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Molecular Characterization of Familial Hypercholesterolemia in a North American Cohort
Abhimanyu Garg1, Sergio Fazio2, P Barton Duell2
1Division of Nutrition and Metabolic Diseases, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas.
Insights
Low-density lipoprotein receptor (LDLR) mutations are the primary genetic cause of familial hypercholesterolemia (FH) in North America. However, 40% of FH patients lacked identifiable mutations, highlighting the need for further research into FH causes.
Area of Science:
- Genetics
- Cardiovascular Medicine
- Metabolic Disorders
Background:
- Familial hypercholesterolemia (FH) significantly increases the risk of premature cardiovascular disease.
- Commonly, FH is caused by mutations in the LDLR, APOB, or PCSK9 genes, and rarely in LDLRAP1.
- Identifying genetic causes is crucial for understanding and managing FH.
Purpose of the Study:
- To determine the prevalence of pathogenic mutations in LDLR, APOB, and PCSK9 genes in a North American FH cohort.
- To compare clinical characteristics between FH patients with and without identified mutations.
Main Methods:
- Targeted sequencing of LDLR, PCSK9 coding regions, and APOB exon 26.
- Detection of LDLR deletions and duplications.
- Analysis of demographic, clinical, and lipid data from 200 FH patients.
Main Results:
- Pathogenic LDLR and APOB mutations were identified in 114 and 6 subjects, respectively.
- Eight novel LDLR mutations were discovered among 58 identified LDLR variants.
- Mutation-negative FH subjects were older and had higher rates of hypertension and elevated triglycerides.
Conclusions:
- LDLR mutations are the most frequent cause of heterozygous FH in this North American cohort.
- A significant 40% of FH patients did not have mutations in the screened genes.
- Further research is needed to identify genetic and environmental factors in mutation-negative FH patients.
Background:
Familial hypercholesterolemia (FH) confers a very high risk of premature cardiovascular disease and is commonly caused by mutations in low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), or proprotein convertase subtilisin/kexin type 9 (PCSK9) and very rarely in LDLR adaptor protein 1 (LDLRAP1) genes.
Objective:
To determine the prevalence of pathogenic mutations in the LDLR, APOB, and PCSK9 in a cohort of subjects who met Simon Broome criteria for FH and compare the clinical characteristics of mutation-positive and mutation-negative subjects.
Methods:
Ninety-three men and 107 women aged 19 to 80 years from lipid clinics in the United States and Canada participated. Demographic and historical data were collected, physical examination performed, and serum lipids/lipoproteins analyzed. Targeted sequencing analyses of LDLR and PCSK9 coding regions and exon 26 of APOB were performed followed by detection of LDLR deletions and duplications.
Results:
Disease-causing LDLR and APOB variants were identified in 114 and 6 subjects, respectively. Of the 58 LDLR variants, 8 were novel mutations. Compared with mutation-positive subjects, mutation-negative subjects were older (mean 49 years vs 57 years, respectively) and had a higher proportion of African Americans (1% vs 12.5%), higher prevalence of hypertension (21% vs 46%), and higher serum triglycerides (median 86 mg/dL vs 122 mg/dL) levels.
Conclusions:
LDLR mutations were the most common cause of heterozygous FH in this North American cohort. A strikingly high proportion of FH subjects (40%) lacked mutations in known culprit genes. Identification of underlying genetic and environmental factors in mutation-negative patients is important to further our understanding of the metabolic basis of FH and other forms of severe hypercholesterolemia.
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