Clinical characterization of familial hypercholesterolemia due to an amish founder mutation in Apolipoprotein B

BACKGROUND: Familial hypercholesterolemia (FH) due to a founder variant in Apolipoprotein B (ApoB(R3500Q)) is reported in 12% of the Pennsylvania Amish community. By studying a cohort of ApoB(R3500Q) heterozygotes and homozygotes, we aimed to characterize the biochemical and cardiac imaging features in children and young adults with a common genetic background and similar lifestyle. METHODS: We employed advanced lipid profile testing, carotid intima media thickness (CIMT), pulse wave velocity (PWV), and peripheral artery tonometry (PAT) to assess atherosclerosis in a cohort of Amish ApoB(R3500Q) heterozygotes (n = 13), homozygotes (n = 3), and their unaffected, age-matched siblings (n = 9). ApoB(R3500Q) homozygotes were not included in statistical comparisons. RESULTS: LDL cholesterol (LDL-C) was significantly elevated among ApoB(R3500Q) heterozygotes compared to sibling controls, though several ApoB(R3500Q) heterozygotes had LDL-C levels in the normal range. LDL particles (LDL-P), small, dense LDL particles, and ApoB were also significantly elevated among subjects with ApoB(R3500Q). Despite these differences in serum lipids and particles, CIMT and PWV were not significantly different between ApoB(R3500Q) heterozygotes and controls in age-adjusted analysis. CONCLUSIONS: We provide a detailed description of the serum lipids, atherosclerotic plaque burden, vascular stiffness, and endothelial function among children and young adults with FH due to heterozygous ApoB(R3500Q). Fasting LDL-C was lower than what is seen with other forms of FH, and even normal in several ApoB(R3500Q) heterozygotes, emphasizing the importance of cascade genetic testing among related individuals for diagnosis. We found increased number of LDL particles among ApoB(R3500Q) heterozygotes but an absence of detectable atherosclerosis. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12872-022-02539-3.