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Published on: September 15, 2018
Novel Finnish-enriched variants causing severe hypercholesterolemia and their clinical impact on coronary artery
Nella Junna1, Sanni Ruotsalainen1, Pietari Ripatti1
1Institute for Molecular Medicine Finland, FIMM, HiLIFE, University of Helsinki, Biomedicum 2U, Tukholmankatu 8, 00290, Helsinki, Finland.
Insights
Severe hypercholesterolemia increases coronary artery disease risk. This study identifies novel genetic variants and uses a large cohort to assess their cardiovascular disease risk, aiding clinical evaluation.
Area of Science:
- Cardiovascular Genetics
- Medical Genomics
- Clinical Lipidology
Background:
- Severe hypercholesterolemia is a significant risk factor for coronary artery disease (CAD).
- Genetic factors play a crucial role, but identifying causative mutations remains challenging.
- A substantial number of mutation carriers are undiagnosed, hindering effective risk management.
Purpose of the Study:
- To evaluate the clinical utility of a large reference cohort (FinnGen Study) for assessing genetic variants associated with severe hypercholesterolemia.
- To aid in the clinical evaluation of candidate gene variants identified through exome sequencing in patients with severe hypercholesterolemia.
Main Methods:
- Leveraged data from the FinnGen Study (356,082 individuals) with extensive health records.
- Performed exome sequence analysis on a target population of 351 individuals with severe hypercholesterolemia.
- Utilized in silico and clinical assessments to evaluate identified genetic variants.
Main Results:
- Identified 23 rare missense mutations in known hypercholesterolemia genes, including 3 previously described.
- Pinpointed two novel likely pathogenic variants in LDLR (Arg574Leu, Glu626Lys) and one in LDLRAP1 (Arg151Trp).
- Found that heterozygous carriers of novel LDLR and LDLRAP1 variants had increased statin treatment use and higher risk for ischemic heart disease.
Conclusions:
- The study elucidates the diverse spectrum of genetic variants contributing to hypercholesterolemia.
- Demonstrates the effectiveness of using a large reference population for assessing the impact of candidate gene variants on cardiovascular disease risk.
- Highlights the importance of genetic assessment in managing severe hypercholesterolemia and associated cardiovascular risks.
Background And Aims:
Severe hypercholesterolemia (LDL-cholesterol ≥ 5 mmol/l) is a major risk factor for coronary artery disease (CAD). The etiology incudes both genetic and nongenetic factors, but persons carrying mutations in known hypercholesterolemia-associated genes are at significantly higher CAD risk than non-carriers. Yet, a significant proportion of mutation carriers remains undetected while the assessment of genetic candidate variants in clinical practice is challenging.
Methods:
To address these challenges, we set out to test the utility of a practical approach to leverage data from a large reference cohort, the FinnGen Study encompassing 356,082 persons with extensive longitudinal health record information, to aid the clinical evaluation of single genetic candidate genes variants detected by exome sequence analysis in a target population of 351 persons with severe hypercholesterolemia.
Results:
We identified 23 rare missense mutations in known hypercholesterolemia genes, 3 of which were previously described mutations (LDLR Pro309Lysfs, LDLR Arg595Gln and APOB Arg3527Gln). Subsequent in silico and clinical assessment of the remaining 20 variants pinpointed two likely hypercholesterolemia-associated variants in LDLR (Arg574Leu and Glu626Lys) and one in LDLRAP1 (Arg151Trp). Heterozygous carriers of the novel LDLR and LDLRAP1 variants received statin treatment more often than non-carriers (OR 2.1, p = 1.8e-6 and OR 1.4, p = 0.001) and untreated carriers had higher risk for ischemic heart disease (OR 2.0, p = 0.03 and OR 1.8, p = 0.008).
Conclusions:
Our data elucidate the wide spectrum of genetic variants impacting hypercholesterolemia and demonstrate the utility of a large reference population to assess the heterogeneous impact of candidate gene variants on cardiovascular disease risk.
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