Stockholm, Sweden (E.A.); and Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden (S.C.S.).
David FinkelsteinDepartment of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee (A.S.C., E.G.S.); Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington (B.P., Y.S., A.F., K.E.T.); Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee (D.F., Y.F., S.W., G.W.); Department of Laboratory Medicine, Division of Clinical Pharmacology, Karolinska Institutet, Stockholm, Sweden (E.A.); and Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden (S.C.S.).
Yiping FanDepartment of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee (A.S.C., E.G.S.); Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington (B.P., Y.S., A.F., K.E.T.); Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee (D.F., Y.F., S.W., G.W.); Department of Laboratory Medicine, Division of Clinical Pharmacology, Karolinska Institutet, Stockholm, Sweden (E.A.); and Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden (S.C.S.).
Shuoguo WangDepartment of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee (A.S.C., E.G.S.); Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington (B.P., Y.S., A.F., K.E.T.); Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee (D.F., Y.F., S.W., G.W.); Department of Laboratory Medicine, Division of Clinical Pharmacology, Karolinska Institutet, Stockholm, Sweden (E.A.); and Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden (S.C.S.).
Gang WuDepartment of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee (A.S.C., E.G.S.); Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington (B.P., Y.S., A.F., K.E.T.); Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee (D.F., Y.F., S.W., G.W.); Department of Laboratory Medicine, Division of Clinical Pharmacology, Karolinska Institutet, Stockholm, Sweden (E.A.); and Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden (S.C.S.).
Eleni AklilluDepartment of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee (A.S.C., E.G.S.); Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington (B.P., Y.S., A.F., K.E.T.); Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee (D.F., Y.F., S.W., G.W.); Department of Laboratory Medicine, Division of Clinical Pharmacology, Karolinska Institutet, Stockholm, Sweden (E.A.); and Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden (S.C.S.).
Sarah C SimDepartment of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee (A.S.C., E.G.S.); Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington (B.P., Y.S., A.F., K.E.T.); Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee (D.F., Y.F., S.W., G.W.); Department of Laboratory Medicine, Division of Clinical Pharmacology, Karolinska Institutet, Stockholm, Sweden (E.A.); and Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden (S.C.S.).
Kenneth E ThummelDepartment of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee (A.S.C., E.G.S.); Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington (B.P., Y.S., A.F., K.E.T.); Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee (D.F., Y.F., S.W., G.W.); Department of Laboratory Medicine, Division of Clinical Pharmacology, Karolinska Institutet, Stockholm, Sweden (E.A.); and Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden (S.C.S.).
Erin G SchuetzDepartment of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee (A.S.C., E.G.S.); Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington (B.P., Y.S., A.F., K.E.T.); Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee (D.F., Y.F., S.W., G.W.); Department of Laboratory Medicine, Division of Clinical Pharmacology, Karolinska Institutet, Stockholm, Sweden (E.A.); and Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden (S.C.S.) erin.schuetz@stjude.org.
St. Jude Children's Research Hospital · USKarolinska Institutet · SEUniversity of Washington · US

Funding

Viral Vector Technology (VVTSR)P30CA021765 · NCI · ST. JUDE CHILDREN'S RESEARCH HOSPITAL · PI CHARLES ROBERTS · 1985 to 2026
$166.9M
PHARMACOGENETICS OF MEMBRANE TRANSPORTERSU01GM061390 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI GIACOMINI, KATHLEEN M · 2000 to 2009
$29.2M
TOXIC DRUG INTERACTIONS WITH VALPROIC ACIDP01GM032165 · NIGMS · UNIVERSITY OF WASHINGTON · PI RETTIE, ALLAN EDWARD · 1985 to 2012
$18.3M
Pharmacogenomics of Membrane TransportersU19GM061390 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI AHITUV, NADAV · 2010 to 2014
$16.3M
Pharmacogenetics of Phase II Drug Metabolizing EnzymesU19GM061388 · NIGMS · MAYO CLINIC ROCHESTER · PI WEINSHILBOUM, RICHARD M. · 2010 to 2014
$15.8M
PHARMACOGENETICS OF PHASE II DRUG METABOLIZING ENZYMESU01GM061388 · NIGMS · MAYO CLINIC ROCHESTER · PI WEINSHILBOUM, RICHARD M. · 2000 to 2009
$15.7M
PAARK4Kids-Pharmacogenomics of Anticancer Agents Research in ChildrenU01GM092666 · NIGMS · ST. JUDE CHILDREN'S RESEARCH HOSPITAL · PI RELLING, MARY V · 2010 to 2014
$8.9M
NCI NIH HHS P30 CA021765NCI NIH HHS P30 CA21765NIGMS NIH HHS GM061388NIGMS NIH HHS GM092666NIGMS NIH HHS GM32165NIGMS NIH HHS GM61390NIGMS NIH HHS P01 GM032165NIGMS NIH HHS U01 GM061388NIGMS NIH HHS U01 GM061390NIGMS NIH HHS U01 GM092666NIGMS NIH HHS U19 GM061388NIGMS NIH HHS U19 GM061390
6 · The paper itself

Abstract

CYP2C19 rs12769205 alters an intron 2 branch point adenine leading to an alternative mRNA in human liver with complete inclusion of intron 2 (exon 2B). rs12769205 changes the mRNA reading frame, introduces 87 amino acids, and leads to a premature stop codon. The 1000 Genomes project (http://browser.1000genomes.org/index.html) indicated rs12769205 is in linkage disequilibrium with rs4244285 on CYP2C19*2, but found alone on CYP2C19*35 in Blacks. Minigenes containing rs12769205 transfected into HepG2 cells demonstrated this single nucleotide polymorphism (SNP) alone leads to exon 2B and decreases CYP2C19 canonical mRNA. A residual amount of CYP2C19 protein was detectable by quantitative proteomics with tandem mass spectrometry in CYP2C19*2/*2 and *1/*35 liver microsomes with an exon 2 probe. However, an exon 4 probe, downstream from rs12769205, but upstream of rs4244285, failed to detect CYP2C19 protein in livers homozygous for rs12769205, demonstrating rs12769205 alone can lead to complete loss of CYP2C19 protein. CYP2C19 genotypes and mephenytoin phenotype were compared in 104 Ethiopians. Poor metabolism of mephenytoin was seen in persons homozygous for both rs12769205 and rs4244285 (CYP2C19*2/*2), but with little effect on mephenytoin disposition of CYP2C19*1/*2, CYP2C19*1/*3, or CYP2C19*1/*35 heterozygous alleles. Extended haplotype homozygosity tests of the HapMap Yorubans (YRI) showed both haplotypes carrying rs12769205 (CYP2C19*35 and CYP2C19*2) are under significant natural selection, with CYP2C19*35 having a higher relative extended haplotype homozygosity score. The phylogenetic tree of the YRI CYP2C19 haplotypes revealed rs12769205 arose first on CYP2C19*35 and that rs4244285 was added later, creating CYP2C19*2. In conclusion, rs12769205 is the ancestral polymorphism leading to aberrant splicing of CYP2C19*35 and CYP2C19*2 alleles in liver.

Indexed as

AcetylationAdultAllelesCytochrome P-450 CYP2C19DNA, ComplementaryEthiopiaExonsFemaleGene FrequencyHaplotypesHumansIsoenzymesLiverMaleMephenytoinPhenotypeCYP2C19 protein, humanCytochrome P-450 CYP2C19DNA, ComplementaryIsoenzymesMephenytoin

Identifiers

PMID26021325
PMCPMC4518065
OpenAlexW2114643090

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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.