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Familial hypercholesterolemia (FH) is commonly caused by mutations in the low-density lipoprotein receptor (LDLR), apolipoprotein B, and proprotein convertase subtilisin/kexin type 9 genes. The study aim was to investigate patients with FH in Taiwan, using molecular diagnostic methods, and compare the abnormalities in the small mutation and large DNA rearrangement subgroups. In total, 102 unrelated probands with FH were tested for mutations by exon-by-exon sequence analysis (EBESA) and multiple ligation-dependent probe amplification (MLPA). EBESA identified gene apolipoprotein B R3500W in 8 probands and 25 mis-sense, 5 nonsense, and 6 frameshift LDLR mutations in 52 probands; 11 were novel mutations. Of the 42 probands with mutations undetected by EBESA, 8 had abnormal MLPA patterns, including 2 with exon 6 to 18 deletions, 2 with exon 9 deletion, 1 with exon 6 to 8 deletions, 1 with exon 11 deletion, 1 with exon 3 to 5 duplications, and 1 with exon 7 to 12 duplications. Pedigree analysis showed mutation cosegregation with hypercholesterolemia in affected family members. Mean lipid profiles and rate of failure to lower LDL cholesterol <100 mg/dl in response to rosuvastatin/ezetimibe treatment were similar in groups with abnormal MLPA patterns and groups carrying nonsense or frameshift mutations. In conclusion, frequency of large LDLR rearrangement was approximately 8% in Taiwanese patients with FH. The response to statin drugs differed between probands with abnormal MLPA patterns and probands carrying mis-sense or undetected mutations.

The aim of this study was to investigate the potential relationships between the carotid intima media thickness (carotid IMT), high sensitive C-reactive protein (hsCRP), and cholesterol burden in heterozygous familial hypercholesterolemia (FH) subjects. Thirty-two genetically-verified heterozygous patients with FH and 34 healthy controls were recruited into our study in Taiwan. We measured conventional risk factors, hsCRP, and carotid IMT of study subjects. The cholesterol-year score was used to estimate the lifetime cholesterol burden. Subjects with heterozygous FH had significantly elevated total cholesterol, elevated low-density lipoprotein cholesterol, and increased carotid IMT compared with control subjects. Carotid IMT correlated well with the cholesterol-year score. In patients with FH, univariate analysis showed that hsCRP was highly correlated with carotid IMT. Multiple linear regression analysis indicated that hsCRP was the only independent predictor of carotid IMT in patients with FH. In conclusion, patients with heterozygous FH had significantly higher carotid IMT and the level of hsCRP was independently associated with atherosclerotic progression. (R: 0.639, R(2): 0.408, p <0.001).

The extent of coronary artery calcium (CAC) is correlated with coronary artery disease prognosis. However, the relation of CAC to endothelial function and high-sensitivity C-reactive protein (hs-CRP) in patients with asymptomatic heterozygous familial hypercholesterolemia (FH) requires clarification. The study aim was to investigate the relations among CAC, endothelial function, and hs-CRP in patients with asymptomatic heterozygous FH. Thirty-two patients with asymptomatic heterozygous FH (mean age 42 years) and 34 healthy control subjects (mean age 36 years) were enrolled. We measured CAC by electron-beam computed tomography and endothelial function by flow-mediated dilation of the brachial artery. A higher percentage of patients with FH had a positive CAC score compared with the control group. Comparing the FH group with detectable CAC (CAC score >0) and undetectable CAC (CAC score of 0), we found higher hs-CRP levels (0.29 +/- 0.23 vs 0.07 +/- 0.08 mg/dl, p = 0.001) and reduced flow-mediated dilation (0.04 +/- 0.03 vs 0.08 +/- 0.03, p = 0.005) in the detectable CAC group. Multivariate analysis showed an independent correlation of hs-CRP with detectable CAC (relative risk 5.034, 95% confidence interval 1.525 to 16.613, p = 0.04). In conclusion, FH subjects with positive CAC scores have decreased flow-mediated dilation and increased hs-CRP levels. Furthermore, hs-CRP level is the only independent predictor of the presence of CAC.