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• W2018455877 abstract "Small, dense LDL particles have been associated with an increased risk of coronary artery disease, and cholesteryl ester transfer protein (CETP) has been suggested to play a role in LDL particle remodeling. We examined the relationship between LDL heterogeneity and plasma CETP mass in familial hypercholesterolemia (FH). LDL particles were characterized by polyacrylamide gradient gel electrophoresis in a total of 259 FH heterozygotes and 208 nonFH controls. CETP mass was measured by enzyme-linked immunosorbent assay in a subgroup of 240 participants, which included 120 FH patients matched with 120 controls. As compared with controls, FH subjects had an 11% higher CETP mass. Moreover, LDL-peak particle diameter (LDL-PPD) was significantly smaller in FH heterozygotes than in controls (258.1 ± 4.8 vs. 259.2 ± 4.1 Å; P = 0.01) after adjustment for covariates. There was also an inverse relationship between LDL-PPD and CETP mass (R = −0.15; P = 0.02), and this relationship was abolished by adjustment for the FH/control status, indicating that LDL-PPD changes in FH are mediated, at least in part, by an increase in plasma CETP mass concentrations.These results suggest that increased plasma CETP mass concentrations could lead to significant LDL particle remodeling in FH heterozygotes and could contribute to the pathogenesis of atherosclerosis. Small, dense LDL particles have been associated with an increased risk of coronary artery disease, and cholesteryl ester transfer protein (CETP) has been suggested to play a role in LDL particle remodeling. We examined the relationship between LDL heterogeneity and plasma CETP mass in familial hypercholesterolemia (FH). LDL particles were characterized by polyacrylamide gradient gel electrophoresis in a total of 259 FH heterozygotes and 208 nonFH controls. CETP mass was measured by enzyme-linked immunosorbent assay in a subgroup of 240 participants, which included 120 FH patients matched with 120 controls. As compared with controls, FH subjects had an 11% higher CETP mass. Moreover, LDL-peak particle diameter (LDL-PPD) was significantly smaller in FH heterozygotes than in controls (258.1 ± 4.8 vs. 259.2 ± 4.1 Å; P = 0.01) after adjustment for covariates. There was also an inverse relationship between LDL-PPD and CETP mass (R = −0.15; P = 0.02), and this relationship was abolished by adjustment for the FH/control status, indicating that LDL-PPD changes in FH are mediated, at least in part, by an increase in plasma CETP mass concentrations. These results suggest that increased plasma CETP mass concentrations could lead to significant LDL particle remodeling in FH heterozygotes and could contribute to the pathogenesis of atherosclerosis. Familial hypercholesterolemia (FH) is an autosomal codominant single-gene disorder caused by mutations in the LDL receptor (LDLR) gene that disrupt the normal clearance of LDL (1Goldstein J.L. Hobbs H.H. Brown M.S. Familial hypercholesterolemia.in: Scriver C.R. Beaudet A.L. Sly W.S. Valle D. The Metabolic Basis of Inherited Diseases. McGraw-Hill Publishing Co., New York1995: 1981-2030Google Scholar). Phenotypic features characteristic of the disease’s heterozygous form are a 2- to 3-fold rise in plasma LDL-cholesterol (LDL-C) concentrations, tendinous xanthomatosis, and premature atherosclerotic coronary artery disease (CAD), usually occurring between the ages of 35 years and 55 years. Homozygous or compound heterozygous patients have plasma LDL concentrations 6- to 8-fold higher than normal and usually manifest a CAD event before the age of 20 years. FH is also one of the most common inherited diseases in the world, with a frequency of 1 in 500 