Clin Chem Lab Med 2007;45(9):1190–1198  2007 by Walter de Gruyter • Berlin • New York. DOI 10.1515/CCLM.2007.267 2007/53 Article in press - uncorrected proof Association between the TaqIB polymorphism in the cholesteryl ester transfer protein gene locus and postprandial plasma lipoprotein levels in heterozygotes for familial hypercholesterolemia Genovefa Kolovou 1, *, Katherine Anagnostopoulou 1 , Peggy Kostakou 1 , Christina Marvaki 2 , Constantinos Mihas 3 , Dimitri P. Mikhailidis 4 and Dennis V. Cokkinos 1 1 1st Cardiology Department, Onassis Cardiac Surgery Center, Athens, Greece 2 Department of Nursing, Technical School of Education, Athens, Greece 3 Internal Medicine Department, General Hospital of Kimi, Kimi, Greece 4 Department of Clinical Biochemistry (Vascular Disease Prevention Clinics), Royal Free Hospital, Royal Free and University College Medical School, London, UK Abstract Background: We examined the influence of cholester- yl ester transfer protein TaqIB polymorphism on tri- glyceride (TG) response to an oral fat tolerance test (OFTT) in patients heterozygous for familial hypercho- lesterolemia (hFH). Methods: We genotyped 67 hFH patients (32 men and 35 postmenopausal women) who were subjected to an OFTT. Results: All B1 allele carriers had lower high-density lipoprotein cholesterol (HDL-C) levels (ps0.013) and higher postprandial TG response at 6 and 8 h (ps0.05 and ps0.04, respectively) compared to B2 allele car- riers. Multiple regression analysis showed that in the hFH group with a positive response, the presence of the B2 allele was significantly related to lower levels of TG-area under the curve (AUC) (p-0.01) compared to B1, adjusting for age, gender and body mass index. In the hFH group with a negative response, although age and female gender had a significant effect on TG- AUC levels (p-0.01 for both), the allele type was not significantly related to the TG-AUC levels (ps0.99). Conclusions: B2 carriers had a lower postprandial TG response compared to B1 carriers. There were no dif- ferences in TG levels between B1 and B2 carriers in patients with a negative OFTT response. Therefore, at higher TG concentration, the B2 allele may protect against an exaggerated postprandial TG increase and subsequent lowering of HDL-C. Clin Chem Lab Med 2007;45:1190–8. *Corresponding author: Genovefa D. Kolovou, MD, PhD, FESC, SFASA, Onassis Cardiac Surgery Center, 356 Sygrou Avenue, 176 74 Athens, Greece Phone: q30-210-9493520, Fax: q30-210-9493336, E-mail: genovefa@kolovou.com Keywords: atherosclerosis; cholesteryl ester transfer protein; familial hypercholesterolemia; high-density lipoprotein cholesterol; postprandial hypertriglyceri- demia; TaqIB polymorphism. Introduction Many studies have shown that hypertriglyceridemia plays a role in the development of premature athero- sclerosis (1–3). Disturbances in triglyceride (TG) metabolism are characterized by postprandial accu- mulation of TG-rich lipoprotein remnants and have been reported in various populations with elevated vascular risk (4–10). Familial hypercholesterolemia (FH) is an autosomal codominant single-gene disor- der caused by mutations in the low-density lipopro- tein (LDL) receptor gene. The clinical manifestations vary among patients. However, patients heterozygous for FH (hFH) are characterized by an increase in plas- ma LDL-cholesterol (LDL-C) concentrations, tendon xanthomata and premature coronary heart disease (CHD) (11). FH in combination with disturbances in postprandial lipoprotein metabolism is associated with a higher risk of CHD (12). Animal studies have shown that LDL receptor deficiency is associated with a delayed clearance of chylomicron remnants since, among other receptors, the LDL receptor is used for remnant hepatic uptake (13–15). We (16, 17) and others (7, 12, 18) have demonstrated a significant postprandial increase in TG-rich lipoproteins in hFH patients compared to normolipidemic controls. Cholesteryl ester transfer protein (CETP) plays a major role in the remodeling of lipoprotein particles by mediating the transfer of cholesteryl ester from high-density lipoprotein (HDL) to apolipoprotein B-containing lipoproteins in exchange for TG. When the level of TG-rich lipoproteins is normal, CETP transfers of HDL cholesteryl esters are directed with preference towards LDL particles (19). In contrast, when the level of TG-rich lipoproteins is increased, CETP transfers of HDL cholesteryl esters are directed towards larger very low-density lipoprotein particles, and there are high net transfer rates of TG to LDL and HDL (20). TG-enriched LDL and HDL are substrates for hepatic lipase, giving rise to small dense LDL and HDL particles, respectively (20). Small dense LDL particles have proatherogenic properties (e.g., increased arte- rial wall retention and susceptibility to oxidation) (19, 21), while small dense HDL particles are more prone to catabolism. TaqIB polymorphism has been found to account for 5.8% of the variance in HDL cholesterol (HDL-C) (22). Subjects with the B2 allele usually have Brought to you by | Karolinska Institute Authenticated Download Date | 5/26/15 6:54 PM