Evidence map›Paper›PMID 30372444›Full record

ArticlePLoS genetics2018

Mouse genome-wide association studies and systems genetics uncover the genetic architecture associated with hepatic pharmacokinetic and pharmacodynamic properties of a constrained ethyl antisense oligonucleotide targeting Malat1.

Elaine Pirie, Shayoni Ray, Calvin Pan, Wuxia Fu, Andrew F Powers, Danielle Polikoff, Colton M Miller, Katrina M Kudrna, Edward N Harris, Aldons J Lusis and 2 more

Open access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in PLoS genetics, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.

0numbers the graph read from it
0cells of the map it votes in
4citing papers in PubMed
0.5field-weighted citation impact, top 36% 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

4 citing papers in PubMed, 9 citations in OpenAlex.

  1. Article
  2. Review
  3. Article
  4. Review
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 1 country.

Elaine PirieCardiovascular Antisense Drug Discovery Group, Ionis Pharmaceuticals, Carlsbad, California, United States of America.ORCID 0000-0002-1992-9106
Shayoni RayCardiovascular Antisense Drug Discovery Group, Ionis Pharmaceuticals, Carlsbad, California, United States of America.
Calvin PanDepartment of Human Genetics, University of California, Los Angeles, Los Angeles, California, United States of America.ORCID 0000-0002-0752-833X
Wuxia FuCardiovascular Antisense Drug Discovery Group, Ionis Pharmaceuticals, Carlsbad, California, United States of America.
Andrew F PowersExploratory Drug Discovery Group, Ionis Pharmaceuticals, Carlsbad, California, United States of America.
Danielle PolikoffCardiovascular Antisense Drug Discovery Group, Ionis Pharmaceuticals, Carlsbad, California, United States of America.
Colton M MillerDepartment of Biochemistry, University of Nebraska-Lincoln, Lincoln, NE, United States of America.
Katrina M KudrnaDepartment of Biochemistry, University of Nebraska-Lincoln, Lincoln, NE, United States of America.
Edward N HarrisDepartment of Biochemistry, University of Nebraska-Lincoln, Lincoln, NE, United States of America.ORCID 0000-0001-7045-1040
Aldons J LusisDepartment of Human Genetics, University of California, Los Angeles, Los Angeles, California, United States of America.
Rosanne M CrookeCardiovascular Antisense Drug Discovery Group, Ionis Pharmaceuticals, Carlsbad, California, United States of America.
Richard G LeeCardiovascular Antisense Drug Discovery Group, Ionis Pharmaceuticals, Carlsbad, California, United States of America.
Ionis Pharmaceuticals (United States) · USUniversity of Nebraska–Lincoln · USUniversity of California, Los Angeles · US

Funding

ULTRASTRUCTURE OF THE INTIMA IN EARLY LESION FORMATIONP01HL030568 · NHLBI · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI FOGELMAN, ALAN M · 1985 to 2019
$55.2M
Systems genomics of metabolic syndrome traitsP01HL028481 · NHLBI · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI REUE, KAREN · 1985 to 2019
$50.2M
Systems Approach to Unraveling the Genetic Basis of Heart FailureR01HL114437 · NHLBI · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI DENG, MARIO C., KARMA, ALAIN S · 2013 to 2016
$4.7M
A Systems Approach to Dissect Genetic Basis of Heart FailureR01HL123295 · NHLBI · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI LUSIS, ALDONS JAKE, WANG, YIBIN · 2014 to 2017
$2.6M
Liver-Mediated Clearance of Low Molecular Weight HeparinsR01HL130864 · NHLBI · UNIVERSITY OF NEBRASKA LINCOLN · PI HARRIS, EDWARD N · 2016 to 2019
$1.6M
NHLBI NIH HHS P01 HL028481NHLBI NIH HHS P01 HL030568NHLBI NIH HHS R01 HL114437NHLBI NIH HHS R01 HL123295NHLBI NIH HHS R01 HL130864
6 · The paper itself

Abstract

Antisense oligonucleotides (ASOs) have demonstrated variation of efficacy in patient populations. This has prompted our investigation into the contribution of genetic architecture to ASO pharmacokinetics (PK) and pharmacodynamics (PD). Genome wide association (GWA) and transcriptomic analysis in a hybrid mouse diversity panel (HMDP) were used to identify and validate novel genes involved in the uptake and efficacy of a single dose of a Malat1 constrained ethyl (cEt) modified ASO. The GWA of the HMDP identified two significant associations on chromosomes 4 and 10 with hepatic Malat1 ASO concentrations. Stabilin 2 (Stab2) and vesicle associated membrane protein 3 (Vamp3) were identified by cis-eQTL analysis. HMDP strains with lower Stab2 expression and Stab2 KO mice displayed significantly lower PK than strains with higher Stab2 expression and the wild type (WT) animals respectively, confirming the role of Stab2 in regulating hepatic Malat1 ASO uptake. GWA examining ASO efficacy uncovered three loci associated with Malat1 potency: Small Subunit Processome Component (Utp11l) on chromosome 4, Rho associated coiled-coil containing protein kinase 2 (Rock2) and Aci-reductone dioxygenase (Adi1) on chromosome 12. Our results demonstrate the utility of mouse GWAS using the HMDP in detecting genes capable of impacting the uptake of ASOs, and identifies genes critical for the activity of ASOs in vivo.

Indexed as

AnimalsCell Adhesion Molecules, NeuronalGene Expression ProfilingGenetic VariationGenome-Wide Association StudyLiverMiceMice, KnockoutOligonucleotides, AntisenseRNA, Long NoncodingRNA, MessengerVesicle-Associated Membrane Protein 3Cell Adhesion Molecules, NeuronalMalat1 long non-coding RNA, mouseOligonucleotides, AntisenseRNA, Long NoncodingRNA, MessengerStab2 protein, mouseVesicle-Associated Membrane Protein 3vesicle-associated membrane protein 3, mouse

Identifiers

PMID30372444
PMCPMC6224167
OpenAlexW2898915993

What OpenQuestion holds

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Registered trials

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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.