for heterozygotes and 1 per million for homozygotes (1Goldstein J.L. Hobbs H.H. Brown M.S. Familial hypercholesterolemia.in: Scriver C.R. Beaudet A.L. Sly W.S. Valle D. The Metabolic Basis of Inherited Diseases. McGraw-Hill Publishing Co., New York1995: 1981-2030Google Scholar). In the Province of Québec, the homozygote prevalence is 6-fold higher, and the minimal heterozygote frequency ranges from 1:81 to 1:154 (2Moorjani S. Roy M. Gagné C. Davignon J. Brun D. Toussaint M. Lambert M. Campeau L. Blaichman S. Lupien P. Homozygous familial hypercholesterolemia among French Canadians in Quebec Province.Arteriosclerosis. 1989; 9: 211-216Crossref PubMed Google Scholar). Nine mutations are responsible for 90% of the heterozygous FH cases in the French-Canadian population, defined on the basis of clinical and biochemical criteria (3Couture P. Vohl M.C. Gagné C. Gaudet D. Torres A.L. Lupien P.J. Després J.P. Labrie F. Simard J. Moorjani S. Identification of three mutations in the low-density lipoprotein receptor gene causing familial hypercholesterolemia among French Canadians.Hum. Mutat. 1998; : S226-S231Crossref PubMed Scopus (27) Google Scholar). Cholesteryl ester transfer protein (CETP) plays a major role in the remodeling of lipoprotein particles by mediating the transfer of cholesteryl ester from HDL to apolipoprotein B (apoB)-containing lipoproteins in exchange for triglycerides, and several lines of evidence support the notion that CETP is linked to LDL size heterogeneity (4Talmud P.J. Edwards K.L. Turner C.M. Newman B. Palmen J.M. Humphries S.E. Austin M.A. Linkage of the cholesteryl ester transfer protein (CETP) gene to LDL particle size: use of a novel tetranucleotide repeat within the CETP promoter.Circulation. 2000; 101: 2461-2466Crossref PubMed Scopus (62) Google Scholar). Small, dense LDL particles have been associated with CAD in a number of studies (5Gardner C.D. Fortmann S.P. Krauss R.M. Association of small low-density lipoprotein particles with the incidence of coronary artery disease in men and women.J. Am. Med. Assoc. 1996; 276: 875-881Crossref PubMed Google Scholar, 6Stampfer M.J. Krauss R.M. Ma J. Blanche P.J. Holl L.G. Sacks F.M. Hennekens C.H. A prospective study of triglyceride level, low-density lipoprotein particle diameter, and risk of myocardial infarction.J. Am. Med. Assoc. 1996; 276: 882-888Crossref PubMed Google Scholar, 7Lamarche B. Tchernof A. Moorjani S. Cantin B. Dagenais G.R. Lupien P.J. Després J.P. Small, dense low-density lipoprotein particles as a predictor of the risk of ischemic heart disease in men. Prospective results from the Quebec Cardiovascular Study.Circulation. 1997; 95: 69-75Crossref PubMed Scopus (1013) Google Scholar). These previous results, however, were obtained in nonFH subjects exhibiting lipoprotein profiles very different from the extremely elevated LDL-C seen in FH patients. To date, only a few studies have examined the heterogeneity of LDL particles in FH patients (8Slack J. Mills G.L. Anomalous low density lipoproteins in familial hyperbetalipoproteinaemia.Clin. Chim. Acta. 1970; 29: 15-25Crossref PubMed Scopus (41) Google Scholar, 9Patsch W. Ostlund R. Kuisk I. Levy R. Schonfeld G. Characterization of lipoprotein in a kindred with familial hypercholesterolemia.J. Lipid Res. 1982; 23: 1196-1205Abstract Full Text PDF PubMed Google Scholar, 10Bagnall T.F. Lloyrd J.K. Composition of low-density lipoprotein in children with hyperlipoproteinaemia.Clin. Chim. Acta. 1975; 59: 271-276Crossref PubMed Scopus (9) Google Scholar, 11Teng B. Thompson G.R. Sniderman A.D. Forte T.M. Krauss R.M. Kwiterovich Jr., P.O. Composition and distribution of low density lipoprotein fractions in hyperapobetalipoproteinemia, normolipidemia, and familial