Atherosclerosis 183 (2005) 355–360 Elevated leptin levels in subjects with familial combined hyperlipidemia are associated with the increased risk for CVD Gerly M. van der Vleuten a,∗ , Mario J. Veerkamp a , Lambertus J.H. van Tits a , Helga Toenhake a , Martin den Heijer a,b , Anton F.H. Stalenhoef a , Jacqueline de Graaf a a Department of Medicine, Division of General Internal Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands b Department of Medicine, Division of Endocrinology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands Received 7 June 2004; received in revised form 2 February 2005; accepted 3 March 2005 Available online 27 April 2005 Abstract Familial combined hyperlipidemia (FCH) is characterized by hypercholesterolemia and/or hypertriglyceridemia and is associated with premature cardiovascular disease (CVD). Other features of FCH are obesity and insulin resistance. Serum leptin levels have been associated with obesity, insulin resistance and CVD. The aim of this study was to determine whether increased leptin levels contribute to the FCH phenotype and its increased risk for CVD. The study population comprised 644 subjects, including 158 FCH patients. Leptin levels were determined, using a commercially available ELISA. For both males and females, the mean leptin level (ng/ml) was higher in FCH patients compared to normolipidemic relatives and spouses. However, after standardization for BMI and insulin resistance, these differences disappeared. The 90th percentile of the leptin level, standardized for BMI, insulin resistance and gender, was associated with an increased risk for CVD in FCH patients (odds ratio = 2.9, 95% CI = 1.1–8.0) and in non-FCH subjects (odds ratio = 3.4, 95% CI = 1.3–9.0). The overall increased risk for CVD, associated with a leptin level >90th percentile, was 3.3 (95% CI = 1.7–6.4). We conclude that in patients with FCH, leptin levels are increased in proportion to their higher BMI and the presence of insulin resistance. These increased leptin levels are associated with an increased risk for CVD both in FCH patients and non-FCH subjects, independent of BMI, insulin resistance and gender. © 2005 Elsevier Ireland Ltd. All rights reserved. Keywords: Leptin; FCH; Obesity; Insulin resistance; CVD 1. Introduction Familial combined hyperlipidemia (FCH) is the most com- mon genetic hyperlipidemia in humans and affects 1–3% of the general population. It is characterized by multiple lipopro- tein phenotypes and is strongly associated with premature cardiovascular disease (CVD). Of the survivors of a prema- ture myocardial infarction, up to 20% are affected with FCH [1]. FCH is characterized by hypercholesterolemia and/or hy- pertriglyceridemia. Other phenotypes of FCH are elevated levels of apolipoprotein B (apo B) and low-density lipopro- ∗ Corresponding author. Present address: Department of Medicine, Di- vision of General Internal Medicine, 541, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands. Tel.: +31 24 3615393; fax: +31 24 3541346. E-mail address: G.vandervleuten@aig.umcn.nl (G.M. van der Vleuten). tein cholesterol (LDLc), decreased levels of high-density lipoprotein cholesterol (HDLc) and the presence of small dense LDL (sdLDL). In addition, FCH is associated with obesity and insulin resistance [2]. Obesity results in an increase in number and size of adi- pocytes. These adipocytes secrete leptin, a hormone, which is increased in obese subjects [3]. Leptin is involved in the reg- ulation of the energy expenditure and appetite via hypotha- lamic receptors [4]. An increase of leptin level will lead to more energy expenditure and less appetite in normal persons via the hypothalamus. Obese persons have increased levels of leptin, but these high levels appear to fail to influence en- ergy intake or expenditure to restore fat mass to normal. It is, therefore, believed that obesity is a state of leptin resistance. Leptin has direct effects on insulin secretion by inhibiting insulin gene transcription [5] and insulin secretion [6]. On 0021-9150/$ – see front matter © 2005 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.atherosclerosis.2005.03.019