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Cited by 24Lipoproteins and Cardiovascular HealthGenetic Associations and EpidemiologyCholesterol and Lipid Metabolism

The DOI matches its Crossref record; 45 of the 45 references it cites were found in a registry or an index; 29 of the 43 sources its claims cite were checked for support.

A common variant in CCDC93 protects against myocardial infarction and cardiovascular mortality by regulating endosomal trafficking of low-density lipoprotein receptor

Open access
Rimbert, Antoine, Dalila, Nawar, Wolters, Justina C, Huijkman, Nicolette, Smit, Marieke, Kloosterhuis, Niels, Riemsma, Marijn, van der Veen, Ydwine, Singla, Amika, van Dijk, Freerk, Biobank-Based Integrative Omics Studies Consortium, Frikke-Schmidt, Ruth, Burstein, Ezra, Tybjærg-Hansen, Anne, van de Sluis, Bart, Kuivenhoven, Jan Albert·2020·European Heart Journal
DOI 10.1093/eurheartj/ehz727
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Abstract

Aims: Genome-wide association studies have previously identified INSIG2 as a candidate gene for plasma low-density lipoprotein cholesterol (LDL-c). However, we suspect a role for CCDC93 in the same locus because of its involvement in the recycling of the LDL-receptor (LDLR). Methods and results: Characterization of the INSIG2 locus was followed by studies in over 107 000 individuals from the general population, the Copenhagen General Population Study and the Copenhagen City Heart Study, for associations of genetic variants with plasma lipids levels, with risk of myocardial infarction (MI) and with cardiovascular mortality. CCDC93 was furthermore studied in cells and mice. The lead variant of the INSIG2 locus (rs10490626) is not associated with changes in the expression of nearby genes but is a part of a genetic block, which excludes INSIG2. This block includes a coding variant in CCDC93 p.Pro228Leu, which is in strong linkage disequilibrium with rs10490626 (r2 > 0.96). In the general population, separately and combined, CCDC93 p.Pro228Leu is dose-dependently associated with lower LDL-c (P-trend 2.5 × 10−6 to 8.0 × 10−9), with lower risk of MI (P-trend 0.04–0.002) and lower risk of cardiovascular mortality (P-trend 0.005–0.004). These results were validated for LDL-c, risk of both coronary artery disease and MI in meta-analyses including from 194 000 to >700 000 participants. The variant is shown to increase CCDC93 protein stability, while overexpression of human CCDC93 decreases plasma LDL-c in mice. Conversely, CCDC93 ablation reduces LDL uptake as a result of reduced LDLR levels at the cell membrane. Conclusion: This study provides evidence that a common variant in CCDC93, encoding a protein involved in recycling of the LDLR, is associated with lower LDL-c levels, lower risk of MI and cardiovascular mortality.

Overview

AI snapshot

Written from the paper’s full text.

TL;DR

A common CCDC93 missense variant, p.Pro228Leu (rs17512204), in complete LD with the LDL-c–associated SNP rs10490626, is linked to lower LDL-c and lower risk of myocardial infarction and cardiovascular mortality in Danish general-population cohorts. The variant increases CCDC93 protein stability and appears to act through improved CCC-complex–mediated endosomal LDL receptor recycling.

Key findings

  • In 107,063 Danish participants, CCDC93 p.Pro228Leu was associated with lower total cholesterol (up to 0.9%; −0.05 mmol/L; P for trend = 4.8 × 10⁻⁸), LDL-c (up to 2.2%; −0.07 mmol/L; P for trend = 8.0 × 10⁻⁹), and apolipoprotein B (up to 1.0%; −1.14 mg/dL; P for trend = 3.4 × 10⁻⁶) in TT homozygotes vs non-carriers, but not with HDL cholesterol, ApoAI, triglycerides, remnant cholesterol, or lipoprotein(a).
  • Multifactorially adjusted MI risk decreased stepwise by genotype: HR 0.88 (95% CI 0.81–0.96) in CT heterozygotes and 0.67 (0.39–1.16) in TT homozygotes (P for trend = 0.002); cardiovascular mortality HRs were 0.87 (0.78–0.97) and 0.64 (0.33–1.22), respectively (P for trend = 0.004).
  • Meta-analyses showed per T-allele LDL-c reduction of −0.05 SD (95% CI −0.06 to −0.04), CAD OR 0.97 (0.94–0.99), and MI OR 0.95 (0.90–0.99 random-effects; 0.95, 0.92–0.98 fixed-effects).
  • Mechanistically, CCDC93 p.Pro228Leu was more stable than wild-type after 24 and 36 h in HEK293T cells (P < 0.05); CCDC93 knockout in Huh7 cells reduced plasma-membrane LDLR by >50% (P < 0.01) and DiI-LDL uptake by ~40% (P < 0.001); AAV8-mediated human CCDC93 overexpression in Ldlr+/− mice increased liver CCDC93 1.8-fold and reduced LDL-c (P = 0.049).

Methods

  • Genetic epidemiology used the Copenhagen General Population Study and Copenhagen City Heart Study (combined n = 107,063; mean follow-up 36 years), with genotyping of rs17512204 and Cox proportional hazards models adjusted for age, gender, BMI, hypertension, diabetes, physical activity, smoking, alcohol, hormone replacement therapy, and lipid-lowering therapy.
  • eQTL analyses used GTEx V7 and BIOS whole-blood RNA-seq (n = 2116); meta-analyses combined Danish data with Global Lipids Genetics Consortium, UK Biobank, and CARDIoGRAMplusC4D 1000 Genomes data.
  • Functional work included transient CCDC93 WT vs p.Pro228Leu expression in HEK293T cells with cycloheximide chase, CRISPR/Cas9 CCDC93 knockout Huh7 cells with LC-MS proteomics, DiI-LDL uptake, and biotinylation assays, plus AAV8-hCCDC93 overexpression in Ldlr+/− mice (n = 5 per group).