hypercholesterolemia.Proc. Natl. Acad. Sci. USA. 1983; 80: 6662-6666Crossref PubMed Scopus (173) Google Scholar), but their limited small sample size precluded any definitive conclusions. As characterization of LDL size could be relevant for the understanding of the variability in CAD risk among FH patients, the objective of the present study was to examine LDL size heterogeneity and its relationship to CETP in a large cohort of genetically-defined FH heterozygotes and controls. A total of 259 FH heterozygotes (122 men and 137 women) from Québec City and Saguenay (Canada) were enrolled. All participants were at least 18 years-of-age. Subjects were excluded if they: had a history of cardiovascular disease; were pregnant or nursing; had acute liver disease, hepatic dysfunction, or persistent elevations of serum transaminases; had plasma triglyceride levels >4.5 mmol/l or homozygous FH; had a secondary hyperlipidemia due to any cause; had a recent history of alcohol or drug abuse; had diabetes mellitus; had a history of cancer; or had hormonal treatment. All FH subjects were carriers of one of the nine previously known French-Canadian mutations in the LDLR gene (3Couture P. Vohl M.C. Gagné C. Gaudet D. Torres A.L. Lupien P.J. Després J.P. Labrie F. Simard J. Moorjani S. Identification of three mutations in the low-density lipoprotein receptor gene causing familial hypercholesterolemia among French Canadians.Hum. Mutat. 1998; : S226-S231Crossref PubMed Scopus (27) Google Scholar) and were apoE3 homozygotes. Of those 259 heterozygous subjects selected, 123 had the deletion >15 kb at the 5′ end of the gene (12Hobbs H.H. Brown M.S. Russell D.W. Davignon J. Goldstein J.L. Deletion in the gene for the low-density-lipoprotein receptor in a majority of French Canadians with familial hypercholesterolemia.N. Engl. J. Med. 1987; 317: 734-737Crossref PubMed Scopus (210) Google Scholar), 112 had the W66G mutation in exon 3 (13Leitersdorf E. Tobin E.J. Davignon J. Hobbs H.H. Common low-density lipoprotein receptor mutations in the French Canadian population.J. Clin. Invest. 1990; 85: 1014-1023Crossref PubMed Scopus (253) Google Scholar), 13 had the Y468× mutation in exon 10 (14Simard J. Moorjani S. Vohl M.C. Couture P. Torres A.L. Gagné C. Després J.P. Labrie F. Lupien P.J. Detection of a novel mutation (stop 468) in exon 10 of the low-density lipoprotein receptor gene causing familial hypercholesterolemia among French Canadians.Hum. Mol. Genet. 1994; 3: 1689-1691Crossref PubMed Scopus (33) Google Scholar), six had the C646Y mutation in exon 14 (15Hobbs H.H. Brown M.S. Goldstein J.L. Molecular genetics of the LDL receptor gene in familial hypercholesterolemia.Hum. Mutat. 1992; 1: 445-466Crossref PubMed Scopus (940) Google Scholar), one had the C347R mutation in exon 8 (3Couture P. Vohl M.C. Gagné C. Gaudet D. Torres A.L. Lupien P.J. Després J.P. Labrie F. Simard J. Moorjani S. Identification of three mutations in the low-density lipoprotein receptor gene causing familial hypercholesterolemia among French Canadians.Hum. Mutat. 1998; : S226-S231Crossref PubMed Scopus (27) Google Scholar), one had the E207K mutation in exon 4 (15Hobbs H.H. Brown M.S. Goldstein J.L. Molecular genetics of the LDL receptor gene in familial hypercholesterolemia.Hum. Mutat. 1992; 1: 445-466Crossref PubMed Scopus (940) Google Scholar), one had the C152W mutation in exon 4 (3Couture P. Vohl M.C. Gagné C. Gaudet D. Torres A.L. Lupien P.J. Després J.P. Labrie F. Simard J. Moorjani S. Identification of three mutations in the low-density lipoprotein receptor gene causing familial hypercholesterolemia among French Canadians.Hum. Mutat. 