Atherosclerosis 138 (1998) 91 – 99 Gender-related association between the - 93T  G/D9N haplotype of the lipoprotein lipase gene and elevated lipid levels in familial combined hyperlipidemia Marie ¨tte J.V. Hoffer a, *, Sebastian J.H. Bredie b , Harold Snieder c , Paul W.A. Reymer d , Pierre N.M. Demacker b , Louis M. Havekes e , Dorret I. Boomsma c , Anton F.H. Stalenhoef b , Rune R. Frants a , Johannes J.P. Kastelein d a MGC-Department of Human Genetics, Leiden Uniersity Medical Center, P.O. Box 9503, 2300 RA Leiden, The Netherlands b Department of Medicine, Diision of General Internal Medicine, Uniersity Hospital Nijmegen, Nijmegen, The Netherlands c Department of Psychophysiology, Free Uniersity, Amsterdam, The Netherlands d Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands e TNO-PG, Gaubius Laboratorium, Leiden, The Netherlands Received 20 June 1997; received in revised form 28 November 1997; accepted 15 December 1997 Abstract Familial combined hyperlipidemia (FCHL) is a frequent cause of premature coronary artery disease. Affected family members are characterized by different combinations of elevated cholesterol and/or triglyceride levels. A reduction in lipoprotein lipase (LPL) activity has been observed in a subgroup of FCHL patients. Recently, we have demonstrated an increased frequency of mutations in the LPL gene in Dutch FCHL patients compared to normolipidemic controls. In the present study, we have applied a pedigree-based maximum likelihood method to study the effect of LPL mutations on the phenotypic expression of FCHL in families. In 40 FCHL probandi, three different previously reported mutations in the LPL gene were identified resulting in amino acid changes, D9N, N291S, and S447X. The D9N mutation in exon 2 appeared to be in strong linkage disequilibrium with a T G substitution at position -93 in the promoter region of the LPL gene. We present data that the -93T G/D9N haplotype is associated with significantly higher levels of LDL and VLDL cholesterol, and VLDL triglycerides. Interestingly, the effect was only observed in male carriers. In line with our previous observations, these results further sustain that the LPL gene is a susceptibility gene for dyslipidemia which explains part of the variability in the phenotype observed among FCHL family members. © 1998 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Familial combined hyperlipidemia; Lipoprotein lipase; Family study; Mutation analysis; Genetic predisposition 1. Introduction Familial combined hyperlipidemia (FCHL) is a com- mon lipid trait found among survivors of premature myocardial infarction. In the general population, FCHL occurs with an estimated frequency of 0.3–2% [1,2]. Goldstein et al. [1] and Rose et al. [2] were the first to show that the FCHL syndrome was distinct from familial hypercholesterolemia and familial hypertriglyceridemia. In FCHL families, affected relatives exhibit different combinations of elevated plasma cholesterol and ele- vated triglyceride levels. In addition, characteristics such as increased very low density lipoprotein (VLDL) production, increased plasma apolipoprotein (APO) B100, predominance of small dense low density lipo- protein (LDL), and insulin resistance have been de- * Corresponding author. Tel.: +31 71 5276085; fax: +31 71 5276075; e-mail: hoffer@ruly46.leidenuniv.nl 0021-9150/98/$19.00 © 1998 Elsevier Science Ireland Ltd. All rights reserved. PII S0021-9150(98)00007-0