http://repub.eur.nl/res/aut/56343/ List of Publications en http://repub.eur.nl/static-eur/img/logo.png http://repub.eur.nl http://repub.eur.nl/res/pub/35481/ 2007-04-01T00:00:00Z Context: The traditional lipid and lipoprotein levels in patients with familial combined hyperlipidemia (FCH) are relatively mildly elevated and do not fully explain the increased risk of cardiovascular disease (CVD). In other populations, high remnant-like particles cholesterol (RLP-C) levels are an independent risk factor for CVD. Objective: The objective of the study was to investigate whether plasma RLP-C concentrations are elevated in patients with FCH and contribute to the increased prevalence of CVD. Design, Setting, Participants: In this cross-sectional study, we studied RLP-C levels in 37 FCH families comprising 582 subjects, of whom 134 subjects were diagnosed FCH based on total cholesterol, triglyceride, and apolipoprotein-B levels. Plasma RLP-C concentrations were determined using an immune-separation technique. Results: For both men and women, the mean plasma RLP-C concentration (mmol/liter) was 2-fold elevated in FCH patients [0.59 (0.54-0.66) and 0.40 (0.37-0.43), respectively] compared with both normolipidemic relatives [0.27 (0.26-0.29) in male and 0.22 (0.21-0.23) in female, all P < 0.000]; and spouses [0.27 (0.23-0.31) in male and 0.24 (0.21-0.27) in female, all P <0.000]. Plasma RLP-C levels above the 90th percentile predicted prevalent CVD, independently of nonlipid cardiovascular risk factors [odds ratio 2.18 (1.02-4.66)] and triglyceride levels [odds ratio 2.35 (1.15-4.83)]. However, in both FCH patients and controls, RLP-C did not provide additional information about prevalent CVD over and above non-high-density lipoprotein cholesterol levels. Conclusions: Patients with FCH have 2-fold elevated plasma RLP-C levels, which add to the atherogenic lipid profile and contribute to the increased risk for CVD. However, for clinical practice, non-high-density lipoprotein cholesterol is the best predictor of prevalent CVD. Copyright http://repub.eur.nl/res/pub/35664/ 2007-01-01T00:00:00Z Recently, the upstream stimulatory factor 1 gene (USF1) was proposed as a candidate gene for familial combined hyperlipidemia (FCH). In this study, we examined the previously identified risk haplotype of USF1 with respect to FCH and its related phenotypes in 36 Dutch FCH families. The diagnosis of FCH was based on both the traditional diagnostic criteria and a nomogram. The two polymorphisms, USF1s1 and USF1s2, were in complete linkage disequilibrium. No association was found for the individual single nucleotide polymorphisms (SNPs) with FCH defined by the nomogram (USF1s1, P = 0.53; USF1s2, P = 0.53), whereas suggestive associations were found when using the traditional diagnostic criteria for FCH (USF1s1, P = 0.08; USF1s2, P = 0.07). USF1 was associated with total cholesterol (USF1s1, P 5 0.05; USF1s2, P = 0.04) and apolipoprotein B (USF1s1, P = 0.06; USF1s2, P = 0.04). Small dense LDL showed a suggestive association (USF1s1, P = 0.10; USF1s2, P = 0.09). The results from the haplotype analyses supported the results obtained for the individual SNPs. In conclusion, the previously identified risk haplotype of USF1 showed a suggestive association with FCH and contributed to the related lipid traits in our Dutch FCH families. Copyright http://repub.eur.nl/res/pub/36528/ 2007-01-01T00:00:00Z 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.