1998; : S226-S231Crossref PubMed Scopus (27) Google Scholar), one had the R329× mutation in exon 7 (3Couture P. Vohl M.C. Gagné C. Gaudet D. Torres A.L. Lupien P.J. Després J.P. Labrie F. Simard J. Moorjani S. Identification of three mutations in the low-density lipoprotein receptor gene causing familial hypercholesterolemia among French Canadians.Hum. Mutat. 1998; : S226-S231Crossref PubMed Scopus (27) Google Scholar), and one had the 5 kb deletion in exons 2 and 3 (15Hobbs H.H. Brown M.S. Goldstein J.L. Molecular genetics of the LDL receptor gene in familial hypercholesterolemia.Hum. Mutat. 1992; 1: 445-466Crossref PubMed Scopus (940) Google Scholar). All eligible FH participants had to withdraw lipid-lowering medications for at least 6 weeks before a blood sample was taken. The study was approved by the Laval University Medical Center ethical review committee and informed consent was obtained from each patient. A total of 208 controls (115 men and 93 women) were selected among the 2,056 participants of the Québec Health Survey, which was comprised of noninstitutionalized men and women, excluding aboriginal populations, selected from health insurance files (16Lemieux I. Almeras N. Mauriege P. Blanchet C. Dewailly E. Bergeron J. Després J.P. Prevalence of ‘hypertriglyceridemic waist’ in men who participated in the Quebec Health Survey: association with atherogenic and diabetogenic metabolic risk factors.Can. J. Cardiol. 2002; 18: 725-732PubMed Google Scholar). As previously described (16Lemieux I. Almeras N. Mauriege P. Blanchet C. Dewailly E. Bergeron J. Després J.P. Prevalence of ‘hypertriglyceridemic waist’ in men who participated in the Quebec Health Survey: association with atherogenic and diabetogenic metabolic risk factors.Can. J. Cardiol. 2002; 18: 725-732PubMed Google Scholar), the Québec Health Survey was designed to obtain relevant information on the prevalence and distribution of cardiovascular disease risk factors in the Québec population. All controls selected for the purpose of this study were apoE3 homozygotes. Blood samples were collected after a 12 h fasting period in tubes containing disodium EDTA and benzamidine (0.03%) (17Cardin A.D. Witt K.R. Chao J. Margolius H.S. Donaldson V.H. Jackson R.L. Degradation of apolipoprotein B-100 of human plasma low density lipoproteins by tissue and plasma kallikreins.J. Biol. Chem. 1984; 259: 8522-8528Abstract Full Text PDF PubMed Google Scholar). Samples were then immediately centrifugated at 4°C for 10 min at 3,000 rpm to obtain plasma and were stored at 4°C until processed. Cholesterol and triglyceride levels were determined in plasma and in lipoprotein fractions by enzymatic methods (Randox Co., Crumlin, UK) using an RA-500 analyzer (Bayer Corporation, Inc., Tarrytown, NY), as previously described (18Moorjani S. Dupont A. Labrie F. Lupien P.J. Brun D. Gagné C. Giguère M. Bélanger A. Increase in plasma high-density lipoprotein concentration following complete androgen blockage in men with prostatic carcinoma.Metabolism. 1987; 36: 244-250Abstract Full Text PDF PubMed Scopus (191) Google Scholar). Plasma VLDLs (d < 1.006 g/ml) were isolated by preparative ultracentrifugation and the HDL fraction obtained after precipitation of LDL in the infranatant (d > 1.006 g/ml) with heparin and MnCl2. The cholesterol and triglyceride contents of the infranatant fraction were measured before and after the precipitation step. Nondenaturing 2% to 16% polyacrylamide gradient gel electrophoresis was performed as described previously (19St-Pierre A.C. Ruel I.L. Cantin B. Dagenais G.R. Bernard P.M. Després J.P. Lamarche B. Comparison of various electrophoretic characteristics of LDL Particles and their relationship to the risk of ischemic heart disease.Circulation. 