Background: Familial combined hyperlipidemia (FCH) is the most common genetic lipid disorder with an undefined genetic etiology. Apolipoprotein A5 gene (APOA5) variants were previously shown to contribute to FCH. The aim of the present study was to evaluate the association of APOA5 variants with FCH and its related phenotypes in Dutch FCH patients. Furthermore, the effects of variants in the APOA5 gene on carotid intima-media thickness (IMT) and cardiovascular disease (CVD) were examined. Materials and methods: The study population consisted of 36 Dutch families, including 157 FCH patients. Two polymorphisms in the APOA5 gene (- 1131T > C and S19W) were genotyped. Results: Haplotype analysis of APOA5 showed an association with FCH (p = 0.029), total cholesterol (p = 0.031), triglycerides (p < 0.001), apolipoprotein B (p = 0.011), HDL-cholesterol (p = 0.013), small dense LDL (p = 0.010) and remnant-like particle cholesterol (p = 0.001). Compared to S19 homozygotes, 19W carriers had an increased risk of FCH (OR = 1.6 [1.0-2.6]; p = 0.026) and a more atherogenic lipid profile, reflected by higher triglyceride (+ 22%) and apolipoprotein B levels (+ 5%), decreased HDL-cholesterol levels (- 7%) and an increased prevalence of small dense LDL (16% vs. 26%). In carriers of the - 1131C allele, small dense LDL was more prevalent than in - 1131T homozygotes (29% vs. 16%). No association of the APOA5 gene with IMT and CVD was evident. Conclusion: In Dutch FCH families, variants in the APOA5 gene are associated with FCH and an atherogenic lipid profile.

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Keywords APOA5 gene, Familial combined hyperlipidemia, Haplotype, Intima-media thickness, Remnant-like particle, Triglyceride level
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van der Vleuten, G.M., Isaacs, A., Zeng, W.-W., ter Avest, E., Talmud, P.J., Dallinga-Thie, G.M., … de Graaf, J.. (2007). Haplotype analyses of the APOA5 gene in patients with familial combined hyperlipidemia. Biochimica et Biophysica Acta - Molecular Basis of Disease, 1772(1), 81–88. doi:10.1016/j.bbadis.2006.10.012