Limitations

  • The paper states that GTEx eQTL analyses were underpowered because of small relevant-tissue sample sizes (e.g., n = 385 subcutaneous adipose, 313 visceral adipose, 153 liver, 125 intestine), and that Huh7 cells cannot recapitulate all aspects of human lipid metabolism.
  • The paper notes that UK Biobank had a 5.5% participation rate, possible healthy-participant bias, and MI frequency <2% vs >5% in the Danish general population, which may explain the null UK Biobank MI result; it also states that proof of loss-of-function CCDC93 mutations causing familial hypercholesterolaemia would strengthen the findings.
  • Evident from the text: the mouse overexpression experiment used small groups (n = 5 per group) and wild-type CCDC93 overexpression does not mimic a gain-of-function mutation; the MI meta-analysis showed modest, non-significant heterogeneity (I² = 53%, P = 0.12).

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1093/eurheartj/ehz727

Cites

45 of 45 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Verification

Claims the paper makes

29 of 43 cited sources checked · 11 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    Loss of proteins of the CCC complex studied thus far causes hypercholesterolaemia in mammals including man.

    “Loss of proteins of the CCC complex studied thus far causes hypercholesterolaemia in mammals including man.”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [12] Fedoseienko, 2018, COMMD family regulates plasma LDL levels and attenuates atherosclerosis through stabilizing the CCC complex in endosomal LDLR trafficking, Circ Res source
    • cites [13] Bartuzi, 2016, CCC- and WASH-mediated endosomal sorting of LDLR is required for normal clearance of circulating LDL, Nat Commun source
  • Premisecitation

    CCDC93 participates in an evolutionary conserved multiprotein complex, the CCC complex (COMMD/CCDC22/CCDC93), that orchestrates the endosomal recycling of the LDL-receptor (LDLR).

    “This because we have recently shown that CCDC93 participates in an evolutionary conserved multiprotein complex, annotated as the CCC complex (COMMD/CCDC22/CCDC93; see Supple- mentary material online for additional information), that orchestrates the endosomal recycling of the LDL-receptor (LDLR).12,13”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [12] Fedoseienko, 2018, COMMD family regulates plasma LDL levels and attenuates atherosclerosis through stabilizing the CCC complex in endosomal LDLR trafficking, Circ Res source
    • cites [13] Bartuzi, 2016, CCC- and WASH-mediated endosomal sorting of LDLR is required for normal clearance of circulating LDL, Nat Commun source

      The paper identifies CCDC93 as a CCC-complex component (opening section; page unavailable) and reports that CCC is required for LDLR endosomal sorting and delivery to the plasma membrane (Discussion; page unavailable). This supports the complex’s role in LDLR recycling, but our copy does not establish the claim that the complex is evolutionarily conserved. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
  • Premisecitation

    Loss of Insig2 does not affect plasma cholesterol levels in mice.

    “Loss of Insig2 does, however, not affect plasma cholesterol levels in mice.11”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [11] Engelking, 2005, Schoenheimer effect explained–feedback regulation of cholesterol synthesis in mice mediated by Insig proteins, J Clin Invest source
  • Findingown data

    In meta-analyses, there were similar CCDC93 p.Pro228Leu per T-allele reductions in LDL-c and risk of CAD in all studies considered, comparable to data reported in a recent consensus statement from the European Atherosclerosis Society Consensus Panel.

    “In meta-analyses, we found similar CCDC93 p.Pro228Leu per T-allele reductions in LDL-c and risk of CAD in all studies considered, comparable to data reported in a recent consensus statement from the European Atherosclerosis Society Consensus Panel. 1”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [1] Ference, 2017, Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel, Eur Heart J source
  • Premisecitation

    Evidence that endosomal LDLR recycling may also be relevant in humans was so far restricted to rare loss-of-function mutations in CCDC22 and WASHC5, which cause hypercholesterolaemia but also developmental defects and intellectual disability.

    “Evidence that the endosomal LDLR recycling may also be relevant in humans was so far restricted to rare loss-of-function mutations in CCDC22 and WASHC5, which cause hypercholesterolaemia but also developmental defects and intellectual disability.13,35,36”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [13] Bartuzi, 2016, CCC- and WASH-mediated endosomal sorting of LDLR is required for normal clearance of circulating LDL, Nat Commun source

      Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured
    • cites [35] Elliott, 2013, A novel mutation in KIAA0196: identification of a gene involved in Ritscher-Schinzel/3C syndrome in a First Nations cohort, J Med Genet source
    • cites [36] Kolanczyk, 2015, Missense variant in CCDC22 causes X-linked recessive intellectual disability with features of Ritscher-Schinzel/3C syndrome, Eur J Hum Genet source
  • The quote only partly states this claim. 2
  • Probably not a substantial claim. 29
  • It may state two separate claims as one. 30

  • The quote only partly states this claim.

    Findingcitation

    Using the GTEx Consortium mRNA dataset, rs10490626 is probably not an eQTL for DDX18, CCDC93, or INSIG2.

    “In line with previous findings, 9 the data show that rs10490626 is probably not an eQTL (plotted association data in adipose, liver, and intestine, Supplementary material online, Figure S2).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [9] Willer, 2013, Discovery and refinement of loci associated with lipid levels, Nat Genet source

      The Results section (‘Regulation of gene expression by associated variants’; page unavailable) reports eQTL findings for other lipid-associated variants, but does not address rs10490626. The Online Methods section (‘Cis-expression quantitative trait locus analysis’; page unavailable) describes liver and fat expression analyses, not a GTEx analysis of rs10490626 and DDX18, CCDC93, or INSIG2. Searches for the variant, genes, and GTEx yielded no passage supporting the attributed finding. (LLM, conf=0.74)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim.