2001; 104: 2295-2299Crossref PubMed Scopus (227) Google Scholar). Briefly, LDL particle size was determined on 8 cm × 8 cm polyacrylamide gradient gels prepared in batches in our laboratory. Aliquots of 3.5 μl of whole plasma samples were mixed in a 1:1 vol ratio, with a sampling buffer containing 20% sucrose and 0.25% bromophenol blue, and loaded onto the gels. A 15 min prerun at 75 V preceded electrophoresis of the plasma samples at 150 V for 3 h. Gels were stained for 1 h with Sudan black (0.07%) and stored in a 0.81% acetic acid/4% methanol solution until analysis by the Imagemaster 1-D Prime computer software (Amersham Pharmacia Biotech). LDL size was extrapolated from the relative migration of four plasma standards of known diameter. The estimated diameter for the major peak in each scan was identified as the LDL-peak particle diameter (LDL-PPD). An integrated (or mean) LDL diameter was also computed by using a modification of the approach described by Tchernof et al. (20Tchernof A. Lamarche B. Prud'Homme D. Nadeau A. Moorjani S. Labrie F. Lupien P.J. Després J.P. The dense LDL phenotype. Association with plasma lipoprotein levels, visceral obesity, and hyperinsulinemia in men.Diabetes Care. 1996; 19: 629-637Crossref PubMed Scopus (274) Google Scholar). This integrated LDL particle size corresponds to the weighed mean size of all LDL subclasses in one individual. It was calculated as a continuous variable and was computed as the sum of the diameter of each LDL subclass multiplied by its relative area. Analysis of pooled plasma standards revealed that measurement of LDL-PPD was highly reproducible, with an interassay coefficient of variation of <2%. The relative proportion of LDL having a diameter <255 Å (LDL%<255 Å) was ascertained by computing the relative area of the densitometric scan <255 Å (21Rainwater D.L. Mitchell B.D. Comuzzie A.G. Haffner S.M. Relationship of low-density lipoprotein particle size and measures of adiposity.Int. J. Obes. Relat. Metab. Disord. 1999; 23: 180-189Crossref PubMed Scopus (51) Google Scholar). The absolute concentration of cholesterol among particles <255 Å (LDL-C<255 Å) was calculated by multiplying the plasma LDL-C levels by the relative proportion of LDL with a diameter <255 Å (21Rainwater D.L. Mitchell B.D. Comuzzie A.G. Haffner S.M. Relationship of low-density lipoprotein particle size and measures of adiposity.Int. J. Obes. Relat. Metab. Disord. 1999; 23: 180-189Crossref PubMed Scopus (51) Google Scholar). A similar approach was used to assess the relative and absolute concentrations of cholesterol in particles with a diameter between 255 Å and 260 Å, or >260 Å (LDL%255–260 Å, LDL-C255–260 Å and LDL%>260 Å, LDL-C>260 Å, respectively). Plasma CETP mass concentration was used to assess plasma CETP activity because they are strongly correlated (22Carr M.C. Ayyobi A.F. Murdoch S.J. Deeb S.S. Brunzell J.D. Contribution of hepatic lipase, lipoprotein lipase, and cholesteryl ester transfer protein to LDL and HDL heterogeneity in healthy women.Arterioscler. Thromb. Vasc. Biol. 2002; 22: 667-673Crossref PubMed Scopus (77) Google Scholar). However, sample handling and storage conditions may influence the stability of lipid transfer activity and, consequently, could have a significant impact on the relationship between CETP mass and activity. In the present study, CETP mass determination was used to minimize the potential effect of storage and sample handling on the stability of the lipid transfer activity. Plasma CETP mass concentration was determined by a commercial sandwich enzyme-linked immunosorbent assay kit (Wako Chemicals, Inc., Richmond, VA) in a subgroup of 240 participants, including 120 FH subjects matched for age, gender, body mass index (BMI), and smoking habits, with 120 controls. Genotyping of apoE was done by PCR-amplification of a 244 bp fragment of the exon 4 of the apoE gene with oligonucleotides F4 and F6 and digestion of PCR fragments with the restriction enzyme HhaI (23Hixson J.E. Vernier D.T. Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with HhaI.J. Lipid Res. 1990; 31: 545-548Abstract Full Text PDF PubMed Google Scholar). Data from FH patients were compared with data from control patients using Chi-square tests for categorical measures and ANOVA tests for continuous measures. Plasma triglycerides were log-transformed to normalize their distribution. Pearson correlation coefficients were determined to assess the significance of associations of LDL-PPD and other parameters. Stepwise multiple linear regression analysis was used to interpret the relationship of these associations. Nominal logistic regression was used to assess the relative risk of having LDL-PPD <255 Å based on plasma triglyceride levels and CETP mass. All analyses were performed using JMP Statistical Software (version 5.01a, SAS Institute, Cary, NC). Results were analyzed from a total of 467 subjects (259 FH heterozygotes and 208 control subjects) who participated in the study and who had lipid values available off lipid-altering medication. The demographic, genotypic, and biochemical characteristics of the two groups are presented in Table 1. There was no significant difference between the control group and FH group for age, gender, BMI, and waist circumference. The deletion >15 kb and the W66G missense mutation were largely predominant over the other seven French-Canadian mutations because they were present in more than 90% of the cases. The percentage of smokers was significantly lower among FH heterozygotes (P < 0.0001). FH heterozygotes had significantly greater plasma concentrations of total cholesterol (67%; P < 0.0001) and LDL-C (116%; P < 0.0001) and lower HDL-C levels (17%; P < 0.0001) compared with controls. There was no significant difference in plasma triglyceride levels between the two groups (P = 0.21).TABLE 1Demographic, genotypic, and biochemical characteristics of participants according to FH/control statusVariableControlsFHPN = 208N = 259—Age (y)35.6 ± 16.237.0 ± 12.5 0.32Gender 0.08Men N, (%)115 (55.3)122 (47.1)Women N, (%)93 (44.7)137 (52.9)BMI (kg/m2)24.7 ± 4.225.2 ± 4.3 0.25Waist circumference (cm)82.3 ± 12.281.9 ± 12.8 0.74LDLR mutationsDeletion >15kb N, (%)—123 (47.5)—W66G N, (%)—112 (43.2)—Y468X N, (%)—13 (5.0)—C646Y N, (%)—6 (2.3)—C347R N, (%)—1 (0.4)—E207K N, (%)—1 (0.4)—C152W N, (%)—1 (0.4)—R329X N, (%)—1 (0.4)—Deletion 5kb N, (%)—1 (0.4)—SmokingEver N, (%)151 (72.6)125 (48.3)<0.0001Never N, (%)57 (27.4)134 (51.7)Total Plasma Cholesterol (mmol/l)5.07 ± 0.898.48 ± 1.71<0.0001*Probability levels were adjusted for age, gender, BMI, and smoking.LDL-C (mmol/l)3.13 ± 0.806.75 ± 1.62<0.0001*Probability levels were adjusted for age, gender, BMI, and smoking.HDL-C (mmol/l)1.31 ± 0.301.09 ± 0.28<0.0001*Probability levels were adjusted for age, gender, BMI, and smoking.Triglycerides (mmol/l)1.39 ± 0.671.48 ± 0.74 0.21*Probability levels were adjusted for age, gender, BMI, and smoking.apoE3, apolipoprotein E3; BMI, body mass index; FH, familial hypercholesterolemia; LDL-C, LDL cholesterol; LDLR, LDL receptor. Results are listed as mean ± SD. All participants included were apoE3 homozygotes.