Molecular Characterization of Familial Hypercholesterolemia in a North American Cohort

BACKGROUND: Familial hypercholesterolemia (FH) confers a very high risk of premature cardiovascular disease and is commonly caused by mutations in LDLR, APOB, or PCSK9 and very rarely in LDLRAP1. 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 –negative subjects. METHODS: 93 men and 107 women aged 19–80 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 versus 57 years, respectively) and had a higher proportion of African-Americans (1% versus 12.5%), higher prevalence of hypertension (21% versus 46%), and higher serum triglycerides (median: 86 mg/dL versus 122 mg/dL) levels. CONCLUSION: 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.