    Premisecitation

    The T allele of rs10490626 has been reported to be associated with reduced plasma LDL-c levels.

    “The T allele is found in $9% of non-Finnish Europeans (http://gnomad.broadinstitute.org)and has been reported to be associated with reduced plasma LDL-c levels.9,10”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [9] Willer, 2013, Discovery and refinement of loci associated with lipid levels, Nat Genet source

      The Results section reports associations between genetic loci and LDL cholesterol, but the passages retrieved for rs10490626 and for a T allele associated with lower LDL cholesterol do not identify this variant or its direction of effect. Our copy therefore does not verify the specific allele-level claim. (LLM, conf=0.72)

      Experimental — accuracy not yet measured
    • cites [10] Liu, 2017, Exome-wide association study of plasma lipids in >300,000 individuals, Nat Genet source

      The passages on LDL-C–lowering variants discuss other named variants, but do not identify rs10490626 or its T allele. Searches for the rsID and for its purported association with lower LDL-C found no passage in our copy that verifies the allele-specific claim; the frequency statement is attributed to gnomAD, not this paper. (LLM, conf=0.72)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Others have shown that over-expression of SNX17, another protein involved in the endosomal sorting machinery, enhances LDL uptake via its positive role on LDLR sorting in cultured cells.

    “Others have shown that over-expression of SNX17, another protein involved in the endosomal sorting machinery, also enhances LDL uptake via its positive role on LDLR sorting in cultured cells.34”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [34] Sotelo, 2014, Sorting nexin 17 regulates ApoER2 recycling and reelin signaling, PLoS One source

      The Discussion (SNX17 regulates the endosomal trafficking of ApoER2; page unavailable) reports that SNX17 overexpression increases LDL-R endocytic cycles, implying more efficient recycling. The Introduction also describes SNX17 as involved in endosomal trafficking. Our copy does not say that LDL uptake increased, so that outcome is not supported by this source. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim.

    Premisecitation

    PCSK9 directs the LDLR to the lysosome compartment for degradation.

    “This protein directs the LDLR to the lysosome compartment for degradation, 29”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [29] Zhang, 2007, Binding of proprotein convertase subtilisin/kexin type 9 to epidermal growth factor-like repeat A of low density lipoprotein receptor decreases receptor recycling and increases degradation, J Biol Chem source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    LDLR can be re-used 100 times after its endocytosis into the endosomal network.

    “can be re-used 100 times after its endocytosis into endosomal network.28”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [28] Anderson, 1976, Localization of low density lipoprotein receptors on plasma membrane of normal human fibroblasts and their absence in cells from a familial hypercholesterolemia homozygote, Proc Natl Acad Sci U S A source

      The Discussion describes LDL-ferritin being ingested through coated pits, but does not say that LDL receptors enter an endosomal network or are reused. Searches for receptor recycling and “100 times” found no passage supporting the claimed reuse count. (LLM, conf=0.74)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    The re-use of LDLR can be prevented by the binding of PCSK9 to LDLR.

    “On the one hand, the re-use of LDLR can be prevented by the binding of pro-protein convertase subtilisin-kexin type 9 (PCSK9) to LDLR.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [29] Zhang, 2007, Binding of proprotein convertase subtilisin/kexin type 9 to epidermal growth factor-like repeat A of low density lipoprotein receptor decreases receptor recycling and increases degradation, J Biol Chem source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Mutations in CCDC22, another gene encoding for a protein of the CCC complex, have been shown to cause hypercholesterolaemia.

    “Proof that loss of function mutations in CCDC93 may cause familial hypercholesterolaemia in man would strengthen our findings, but mutations in CCDC22, another gene encoding for a protein of the CCC complex, have been shown to cause hypercholesterolaemia.13”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [13] Bartuzi, 2016, CCC- and WASH-mediated endosomal sorting of LDLR is required for normal clearance of circulating LDL, Nat Commun source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    The LDLR can be re-used up to 100 times after its internalization into early endosomes.

    “Central to the current study is that Goldstein and Brown also reported that the LDLR can be re-used up to 100 times after its internalization into early endosomes.28”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [28] Anderson, 1976, Localization of low density lipoprotein receptors on plasma membrane of normal human fibroblasts and their absence in cells from a familial hypercholesterolemia homozygote, Proc Natl Acad Sci U S A source

      The Discussion describes LDL-ferritin entering cells through coated vesicles, but does not say that LDL receptors are internalized and reused. Searches for receptor recycling, early endosomes, and “100 times” found no supporting passage in our copy. (LLM, conf=0.76)

      Experimental — accuracy not yet measured

  • It may state two separate claims as one.

    Interpretationcitation

    The fact that the endosomal recycling process is primarily regulated at the post-translational (protein) level supports the hypothesis that the CCDC93 variant (rs17512204) encodes a protein with improved function.

