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Published on: September 15, 2018
ANKS1A genotype predicts cardiovascular events in patients with familial hypercholesterolemia
Manon Fantino1, Martine Paquette1, Sophie Bernard2
1Genetic Dyslipidemias Clinic of the Montreal Clinical Research Institute, Québec, Canada.
Insights
The ANKS1A gene variant rs17609940 is linked to reduced risk of major adverse cardiovascular events (MACE) in familial hypercholesterolemia (FH) patients. This finding requires further investigation into the underlying mechanisms.
Area of Science:
- Genetics
- Cardiovascular Medicine
- Pharmacogenomics
Background:
- Genome-wide association studies (GWAS) identified the rs17609940 variant in the ANKS1A gene associated with coronary artery disease (CAD) risk.
- Replication of this association in familial hypercholesterolemia (FH) populations is lacking.
Purpose of the Study:
- To validate the association between the rs17609940 genotype and incident major adverse cardiovascular events (MACE) in a cohort of genetically confirmed FH patients.
- To investigate the role of ANKS1A gene variants in cardiovascular risk stratification within the FH population.
Main Methods:
- An association study was conducted on 725 genetically confirmed FH patients with a median follow-up of 50 years.
- Major adverse cardiovascular events (MACE) included myocardial infarction, stroke, coronary revascularization, unstable angina, and cardiovascular disease death.
- Genotyping of the rs17609940 variant was performed using exome chip genotyping with imputation quality of 0.831.
Main Results:
- The cohort consisted of 469 GG, 218 CG, and 38 CC genotype carriers.
- A recessive model revealed that the CC genotype of rs17609940 was significantly associated with a lower risk of incident MACE (HR 0.30, 95% CI 0.11-0.82, p=0.02).
- This association remained significant after adjusting for confounding cardiovascular risk factors.
Conclusions:
- The rs17609940 single nucleotide polymorphism (SNP) in the ANKS1A gene is associated with incident MACE risk in FH subjects.
- The precise biological mechanism driving this observed association warrants further elucidation.
Background:
The rs17609940 variant of the ANKS1A gene has been associated with coronary artery disease (CAD) risk in genome-wide association studies (GWAS), but no study has yet replicated this association in familial hypercholesterolemia (FH) population.
Objective:
The aim of this study is to validate the association between the rs17609940 genotype and incident major adverse cardiovascular events (MACE) in a cohort of genetically-confirmed FH patients.
Methods:
This association study includes 725 genetically-confirmed FH patients with a median observation period of 50 years (33 805 person-years). MACE were defined as either myocardial infarction (MI), stroke, coronary revascularization, hospital admission for unstable angina and cardiovascular disease (CVD) death. The rs17609940 genotype was imputed with an imputation quality of 0.831 following an exome chip genotyping method (Illumina).
Results:
The cohort comprised 469 subjects with GG genotype, 218 subjects with CG genotype and 38 subjects with CC genotype. All baseline characteristics were balanced between the three groups. The CC genotype of rs17609940 was associated with a significant lower risk of incident MACE compared to GG and GC carriers in a recessive model (HR 0.30, 95% CI 0.11-0.82, p=0.02). Even after correction for confounding cardiovascular risk factors, the association between the ANKS1A polymorphism and incident MACE remained strongly significant.
Conclusions:
We demonstrated that the rs17609940 SNP of the ANKS1A gene is associated with the risk of incident MACE in FH subjects. The exact mechanism underlying this association remains to be clarified.
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