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

Antoine Rimbert, Nawar Dalila, Justina C. Wolters, Nicolette Huijkman, Marieke Smit, Niels Kloosterhuis, Marijn Riemsma, Ydwine Van Der Veen, Amika Singla, Freerk Van Dijk, Ruth Frikke-Schmidt, Ezra Burstein, Anne Tybjærg-Hansen, Bart Van De Sluis, Jan Albert Kuivenhoven

Research output: Contribution to journalArticle

3 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1040-1053
Number of pages14
JournalEuropean heart journal
Volume41
Issue number9
DOIs
StatePublished - Mar 1 2020

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Keywords

  • Cardiovascular mortality
  • CCC complex
  • CCDC93
  • Endosomal trafficking
  • LDL-receptor
  • Low-density lipoprotein cholesterol
  • Myocardial infarction

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Rimbert, A., Dalila, N., Wolters, J. C., Huijkman, N., Smit, M., Kloosterhuis, N., Riemsma, M., Van Der Veen, Y., Singla, A., Van Dijk, F., Frikke-Schmidt, R., Burstein, E., Tybjærg-Hansen, A., Van De Sluis, B., & Kuivenhoven, J. A. (2020). A common variant in CCDC93 protects against myocardial infarction and cardiovascular mortality by regulating endosomal trafficking of low-density lipoprotein receptor. European heart journal, 41(9), 1040-1053. https://doi.org/10.1093/eurheartj/ehz727