    “This can be explained by the fact that this process is primarily regulated at the post-translational (protein) level, 12,13,40 which, in turn, supports our hypothesis that the CCDC93 variant (rs17512204) encodes a protein with improved function.”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites [12] Fedoseienko, 2018, COMMD family regulates plasma LDL levels and attenuates atherosclerosis through stabilizing the CCC complex in endosomal LDLR trafficking, Circ Res source

      In “COMMD6 Is Indispensable for COMMD1, CCDC22, and CCDC93 Protein Expression” (page unavailable), the paper reports reduced CCC-component protein levels without aberrant gene expression and links protein stability to endosomal receptor recycling. This supports protein-level regulation of the CCC complex, but not the broader assertion that endosomal recycling is primarily regulated post-translationally. The CCDC93-variant hypothesis is the citing authors’ own inference, not a finding attributed to this source. (LLM, conf=0.83)

      Experimental — accuracy not yet measured
    • cites [13] Bartuzi, 2016, CCC- and WASH-mediated endosomal sorting of LDLR is required for normal clearance of circulating LDL, Nat Commun source

      The Results section (‘COMMD1 and WASH facilitate LDLR trafficking’; page unavailable) reports that COMMD1 loss reduces cell-surface LDLR without changing total LDLR in the cells tested, supporting regulation through protein trafficking. The paper does not establish that endosomal recycling is primarily regulated at the post-translational level. The improved-function interpretation of rs17512204 is the citing authors’ own hypothesis, not a finding attributed to this source. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
    • cites [40] Maine, 2009, COMMD1 expression is controlled by critical residues that determine XIAP binding, Biochem J source

      The Results section, “COMMD1 ubiquitination controls basal levels of expression” (page unavailable), says COMMD1 protein levels are regulated primarily through a post-transcriptional mechanism involving ubiquitination. It does not establish that endosomal recycling as a process is primarily regulated at the protein level. The CCDC93 variant’s improved function is presented as the citing authors’ hypothesis, not a finding attributed to this source. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • It may state two separate claims as one.

    Findingcitation

    The proportion of smokers and the proportion with no qualifications were considerably lower than in the background population, and the 5-year mortality rate was several-fold lower than in the UK population as a whole.

    “The latter is supported by the observation that the proportion of smokers and the proportion with no qualifications-reflecting social position-were considerably lower than in the background population, and that the 5-year mortality rate was several-fold lower than in the UK population as a whole.38,39”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [38] Munafò, 2018, Collider scope: when selection bias can substantially influence observed associations, Int J Epidemiol source

      Box 2 (UK Biobank; page not specified) reports lower proportions of current smokers (11% versus 19%) and people with no qualifications (17% versus 25%) than in the general population. It also says UK Biobank participants had far lower 5-year mortality, but gives no figure establishing that the rate was several-fold lower. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [39] Macfarlane, 2015, Can large surveys conducted on highly selected populations provide valid information on the epidemiology of common health conditions? An analysis of UK Biobank data on musculoskeletal pain, Br J Pain source

      The UK Biobank and Discussion sections describe a 5.5% participation rate and compare pain prevalence, but do not compare smoking, qualifications, or five-year mortality with the UK population. Searches for smokers, qualifications, and mortality found no passage in our copy addressing those comparisons; page numbers were unavailable. (LLM, conf=0.73)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim.

    Premisecitation

    Experimental studies in mice have shown that a loss of proteins of the endosomal sorting machinery causes hypercholesterolaemia and increased atherosclerosis.

    “These experimental studies in mice have shown that a loss of proteins of the endosomal sorting machinery causes hypercholesterolaemia and increased atherosclerosis.12,13”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [12] Fedoseienko, 2018, COMMD family regulates plasma LDL levels and attenuates atherosclerosis through stabilizing the CCC complex in endosomal LDLR trafficking, Circ Res source
    • cites [13] Bartuzi, 2016, CCC- and WASH-mediated endosomal sorting of LDLR is required for normal clearance of circulating LDL, Nat Commun source

      The Results section, “Ablation of hepatic Commd1 increases plasma LDL in mice” (page unavailable), reports higher plasma cholesterol and LDL after loss of an endosomal-sorting protein in mice. The passages do not report increased atherosclerosis in those mice, so that part of the claim is unsupported by this paper. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    It has been shown that it is possible to pharmaceutically target the endosomal-sorting pathway with small molecules.

    “It remains to be seen whether this insight may lead to new tools for pharmaceutical intervention, but it has been shown that it is possible to pharmaceutically target the endosomal-sorting pathway with small molecules.41”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [41] Mecozzi, 2014, Pharmacological chaperones stabilize retromer to limit APP processing, Nat Chem Biol source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Changes in LDLR transcription, internalization, stability, subcellular localization, and degradation all affect the concentration of LDL-c in blood.

    “Its central role in this process is illustrated by the notion that changes in its transcription, 22 internalization, 23,24 stability, 25 subcellular localization, and degradation 26,27 all affect the concentration of LDL-c in blood.”
    Quote in the paperNot a substantial claim1 of 4 sources checked
    • cites [22] Grand-Perret, 2001, SCAP ligands are potent new lipid-lowering drugs, Nat Med source
    • cites [23] Maurer, 2006, The adaptor protein Dab2 sorts LDL receptors into coated pits independently of AP-2 and ARH, J Cell Sci source
    • cites [24] Garcia, 2001, Autosomal recessive hypercholesterolemia caused by mutations in a putative LDL receptor adaptor protein, Science source
    • cites [25] Kim, 2018, γ-secretase inhibition lowers plasma triglyceride-rich lipoproteins by stabilizing the LDL receptor, Cell Metab source

      Citation 25 is attached to LDLR stability, not to the sentence’s other listed mechanisms. The Results section, “γ-secretase regulates LDLR protein stability,” shows that γ-secretase inhibition stabilizes LDLR, but the paper primarily links this pathway to clearance of triglyceride-rich lipoproteins; it does not establish that this change in stability alters blood LDL-c. The Discussion separately notes that PCSK9 inhibition lowers LDL cholesterol. (LLM, conf=0.82)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim. It may state two separate claims as one.

    Premisecitation

    At endosomes, LDLR is sorted for lysosomal degradation, promoted through binding of PCSK9 to LDLR.

