Evidence map›Paper›PMID 25770315›Full record

ArticleJournal of the American College of Cardiology2015

Effect of naturally random allocation to lower low-density lipoprotein cholesterol on the risk of coronary heart disease mediated by polymorphisms in NPC1L1, HMGCR, or both: a 2 × 2 factorial Mendelian randomization study.

Brian A Ference, Faisal Majeed, Raju Penumetcha, John M Flack, Robert D Brook

Registry-linked trialOpen access · greenAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Journal of the American College of Cardiology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT04826354 (Effects of High-dose StAtin Versus Low-dose Statin Plus Ezetimibe on Statin-Associated Muscle Symptoms & on Reaching Target LDL-C Levels Among Elderly Patients With Atherosclerotic Cardiovascular Disease), which is not on this map. Cited by 191 papers, 9 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
191citing papers in PubMed, 9 pooled it
33.1field-weighted citation impact, top 1% 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.

NCT04826354 phase4completedstarted 2021, after this paper: background citation

Effects of High-dose StAtin Versus Low-dose Statin Plus Ezetimibe on Statin-Associated Muscle Symptoms & on Reaching Target LDL-C Levels Among Elderly Patients With Atherosclerotic Cardiovascular Disease

Ran2021Enrolled582Registered outcomes11Posted comparisons0ConditionsAtheroscleroses, CoronaryArmsRosuvastatin, rosuvastatin and ezetimibe
PMID 30423391PMID 28249067PMID 30403574PMID 28007331PMID 28304224PMID 26039521PMID 28444290PMID 16453090PMID 22686958PMID 29020411PMID 30580575PMID 25614424other papers from this trial
Open the trial in the graph
3 · Its place in the literature

Who cites it

191 citing papers in PubMed, 9 syntheses or guidelines pooled it, 423 citations in OpenAlex.

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131 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

5 authors at 2 institutions in 1 country.

Brian A FerenceDivision of Translational Research and Clinical Epidemiology, Wayne State University School of Medicine, Detroit, Michigan; Division of Cardiovascular Medicine, Wayne State University School of Medicine, Detroit, Michigan; Department of Internal Medicine, Wayne State University School of Medicine, Detroit, Michigan. Electronic address: bference@med.wayne.edu.
Faisal MajeedDivision of Translational Research and Clinical Epidemiology, Wayne State University School of Medicine, Detroit, Michigan.
Raju PenumetchaDepartment of Internal Medicine, Wayne State University School of Medicine, Detroit, Michigan.
John M FlackDivision of Translational Research and Clinical Epidemiology, Wayne State University School of Medicine, Detroit, Michigan; Department of Internal Medicine, Wayne State University School of Medicine, Detroit, Michigan.
Robert D BrookDivision of Cardiovascular Medicine, University of Michigan Medical School, Ann Arbor, Michigan.
Wayne State University · USUniversity of Michigan · US

Funding

Randomized Clinical Trials - Whole Genome Studies Coordinating CenterU01HG005157 · NHGRI · UNIVERSITY OF WASHINGTON · PI HEAGERTY, PATRICK J, WEIR, BRUCE S. · 2009 to 2011
$2.4M
NHGRI NIH HHS U01 HG005157
6 · The paper itself

Abstract

backgroundConsiderable uncertainty exists as to whether lowering low-density lipoprotein cholesterol (LDL-C) by inhibiting the Niemann-Pick C1-Like 1 (NPC1L1) receptor with ezetimibe, either alone or in combination with a 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) inhibitor (statin), will reduce the risk of coronary heart disease (CHD).

objectivesThis study evaluated the effect of naturally random allocation to lower LDL-C mediated by polymorphisms in the NPC1L1 gene (target of ezetimibe), the HMGCR gene (target of statins), or both (target of combination therapy) on the risk of CHD.

methodsWe constructed NPC1L1 and HMGCR genetic LDL-C scores to naturally randomize participants into 4 groups: reference, lower LDL-C mediated by NPC1L1 polymorphisms, lower LDL-C mediated by HMGCR polymorphisms, or lower LDL-C mediated by polymorphisms in both NPC1L1 and HMGCR. We compared the risk of CHD (fatal or nonfatal myocardial infarction) among each group using a 2 × 2 factorial mendelian randomization study design.

resultsA total of 108,376 persons (10,464 CHD events) from 14 studies were included. There were no significant differences in baseline characteristics among the 4 groups, thus confirming that allocation was random. Compared to the reference group, the NPC1L1 group had 2.4 mg/dl lower LDL-C and 4.8% lower risk of CHD (odds ratio [OR]: 0.952, 95% confidence interval [CI]: 0.920 to 0.985); whereas the HMGCR group had 2.9 mg/dl lower LDL-C and a similar 5.3% lower risk of CHD (OR: 0.947, 95% CI: 0.909 to 0.986). The group with lower LDL-C mediated by both NPC1L1 and HMGCR polymorphisms had 5.8 mg/dl additively lower LDL-C and a 10.8% log-linearly additive lower risk of CHD (OR: 0.892, 95% CI: 0.854 to 0.932).

conclusionsThe effect of lower LDL-C on the risk of CHD mediated by polymorphisms in NPC1L1, HMGCR, or both is approximately the same per unit lower LDL-C and log-linearly proportional to the absolute exposure to lower LDL-C.

Indexed as

Polymorphism, GeneticCholesterol, LDLCoronary DiseaseFemaleGenetic Predisposition to DiseaseHumansHydroxymethylglutaryl CoA ReductasesMaleMembrane ProteinsMembrane Transport ProteinsMendelian Randomization AnalysisMiddle AgedRisk AssessmentCholesterol, LDLHMGCR protein, humanHydroxymethylglutaryl CoA ReductasesMembrane ProteinsMembrane Transport ProteinsNPC1L1 protein, humanezetimibegenetic associationPCSK9statins

Identifiers

PMID25770315
PMCPMC6101243
OpenAlexW65262745

What Socratic holds

Textmetadata
LicenceTDM
Read underepoch 390

Registered trials

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 Socratic graph.