* Probability levels were adjusted for age, gender, BMI, and smoking. Open table in a new tab apoE3, apolipoprotein E3; BMI, body mass index; FH, familial hypercholesterolemia; LDL-C, LDL cholesterol; LDLR, LDL receptor. Results are listed as mean ± SD. All participants included were apoE3 homozygotes. Plasma CETP mass concentration and electrophoretic characteristics of LDL according to FH/control status are presented in Table 2. Plasma CETP mass concentration was measured in a subgroup of 240 subjects, including 120 FH subjects matched for age, gender, BMI, and smoking with 120 controls, and was 11% higher in FH patients than in controls. This difference remained highly significant after adjustment for plasma triglyceride levels (P = 0.009).TABLE 2Plasma CETP mass concentration and electrophoretic characteristics of LDL according to FH/control statusVariableControlsFHPN = 120N = 120—CETP mass (μg/ml)1.52 ± 0.451.68 ± 0.45 0.009aProbability levels were adjusted for plasma triglyceride levels.N = 208N = 259—LDL-PPD (Å)259.2 ± 4.1258.1 ± 4.8 0.01bProbability levels were adjusted for age, gender, BMI, smoking, and plasma triglyceride levels.Integrated LDL size (Å)258.9 ± 4.3259.2 ± 4.2 0.09bProbability levels were adjusted for age, gender, BMI, smoking, and plasma triglyceride levels.LDL%<255Å31.2 ± 13.727.5 ± 14.9 0.01bProbability levels were adjusted for age, gender, BMI, smoking, and plasma triglyceride levels.LDL%255–260Å20.2 ± 4.823.2 ± 7.3<0.0001bProbability levels were adjusted for age, gender, BMI, smoking, and plasma triglyceride levels.LDL%>260Å48.6 ± 14.749.3 ± 15.3 0.98bProbability levels were adjusted for age, gender, BMI, smoking, and plasma triglyceride levels.LDL-C<255Å (mmol/l)0.98 ± 0.531.86 ± 1.07<0.0001bProbability levels were adjusted for age, gender, BMI, smoking, and plasma triglyceride levels.LDL-C255–260Å (mmol/l)0.64 ± 0.041.35 ± 0.04<0.0001bProbability levels were adjusted for age, gender, BMI, smoking, and plasma triglyceride levels.LDL-C>260Å (mmol/l)1.51 ± 0.603.39 ± 1.37<0.0001bProbability levels were adjusted for age, gender, BMI, smoking, and plasma triglyceride levels.CETP, cholesteryl ester transfer protein; LDL-PPD, LDL-peak particle diameter. Results are listed as mean ± SD. All participants included were apoE3 homozygotes.a Probability levels were adjusted for plasma triglyceride levels.b Probability levels were adjusted for age, gender, BMI, smoking, and plasma triglyceride levels. Open table in a new tab CETP, cholesteryl ester transfer protein; LDL-PPD, LDL-peak particle diameter. Results are listed as mean ± SD. All participants included were apoE3 homozygotes. After adjustment for age, gender, BMI, smoking, and plasma triglyceride levels, LDL-PPD, which represents the diameter of the most abundant subclass of LDL particles, was found to be significantly smaller in FH heterozygotes than in control subjects (258.1 ± 4.8 vs. 259.2 ± 4.1; P = 0.01). Figure 1shows that the correlation between LDL-PPD and the integrated LDL size, which corresponds to the weighed mean size of all LDL subclasses in each individual, was stronger among controls (r = 0.93; P < 0.0001) than in FH subjects (r = 0.74; P < 0.0001), suggesting that the distribution of LDL particle size differs between the two groups. Despite the presence of a significantly smaller proportion of LDL with a diameter <255 Å in FH subjects, the integrated LDL size of FH subjects did not differ significantly from that of controls (259.2 ± 4.2 vs. 258.9 ± 4.3 Å; P = 0.09). It is important to note, however, that the smaller proportion of LDL <255 Å found in FH was associated with a reciprocal increase in the relative proportion of LDL with a diameter between 255 Å and 260 Å. No significant difference in the relative proportion of large LDL (>260 Å) was observed between FH heterozygotes and controls. The distribution of integrated LDL size among FH subjects and controls is depicted in Fig. 2. As expected, the LDL-C<255 Å, LDL-C255–260 Å, and LDL-C>260 Å were significantly higher in FH heterozygotes than in controls.Fig. 2Distribution of integrated (mean) LDL size among (A) controls and (B) FH heterozygotes.