    “At the endosomes, low-density lipoprotein receptor is sorted for lysosomal degradation, which is promoted through the binding of proprotein convertase subtilisin-kexin type 9 to low-density lipoprotein receptor,29”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [29] Zhang, 2007, Binding of proprotein convertase subtilisin/kexin type 9 to epidermal growth factor-like repeat A of low density lipoprotein receptor decreases receptor recycling and increases degradation, J Biol Chem source

  • It may state two separate claims as one.

    Findingown data

    LD between the minor alleles of rs10490626 and rs17512204 was near complete (r2 = 0.98) in both the CGPS and CCHS, validating the use of rs17512204 in the study.

    “In agreement with publicly available data, LD between the minor alleles of the intergenic lead GWAS SNP, rs10490626 and rs17512204 (CCDC93 p.Pro228Leu) was near complete (r 2 = 0.98) in both the CGPS and the CCHS population cohorts, thereby validating the use of the latter variant in our study.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    In whole blood RNA-seq (n = 2116), rs10490626 is not associated with changes in expression of DDX18 (P = 0.31), CCDC93 (P = 0.17), or INSIG2 (P = 0.94).

    “Figure 1B shows that rs10490626 is not associated with changes in the expression of DDX18, (P = 0.31), CCDC93 (P = 0.17), or INSIG2 (P = 0.94) in blood, which suggests that rs10490626 is not an eQTL for the genes studied.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Findingnone given

    rs10490626 is located in the locus 2q14 upstream of INSIG2.

    “This variant is located in the locus 2q14 upstream of the INSulin Induced Gene 2 (INSIG2) which is implicated in the regulation of cholesterol synthesis.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingcitation

    rs10490626 is part of an LD block of 200 kb (r2 > 0.8) that includes CCDC93, but not INSIG2 and DDX18.

    “We found that rs10490626 is part of an LD block of 200 kb (r 2 > 0.8, data from the Phase 3 release of the 1000 Genomes project 15 ) that includes CCDC93, but not INSIG2 and DDX18 (Figure 1A).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [15] Abecasis, 2012, An integrated map of genetic variation from 1092 human genomes, Nature source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Findingown data

    During a mean follow-up of 36 years ending in March 2017, MI developed in 5291 individuals and 3635 died from ischaemic cardiovascular disease.

    “During a mean follow-up of 36 years (range: <1-40 years) which ended in March 2017, MI developed in 5291 individuals and 3635 died from ischaemic cardiovascular disease.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim.

    Findingown data

    Combining participants in the CGPS and CCHS yielded a total of 107,063 participants at baseline.

    “Combining the participants in the CGPS and CCHS yielded a total of 107 063 participants at baseline.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    This LD block includes rs17512204, a SNP that leads to the substitution of a leucine for a proline residue at position 228 of CCDC93.

    “This LD block includes rs17512204, a SNP that leads to the substitution of a leucine for a proline residue at position 228 of CCDC93 (NM_019044.4:rs17512204_c.683C>T,p.Pro228Leu).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    rs10490626 is located 246 kb downstream of DDX18, 64 kb upstream of CCDC93, and 10 kb upstream of INSIG2.

    “The respective SNP is located 246 kb downstream of DDX18, 64 kb upstream of CCDC93, and 10 kb upstream of INSIG2 (x axis, Figure 1A).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Findingown data

    There was modest, nonsignificant heterogeneity between studies in the MI meta-analysis (I2 = 53%, P = 0.12) with overlapping confidence intervals.

    “There was modest, nonsignificant heterogeneity between studies (I 2 = 53%, P = 0.12) with overlapping confidence intervals.”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Findingown data

    There was no evidence of heterogeneity between studies in the CAD meta-analysis (I2 = 0%, P = 0.96).

    “There was no evidence of heterogeneity between studies (I 2 =0%, P = 0.96) (Figure 3B).”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    CCDC93 p.Pro228Leu was not associated with HDL cholesterol, apolipoprotein AI, triglycerides, calculated remnant cholesterol, or lipoprotein(a).

    “but was not associated with HDL cholesterol, apolipoprotein AI (ApoAI), triglycerides, calculated remnant cholesterol (which mirrors triglycerides), or lipoprotein(a) (Figure 2A, Panels 4-7; data not shown for calculated remnant cholesterol).”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    In the individual studies, the corresponding hazard ratios for MI were 0.92 (0.83-1.01) and 0.67 (0.36-1.24) in the CGPS (P for trend = 0.04), and 0.77 (0.63-0.93) and 0.71 (0.23-2.20) in the CCHS (P for trend = 0.007).

    “In the individual studies, the corresponding hazard ratios were 0.92 (0.83-1.01) and 0.67 (0.36- .24) in the CGPS (P for trend = 0.04), and 0.77 (0.63-0.93) and 0.71 (0.23-2.20) in the CCHS (P for trend = 0.007) (Supplementary material online, Figure S5A and C).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    In meta-analysis of MI, the overall odds ratio for MI per T-allele was 0.95 (0.90-0.99) using a random-effects model and 0.95 (0.92-0.98) using a fixed-effects model.

    “In meta-analysis of MI, the overall odds ratio for MI per T-allele was 0.95 (0.90-0.99) using a random-effects model, and 0.95 (0.92-0.98) using a fixed-effects model (Figure 3C).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    The MI meta-analysis estimates became significant for CARDIoGRAMplusC4D 1000 Genomes [0.96 (0.92-0.99)] and our study [0.88 (0.81-0.96)], but not different from unity for the UK Biobank, on the hard endpoint MI.

