Atherosclerosis 180 (2005) 93–99 Effect of low-density lipoprotein receptor mutation on lipoproteins and cardiovascular disease risk: a parent–offspring study Kristel C.M.C. Koeijvoets a , Albert Wiegman b , Jessica Rodenburg b , Joep C. Defesche b , John J.P. Kastelein b , Eric J.G. Sijbrands a,∗ a Department of Internal Medicine, Erasmus Medical Centre-D435, P.O. Box 2040, 3000 AC Rotterdam, The Netherlands b Department of Vascular Medicine, Academic Medical Centre, Amsterdam, The Netherlands Received 29 March 2004; received in revised form 8 October 2004; accepted 21 October 2004 Available online 19 December 2004 Abstract Studies on the clinical consequences of different low-density lipoprotein (LDL) receptor genotypes in adult patients have yielded conflicting results. We hypothesized that children with familial hypercholesterolemia (FH) provide a better model to perform genotype–phenotype analyses than adults. We tested this hypothesis and assessed the effect of LDL receptor genotypes on lipoprotein levels and on parental risk of cardiovascular disease (CVD) in a pediatric FH cohort. We identified 75 different LDL receptor mutations in 645 children with heterozygous FH; in these children, null alleles were clearly associated with more elevated LDL cholesterol levels compared to receptor-defective mutations. Familial factors explained 50.4% of the variation in LDL cholesterol levels of this pediatric cohort compared to only 9.5% in adults. Parental CVD risk was not significantly different between carriers of null alleles and receptor-defective mutations (RR, 1.22; 95% CI, 0.76–1.95; p = 0.4). The N543H/2393del9 mutation was associated with a less deteriorated lipid profile and the parents had less often CVD relative to parents with other mutations (RR, 0.39; 95% CI, 0.20–0.78; p =0.008). We could confirm that children with FH provide a better model to perform genotype–phenotype analyses. In particular, children with null alleles had significantly more elevated LDL cholesterol levels than carriers of other alleles but this was not associated with higher risk of CVD in the parents. Nonetheless, a specific LDL receptor mutation was associated with less deteriorated lipoprotein levels and a milder CVD risk. © 2004 Elsevier Ireland Ltd. All rights reserved. Keywords: Cardiovascular disease; Children; Familial hypercholesterolemia; Genotype–phenotype relation; LDL receptor mutations 1. Introduction Familial hypercholesterolemia (FH) is a common disorder caused by mutations in the low-density lipoprotein (LDL) receptor gene. FH is characterized by elevated plasma LDL cholesterol (LDL-C) levels, tendinous xanthomas, and pre- mature cardiovascular disease (CVD) [1]. Despite the mono- genic nature of the disorder, heterozygous FH shows large variability in phenotypic expression related to both environ- mental and genetic factors [2]. At present, more than 800 sequence variations in the LDL receptor gene have been iden- ∗ Corresponding author. Tel.: +31 10 4639222x3621; fax: +31 10 4633268. E-mail address: e.sijbrands@erasmusmc.nl (E.J.G. Sijbrands). tified and the residual LDL receptor activity varies consider- ably between mutations [3,4]. Previous studies in adult heterozygous FH patients have assessed whether the residual LDL receptor function in- fluenced lipoprotein metabolism and, consequently, cardio- vascular risk. These studies have yielded conflicting results [5–14]. Additional familial factors were proposed to have greater influence on the clinical consequences of FH [2,15]. In effect, it is not clear whether variance of lipoprotein lev- els and CVD risk could be attributed to variation at the LDL receptor locus or to additional familial factors. For instance, adult FH patients referred to lipid clinics often suffered from additional lipid disorders [16]. Such additional lipid disorders are not yet expressed in childhood. Therefore, FH children might be more suited to analyze the exact effects of LDL 0021-9150/$ – see front matter © 2004 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.atherosclerosis.2004.10.042