Coronary disease & ACSMechanistic study
A common variant in CCDC93 protects against myocardial infarction and cardiovascular mortality by regulating endosomal trafficking of low-density lipoprotein receptor
- Genetic association study with mechanistic studies
- general population cohorts
- cell and mouse studies
- meta-analysis validation
Authors' 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.
Study context
- Population
- General population (Copenhagen General Population Study and Copenhagen City Heart Study)over 107,000
- Participants
- 107,000 participants
- Comparison
- CCDC93 p.Pro228Leu carriers vs non-carriers
Main finding
As reported in the abstract
LDL-C, MI risk and CV mortality by CCDC93 p.Pro228Leu genotype (general population, separately and combined)
Dose-dependently associated with lower LDL-C
P-trend 2.5 × 10-6 to 8.0 × 10-9
Lower risk of myocardial infarction (MI)
P-trend 0.04-0.002
Lower risk of CV mortality
P-trend 0.005-0.004
Further findings
Validation in meta-analyses (low-density lipoprotein cholesterol (LDL-c), CAD, MI)
- Results validated for LDL-c, risk of CAD and MI in meta-analyses of 194 000 to >700 000 participants
Mechanistic findings
- CCDC93 p.Pro228Leu in strong linkage disequilibrium with lead variant rs10490626
- r2 > 0.96
- Variant increases CCDC93 protein stability
- Overexpression of human CCDC93 decreases plasma LDL-c in mice
- CCDC93 ablation reduces LDL uptake via reduced LDLR levels at the cell membrane
Original publication
A common variant in CCDC93 protects against myocardial infarction and cardiovascular mortality by regulating endosomal trafficking of low-density lipoprotein receptor. Eur Heart J. Published 19 October 2019. doi:10.1093/eurheartj/ehz727
Summarised from the published abstract; every number is checked against it