    “The estimates became significant for both CARDIoGRAMplusC4D 1000 Genomes [0.96 (0.92-0.99)] and our study [0.88 (0.81-0.96)], but not different from unity for the UK Biobank, on the hard endpoint MI.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingcitation

    rs17512204 is in complete LD with rs10490626 (r2 = 0.96, P < 0.0001; 1000 Genomes), implying that these SNPs are co-inherited.

    “Importantly, rs17512204 is in complete LD with rs10490626 (r 2 = 0.96, P-value: <0.0001; data from 1000 Genomes project) (Figure 1A) implying that these SNPs are co-inherited.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites 1000 Genomes project

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • It may state two separate claims as one.

    Findingown data

    In meta-analyses of CCDC93 rs17512204 on LDL-c including the Global Lipids Genetics Consortium and the Danish general population, the per T-allele reduction in LDL-c was -0.05 SD (95% CI -0.06 to -0.04) using random and fixed effects models, corresponding to an approximate reduction of 0.05 mmol/L (2 mg/dL) in the study.

    “In meta-analyses of CCDC93 rs17512204 (p.Pro228Leu) on LDL-c including data from the Global Lipids Genetics Consortium (Ref.9 and http://lipidgenetics.org) and the Danish general population (CGPS þ CCHS), the per T-allele reduction in LDL-c was -0.05 standard deviation for the inversed normalized distribution of LDL-c (95% CI: -0.06 to -0.04) using both random and fixed effects models (Figure 3A),”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Ref.9

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites http://lipidgenetics.org

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • It may state two separate claims as one.

    Findingnone given

    These results were validated for LDL-c, risk of both CAD and MI in meta-analyses including from 194,000 to >700,000 participants.

    “These results were validated for LDL-c, risk of both CAD and MI in meta-analyses including from 194 000 to >700 000 participants.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingreasoning

    The per T-allele reduction in risk of MI was 5% overall, similar between studies, and significant in both CARDIoGRAMplusC4D and the study, but not different from unity in the UK Biobank.

    “The per T-allele reduction in risk of MI which is a harder endpoint than CHD/CAD was 5% overall, similar between studies (overlapping confidence intervals for all studies), and significant in both CARDIoGRAMplusC4D and in our own study, but not different from unity in the UK Biobank.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    In agreement with these findings, CCDC93 p.Pro228Leu is associated with per allele lower levels of plasma LDL-c and a corresponding lower risk of MI and cardiovascular mortality in over 107,000 individuals from the general population.

    “In agreement with these findings, CCDC93 p.Pro228Leu is associated with per allele lower levels of plasma LDLc and a corresponding lower risk of MI and cardiovascular mortality in over 107 000 individuals from the general population (Take home figure).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    The frequency of MI in the UK Biobank was <2% compared to >5% in the Danish general population, suggesting that the UK Biobank represents a low-risk population.

    “Furthermore, the frequency of MI in the UK Biobank was <2% compared to >5% in the Danish general population, suggesting D E Figure 6 Continued.that the UK Biobank represents a low-risk population.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Destabilization of the CCC complex was accompanied by a ~50% reduction of LDLR at the plasma membrane (P < 0.01) and a ~40% reduction in the uptake of DiI-LDL compared to control cells (P < 0.001).

    “This destabilization of the CCC complex was accompanied by a $50% reduction of LDLR at the plasma membrane (P < 0.01) (Figure 6C) and a $40% reduction in the uptake of fluorescently labelled LDL (DiI-LDL) compared to control cells (P < 0.001) (Figure 6D).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    rs10490626 is in complete linkage disequilibrium (R2 > 0.80) with rs17512204 (CCDC93 p.Pro228Leu) and with other non-coding single nucleotide polymorphisms spanning CCDC93.

    “As shown, rs10490626 is in complete linkage disequilibrium (R 2 > 0.80) with rs17512204 (CCDC93 p.Pro228Leu) and with other non-coding single nucleotide polymorphisms spanning CCDC93.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    LC-MS confirmed that CCDC93 protein concentration was increased (1.6 fold) (P < 0.001) in liver homogenates, accompanied by an increase of the CCC complex component CCDC22 (P < 0.001) in mice treated with AAV8 hCCDC93 compared to controls.

    “Using LC-MS based targeted proteomics, we con- firmed that CCD93 protein concentration was increased (1.6 fold) (P < 0.001) in liver homogenates, which was accompanied by an in- crease of the CCC complex component CCDC22 (P < 0.001) in mice that were treated with AAV8 hCCDC93 compared to controls (Supplementary material online, Figure S10).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductown data

    More than 700 cells per condition were recorded.

    “More than 700 cells per condition were recorded.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim.

    Study design and conductnone given

    Multifactorial adjustments were for well-known risk factors for MI: age, gender, body mass index, hypertension, diabetes mellitus, physical activity, smoking, alcohol consumption, hormone replacement therapy (women only), and lipid-lowering therapy.

    “Multifactorial adjustments were for well-known risk factors for MI: age, gender, body mass index, hypertension, diabetes mellitus, physical activity, smoking, alcohol consumption, hormone replacement therapy”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductown data

    Follow-up was 100% complete in both studies.

    “In both studies, follow-up was 100% complete, i.e. we did not lose track of a single individual.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim.

    Study design and conductown data

    DiI-LDL uptake was quantified and normalized by fluorescent microscopy in a blinded fashion.

    “DiI-LDL uptake was quantified and normalized by fluorescent microscopy in a blinded fashion.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    The T allele of rs10490626 is found in 9% of non-Finnish Europeans.

    “The T allele is found in $9% of non-Finnish Europeans (http://gnomad.broadinstitute.org)and has been reported to be associated with reduced plasma LDL-c levels.9,10”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites http://gnomad.broadinstitute.org

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Study design and conductnone given

    The study was approved by institutional review boards and Danish ethics committees and was conducted according to the principles of the Declaration of Helsinki.

