Evidence map›Paper›PMID 34590679›Full record

SynthesisHuman molecular genetics2022

Meta-GWAS of PCSK9 levels detects two novel loci at APOB and TM6SF2.

Janne Pott, Jesper R Gådin, Elizabeth Theusch, Marcus E Kleber, Graciela E Delgado, Holger Kirsten, Stefanie M Hauck, Ralph Burkhardt, Hubert Scharnagl, Ronald M Krauss and 6 more

Open access · hybridAbstract readMeta-Analysis
PubMed Full text at PMC Publisher
In one paragraph

Synthesis in Human molecular genetics, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
9citing papers in PubMed, 1 pooled it
3.6field-weighted citation impact, top 6% 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

9 citing papers in PubMed, 1 synthesis or guideline pooled it, 17 citations in OpenAlex.

  1. Pooled it
  2. Effects of theGenes · 2025
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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

16 authors at 8 institutions in 4 countries.

Janne PottInstitute for Medical Informatics, Statistics and Epidemiology, Medical Faculty, University of Leipzig, Leipzig, Germany.ORCID 0000-0002-5983-5331
Jesper R GådinDivision of Cardiovascular Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Karolinska University Hospital Solna, Solna, Sweden.
Elizabeth TheuschDepartment of Pediatrics, University of California San Francisco, Oakland, CA, USA.ORCID 0000-0002-5678-759X
Marcus E KleberVth Department of Medicine (Nephrology, Hypertensiology, Rheumatology, Endocrinology, Diabetology), Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
Graciela E DelgadoVth Department of Medicine (Nephrology, Hypertensiology, Rheumatology, Endocrinology, Diabetology), Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
Holger KirstenInstitute for Medical Informatics, Statistics and Epidemiology, Medical Faculty, University of Leipzig, Leipzig, Germany.ORCID 0000-0002-3126-7950
Stefanie M HauckMetabolomics and Proteomics Core and Research Unit Protein Science, Helmholtz Zentrum München, Neuherberg, Germany.
Ralph BurkhardtLIFE Research Center for Civilization Diseases, Medical Faculty, University of Leipzig, Leipzig, Germany.
Hubert ScharnaglClinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria.
Ronald M KraussDepartment of Pediatrics, University of California San Francisco, Oakland, CA, USA.
Markus LoefflerInstitute for Medical Informatics, Statistics and Epidemiology, Medical Faculty, University of Leipzig, Leipzig, Germany.
Winfried MärzVth Department of Medicine (Nephrology, Hypertensiology, Rheumatology, Endocrinology, Diabetology), Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
Joachim ThieryLIFE Research Center for Civilization Diseases, Medical Faculty, University of Leipzig, Leipzig, Germany.
Angela SilveiraDivision of Cardiovascular Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Karolinska University Hospital Solna, Solna, Sweden.
Ferdinand M Van't HooftDivision of Cardiovascular Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Karolinska University Hospital Solna, Solna, Sweden.
Markus ScholzInstitute for Medical Informatics, Statistics and Epidemiology, Medical Faculty, University of Leipzig, Leipzig, Germany.
Leipzig University · DEKarolinska University Hospital · SEHeidelberg University · DEMedical University of Graz · ATUniversity of California, San Francisco · USChristian-Albrechts-Universität zu Kiel · DEHelmholtz Zentrum München · DEUniversity Hospital Regensburg · DE

Funding

Pharmacogenomics and Risk of Cardiovascular DiseaseU01HL069757 · NHLBI · UNIVERSITY OF CALIF-LAWRENC BERKELEY LAB · PI KRAUSS, RONALD M · 2001 to 2009
$24.7M
NHLBI NIH HHS U01 HL069757
6 · The paper itself

Abstract

backgroundProprotein convertase subtilisin/kexin type 9 (PCSK9) is a key player in lipid metabolism, as it degrades low-density lipoprotein (LDL) receptors from hepatic cell membranes. So far, only variants of the PCSK9 gene locus were found to be associated with PCSK9 levels. Here we aimed to identify novel genetic loci that regulate PCSK9 levels and how they relate to other lipid traits. Additionally, we investigated to what extend the causal effect of PCSK9 on coronary artery disease (CAD) is mediated by low-density lipoprotein-cholesterol (LDL-C). METHODS AND

resultsWe performed a genome-wide association study meta-analysis of PCSK9 levels in up to 12 721 samples of European ancestry. The estimated heritability was 10.3%, which increased to 12.6% using only samples from patients without statin treatment. We successfully replicated the known PCSK9 hit consisting of three independent signals. Interestingly, in a study of 300 African Americans, we confirmed the locus with a different PCSK9 variant. Beyond PCSK9, our meta-analysis detected three novel loci with genome-wide significance. Co-localization analysis with cis-eQTLs and lipid traits revealed biologically plausible candidate genes at two of them: APOB and TM6SF2. In a bivariate Mendelian Randomization analysis, we detected a strong effect of PCSK9 on LDL-C, but not vice versa. LDL-C mediated 63% of the total causal effect of PCSK9 on CAD.

conclusionOur study identified novel genetic loci with plausible candidate genes affecting PCSK9 levels. Ethnic heterogeneity was observed at the PCSK9 locus itself. Although the causal effect of PCSK9 on CAD is mainly mediated by LDL-C, an independent direct effect also occurs.

Indexed as

Coronary Artery DiseaseProprotein Convertase 9Apolipoproteins BCholesterol, LDLGenome-Wide Association StudyHumansMembrane ProteinsReceptors, LDLApolipoproteins BCholesterol, LDLMembrane ProteinsPCSK9 protein, humanProprotein Convertase 9Receptors, LDLTM6SF2 protein, human

Identifiers

PMID34590679
PMCPMC8947322
OpenAlexW3203691912

What Socratic holds

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LicenceCC BY-NC
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Registered trials

None linked

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.