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Published on: September 15, 2018
Effects of Different Types of Pathogenic Variants on Phenotypes of Familial Hypercholesterolemia
Hayato Tada1, Nobuko Kojima1, Kan Yamagami1
1Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan.
Insights
Pathogenic variants in familial hypercholesterolemia (FH) are linked to worse outcomes. Protein-truncating variants (PTVs) and missense variants significantly increase the risk of major adverse cardiac events (MACEs) in FH patients.
Area of Science:
- Cardiovascular Genetics
- Medical Biochemistry
- Clinical Lipidology
Background:
- Pathogenic variants in familial hypercholesterolemia (FH) are known to correlate with adverse clinical outcomes.
- Limited data exists on how specific types of pathogenic variants influence the FH phenotype and patient prognosis.
- Understanding genotype-phenotype correlations is crucial for accurate risk stratification in FH.
Purpose of the Study:
- To investigate the association between different genotypes (no variant, missense, protein-truncating variants) and FH phenotypes.
- To determine the impact of various pathogenic variants on low-density lipoprotein (LDL) cholesterol levels and major adverse cardiac events (MACEs).
- To assess the independent predictive value of genetic variants for MACEs in FH patients.
Main Methods:
- Retrospective analysis of 1,050 FH patients, categorized by genotype: no pathogenic variants, missense variants, or protein-truncating variants (PTVs).
- Phenotypic data collected included LDL cholesterol levels and the occurrence of MACEs (cardiovascular death, myocardial infarction, unstable angina, coronary revascularization).
- Cox proportional hazard models were employed to identify factors associated with MACEs, adjusting for classical risk factors.
Main Results:
- Patients with PTVs exhibited significantly higher LDL cholesterol levels (256 mg/dl) compared to those with missense variants (236 mg/dl) and no pathogenic variants (216 mg/dl).
- Both PTVs (HR=1.58) and missense variants (HR=3.24) were significantly associated with an increased risk of MACEs, independent of other risk factors.
- The median follow-up was 12.6 years, during which 175 MACEs were recorded among the 1,050 patients.
Conclusions:
- Pathogenic variants, particularly PTVs, are strongly associated with poor clinical outcomes in patients with familial hypercholesterolemia.
- Genetic testing aids in the diagnosis and, importantly, the risk stratification of FH patients.
- Genotype-specific risk assessment can potentially guide more personalized treatment strategies for FH.
Abstract:
Objective: It has been shown that pathogenic variants are associated with poor clinical outcomes in patients with familial hypercholesterolemia (FH). However, data on the effect of different types of pathogenic variants on FH phenotype is limited. Methods: We retrospectively investigated the associations between genotypes and phenotypes, including low-density lipoprotein (LDL) cholesterol level and the occurrence of major adverse cardiac events (MACEs), defined as cardiovascular death, myocardial infarction, unstable angina, or coronary artery revascularization, in patients with FH (N = 1,050, male/female = 490/560). Based on genotype, the patients were divided into the following three groups: patients without pathogenic variants, patients with missense variants, and patients with protein-truncating variants (PTVs). Cox proportional hazard model was used to identify the factors associated with MACEs. Results: The median follow-up duration was 12.6 years (interquartile range = 9.5-17.9 years). There were 665 patients with FH-mutation (277 patients with missense variants and 388 patients with PTVs) and 385 patients without FH-mutation. Over the follow-up duration, 175 MACEs were observed. We identified 89 different pathogenic variants in the 665 patients with FH. LDL cholesterol level was found to be significantly higher in patients with PTVs (256 mg/dl) than in patients with missense variants (236 mg/dl) and patients without pathogenic variants (216 mg/dl). It was also found that PTVs and missense variants are significantly associated with MACEs (hazard ratio [HR] = 1.58, 95% confidence interval [CI] = 1.08-2.08, p = 0.0033 and HR = 3.24, 95% CI = 2.12-4.40, p = 3.9 × 10-6, respectively), independent of classical risk factors. Conclusion: Pathogenic variants, especially PTVs, are significantly associated with poor outcomes in patients with FH. Genetic testing is useful for the diagnosis and risk stratification of patients with FH.
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