    “The study was approved by institutional review boards and Danish ethics committees and was conducted according to the principles of the Declaration of Helsinki.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given

    The mouse study was approved by the Institutional Animal Care and Use Committee, University of Groningen (the Netherlands).

    “This study was approved by the Institutional Animal Care and Use Committee, University of Groningen (the Netherlands).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Study design and conductown data

    DNA was available for all individuals, and lipid values were available for more than 98%.

    “DNA was available for all individuals, and lipid values were available for more than 98%.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Interpretationown data

    Risk of MI, a more valid endpoint, was higher than risk of CAD for most variants in the study, and therefore these two endpoints are not directly comparable.

    “Finally as expected, risk of MI, a more valid endpoint, was higher than risk of CAD for most variants in our study, and therefore, these two endpoints are not directly comparable, as also shown for CARDIoGRAMplusC4D 1000 Genomes in the meta-analyses (Figure 3).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given

    Written informed consent was obtained from all individuals.

    “Written informed consent was obtained from all individuals.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim.

    Study design and conductown data

    Hazard ratios for myocardial infarction and cardiovascular mortality as a function of CCDC93 P228L genotype were adjusted for age or multifactorially adjusted for age, gender, body mass index, hypertension, diabetes mellitus, physical activity, smoking, alcohol consumption, hormone replacement therapy (women only), and lipid-lowering therapy.

    “Hazard ratios were adjusted for age (left panel) or multifactorially adjusted for age, gender, body mass index, hypertension, diabetes mellitus, physical activity, smoking, alcohol consumption, hormone replacement therapy (women only), and lipid-lowering therapy.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Interpretationreasoning

    The most likely explanation for the UK Biobank finding is that the participation rate was 5.5%, limiting representativeness for the UK general population and possibly leading to a healthy participant bias.

    “The most likely explanation for the latter finding is that the participation rate in that study was 5.5% (9 million invited, $500 000 participants), limiting the representativeness of the study for the UK general population, and possibly leading to a healthy participant bias (the participation rates were 61% and 45%, respectively, in the CCHS and CGPS).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Interpretationown data

    Although overexpression of the WT form of CCDC93 does not mimic a gain-of-function mutation, these results support the idea that increasing the amount of hepatic CCDC93 can lower plasma LDL-c.

    “Although the overexpression of the WT form of CCDC93 does not mimic a gain of function mutation, these results support the idea that increasing the amount of hepatic CCDC93 can lower plasma LDL-c.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. It may be too vague to check against evidence.

    Interpretationreasoning

    This study shows that large-scale genetic studies can help find other angles to study LDL metabolism.

    “In conclusion, this study shows that large-scale genetic studies can help us find other angles to study LDL metabolism.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Interpretationown data

    The current study provides evidence for a role of CCDC93 in human LDL metabolism, cardiovascular disease, and cardiovascular mortality with molecular clues from in vitro and in vivo experiments related to LDLR-mediated LDL-c clearance.

    “The current study provides evidence for a role of CCDC93 in human LDL metabolism, cardiovascular disease, and cardiovascular mortality with molecular clues from in vitro and in vivo experiments that is related to LDLR-mediated LDL-c clearance (Take home figure).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Interpretationown data

    The current study shows that a common genetic variant, presumably associated with a gain-of-function, is associated with cardiovascular risk reduction including a reduction in cardiovascular mortality in the general population.

    “In contrast, the current study shows that a common genetic variant, presumably associated with a 'gain-of-function', is associated with cardiovascular risk reduction including a reduction in cardiovascular mortality in the general population.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim.

    Interpretationreasoning

    The study has implicated yet another pathway that was already known to control the activity and/or functionality of LDLR, i.e. endosomal sorting and recycling in humans.

    “It has implicated yet another pathway that was already known to control the activity and/or functionality of LDLR, i.e. it is endosomal sorting and recycling in humans.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim.

    Premisecitation

    LDLR is the central regulator of plasma levels of LDL cholesterol.

    “Low-density lipoprotein-receptor is the central regulator of plasma levels of low-density lipoprotein cholesterol”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [28] Anderson, 1976, Localization of low density lipoprotein receptors on plasma membrane of normal human fibroblasts and their absence in cells from a familial hypercholesterolemia homozygote, Proc Natl Acad Sci U S A source

      Checked before — its earlier verdict is held back until a new check runs.

  • Probably not a substantial claim.

    Premisecitation

    The LDLR has been recognized as the principal regulator of LDL clearance from the circulation.

    “The LDLR has, since its discovery by Goldstein and Brown in the '70s, 21 been recognized as the principal regulator of LDL clearance from the circulation.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [21] Brown, 1976, Receptor-mediated control of cholesterol metabolism, Science source
56 of 56

  • The paper relies on this without support.

    Findings in Huh7 cells and mice about CCDC93 and LDLR trafficking apply to the mechanism by which rs17512204 affects LDL-c and cardiovascular risk in humans.

    “The data suggest that the beneficial effects observed are associated with improved functioning of the CCC complex (COMMDs/CCDC22/CCDC93), an endosomal sorting protein complex that orches- trates LDL-Receptor recycling.”
1 of 1

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Most transmembrane proteins sorted by Commander contain ΦxNxx[YF] sequence motifs that are recruited to Commander via the sorting nexin 17 (SNX17) cargo adaptor.