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Univariate analyses revealed that LDL-PPD was inversely correlated with plasma triglyceride levels (r = −0.45; P = < 0.0001) and plasma CETP mass concentrations (r = −0.15; P = 0.02). Furthermore, LDL-PPD was found to be significantly smaller in males than in females (257.4 ± 4.7 vs. 259.8 ± 4.0; P < 0.0001). The significance of the association between LDL-PPD and plasma CETP mass concentrations was abolished after adjustment for the FH/control status, indicating that the LDL-PPD changes in FH were mediated, at least in part, by CETP. Stepwise multiple linear regression analyses were performed to identify independent contributors to the LDL-PPD variability. We found that 26.7% of the variability in LDL-PPD was attributable to plasma triglyceride levels (23.3%, P < 0.0001), plasma CETP mass concentrations (1.9%, P = 0.02), and gender (1.5%, P = 0.03). Age, BMI, and plasma LDL-C did not contribute significantly to LDL-PPD variance after adjustment for covariates. The combined impact of concomitant variations in plasma CETP mass concentrations and plasma triglyceride levels on the risk of having LDL-PPD <255 Å is shown in Fig. 3. Triglyceride levels ≥1.20 mmol/l (median of the cohort) were associated with a significant increase in the risk of having LDL-PPD <255 Å, and this risk was further increased in subjects with CETP mass concentration above median. The presence of plasma CETP concentrations above median was not associated with a higher risk of having small LDL in subjects with low triglyceride levels. To the best of our knowledge, this was the first study to examine the role of CETP as the determinant of LDL size heterogeneity in a large cohort of FH heterozygotes and controls. Our results suggested that LDLR gene mutations leading to FH are associated with significant variations in electrophoretic characteristics of LDL particle size; FH heterozygotes having smaller LDL-PPD associated with an accumulation of mid-size LDL particles (255–260 Å). Our results also showed that plasma triglyceride levels and CETP mass concentrations, as well as gender, are independent predictors of LDL-PPD in this cohort of FH and control subjects. Heterogeneity of LDL particles was reported before in FH patients, albeit in very small cohorts. Slack and Mills (8Slack J. Mills G.L. Anomalous low density lipoproteins in familial hyperbetalipoproteinaemia.Clin. Chim. Acta. 1970; 29: 15-25Crossref PubMed Scopus (41) Google Scholar) examined LDL particle density in 18 FH heterozygotes compared with 20 controls and found higher LDL peak flotation rate in FH patients (8.2 Sf vs. 7.1 Sf), thus indicating less dense LDL particles. Patsch et al. (9Patsch W. Ostlund R. Kuisk I. Levy R. Schonfeld G. Characterization of lipoprotein in a kindred with familial hypercholesterolemia.J. Lipid Res. 1982; 23: 1196-1205Abstract Full Text PDF PubMed Google Scholar) also found that, as compared with LDL particles of control subjects, the LDL of seven FH heterozygotes were cholesterol-enriched and triglyceride-poor, suggesting decreased density, increased size, or both. Similarly, Bagnall and Lloyrd (10Bagnall T.F. Lloyrd J.K. Composition of low-density lipoprotein in children with hyperlipoproteinaemia.Clin. Chim. Acta. 1975; 59: 271-276Crossref PubMed Scopus (9) Google Scholar) and Teng et al. (11Teng B. Thompson G.R. Sniderman A.D. Forte T.M. Krauss R.M. Kwiterovich Jr., P.O. Composition and dist" @default.
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• W2018455877 title "Relationship between cholesteryl ester transfer protein and LDL heterogeneity in familial hypercholesterolemia" @default.
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