    “Most transmembrane proteins sorted by Commander, including α5β1 integrin, the amyloid precursor protein (APP), and lipoprotein receptors contain ΦxNxx[YF] sequence motifs (where Φ is a hydrophobic amino acid) that are recruited to Commander via the sorting nexin 17 (SNX17) cargo adaptor.6,20,23,24,25,26,27,28,29”

    From Structure of the endosomal Commander complex linked to Ritscher-Schinzel syndrome (2023) · cites this paper as [29]

    The Discussion (page not supplied) says SNX17 has a positive role in LDLR sorting, and the Results section on CCDC93 and LDLR recycling (page not supplied) links the CCC complex to LDLR trafficking. Our copy does not say that most Commander-sorted proteins carry ΦxNxx[YF] motifs, that SNX17 recruits them to Commander, or that the listed integrin and APP are examples. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • A coding variant in CCDC93 increases the stability of the protein and is associated with lower LDL-cholesterol, lower risk of myocardial infarction and of CVD mortality.

    “A coding variant in CCDC93 increases the stability of the protein and is associated with lower LDL-cholesterol, lower risk of myocardial infarction and of CVD mortality [26]”

    From Post-translational regulation of the low-density lipoprotein receptor provides new targets for cholesterol regulation (2024) · cites this paper as [26]

  • A coding variant in CCDC93 increases CCDC93 protein stability, which is associated with lower LDL-C levels and reduced CVD mortality.

    “Importantly, a coding variant in CCDC93 increases CCDC93 protein stability, which is associated with lower LDL-C levels and reduced CVD mortality100”

    From Pathways and Molecular Mechanisms Governing LDL Receptor Regulation (2025) · cites this paper as [100]

  • Both CCDC93 and the CCC complex mediate endosomal sorting of the low-density lipoprotein receptor (LDLR).

    “Both CCDC93 and the CCC complex mediate endosomal sorting of the low-density lipoprotein receptor (LDLR) [43,48,49].”

    From Genetic variation in CCDC93 is associated with elevated central systolic blood pressure, impaired arterial relaxation, and mitochondrial dysfunction (2024) · cites this paper as [43]

  • In a previous genetic study of individuals of European ancestry, CCDC93 rs17512204 was associated with lower LDL-C levels, lower cardiovascular mortality, and lower risk of myocardial infarction.

    “In a previous genetic study of individuals of European ancestry, CCDC93 (rs17512204; C>T, p.Pro228Leu) was associated with lower LDL-C levels, lower cardiovascular mortality, and lower risk of myocardial infarction [43].”

    From Genetic variation in CCDC93 is associated with elevated central systolic blood pressure, impaired arterial relaxation, and mitochondrial dysfunction (2024) · cites this paper as [43]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Reported Danish MI frequency exceeds the count-derived frequency

    Minor

    The stated 5291 MI cases among 107 063 participants give a frequency of about 4.94%, not greater than 5%.

1 of 1

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Metadata

Authors
Rimbert, A., Dalila, N., Wolters, J. C., Huijkman, N., Smit, M., Kloosterhuis, N., Riemsma, M., van der Veen, Y., Singla, A., van Dijk, F., Biobank-Based Integrative Omics Studies Consortium, Frikke-Schmidt, R., Burstein, E., Tybjærg-Hansen, A., van de Sluis, B., & Kuivenhoven, J. A.
Affiliations
  • University Medical Center Groningen (NL)
  • University of Copenhagen (DK)
  • The University of Texas Southwestern Medical Center (US)
  • Section for Molecular Genetics, Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Faculty of Health and Medical Sciences, University of Copenhagen , Blegdamsvej 9, DK-2100 Copenhagen, Denmark
Corresponding author
Kuivenhoven, Jan Albert
ORCID
Venue
European Heart Journal
Publisher
Oxford University Press (OUP)
Published
2019-10-19
Volume
41
Issue
9
Pages
1040-1053
ISSN
  • 0195-668X (ISSN-L)
  • 1522-9645
DOI
10.1093/eurheartj/ehz727
OpenAlex
W2980945503
Semantic Scholar
b892ca6019bd8101f0c1a998c5fcd26a48eb22e3
Cited by
24
References
42
Citations by year
2026: 1 · 2025: 3 · 2024: 4 · 2023: 3 · 2022: 5 · 2021: 1 · 2020: 5 · 2019: 2
FWCI
2.34
Type
journal article
Language
en
Open access
Licence
Locations
  • European Heart Journal (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, cc-by-nc)
  • HAL (submittedVersion, other-oa)
  • University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, cc-by-nc)
Funders
  • BBMRI-NL
  • European Union (FP7-603091)
  • Netherlands CardioVascular Research Initiative: ‘the Dutch Heart Foundation
  • Dutch Federation of University Medical Centers
  • Netherlands Organization for Health Research and Development
  • Royal Netherlands Academy of Sciences (CVON2017-2020)
  • Acronym Genius2
  • Netherlands Heart Foundation (2015T068)
  • The Research Fund at Rigshospitalet
  • Copenhagen University Hospital, Chief Physician Johan Boserup and Lise Boserup’s Fund, Ingeborg and Leo Dannin’s
  • Henry Hansen’s and Wife’s Grant
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipoproteins and Cardiovascular Health
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Cholesterol and Lipid Metabolism
Keywords
LDL cholesterol, LDL receptor, LDL receptor recycling, endosomal trafficking, myocardial infarction, cardiovascular mortality, coronary artery disease, protein stability, plasma lipid levels, genetic association
MeSH terms
Animals, Coronary Artery Disease, Humans, Cholesterol, LDL, Myocardial Infarction, Receptors, LDL, Vesicular Transport Proteins, Mice, Genome-Wide Association Study

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

A language model drew the claims from the paper on 2026-11-08, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).

A second model labelled each claim on 2026-11-08 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).

Cited sources are checked with a language model’s help (gpt-6-sol).

Statistics and arithmetic are recomputed, not judged.

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