Association of the A-204C polymorphism in the cholesterol 7α-hydroxylase gene with variations in plasma low density lipoprotein cholesterol levels in the Framingham Offspring Study
1999; Elsevier BV; Volume: 40; Issue: 10 Linguagem: Inglês
10.1016/s0022-2275(20)34905-1
ISSN1539-7262
AutoresPatrick Couture, James D. Otvos, L. Adrienne Cupples, Peter W.F. Wilson, Ernst J. Schaefer, José M. Ordovás,
Tópico(s)Liver Disease Diagnosis and Treatment
ResumoThe first reaction of the catabolic pathway of cholesterol is catalyzed by CYP7 and serves as the rate-limiting step and major site of regulation of bile acid synthesis in the liver. A common A to C substitution at position -204 of the promoter of CYP7 gene has been associated with variations in plasma LDL-cholesterol concentrations but the effect of this polymorphism is unknown in the general population. The aim of the present study was therefore to investigate the association of this polymorphism to lipoprotein levels in a population-based sample of 1139 male and 1191 female Framingham Offspring participants. In men, the C variant was associated with higher plasma concentrations of LDL-cholesterol and this association remained significant after adjustment for familial relationship, age, BMI, smoking, alcohol intake, the use of beta-blockers, and apoE genotype. The C variant was also associated with an increased TC/HDL ratio in men. Variance components analysis indicated that allelic variability at nucleotide -204 of the CYP7 gene and polymorphism of the apoE gene accounted for 1 and 5% of the variation of plasma LDL-cholesterol concentrations, respectively. In women, however, there was no relationship between LDL-cholesterol and the A-204C polymorphism but subjects homozygous for the CC genotype had significantly lower triglyceride levels than heterozygotes. Moreover, no significant relationship was found between the A-204C variants and lipoprotein particle diameter or the prevalence of coronary heart disease in both genders. Thus, our results show that the A-204C polymorphism in the CYP7 gene is associated with statistically significant variations in LDL-C and triglyceride concentrations in men and women, respectively, but the cumulative effects of these variations on atherosclerotic risk remain uncertain.—Couture, P., J. D. Otvos, L. A. Cupples, P. W. F. Wilson, E. J. Schaefer, and J. M. Ordovas. Association of the A-204C polymorphism in the cholesterol 7α-hydroxylase gene with variations in plasma low density lipoprotein cholesterol levels in the Framingham Offspring Study. J. Lipid Res. 1999. 40: 1883–1889. The first reaction of the catabolic pathway of cholesterol is catalyzed by CYP7 and serves as the rate-limiting step and major site of regulation of bile acid synthesis in the liver. A common A to C substitution at position -204 of the promoter of CYP7 gene has been associated with variations in plasma LDL-cholesterol concentrations but the effect of this polymorphism is unknown in the general population. The aim of the present study was therefore to investigate the association of this polymorphism to lipoprotein levels in a population-based sample of 1139 male and 1191 female Framingham Offspring participants. In men, the C variant was associated with higher plasma concentrations of LDL-cholesterol and this association remained significant after adjustment for familial relationship, age, BMI, smoking, alcohol intake, the use of beta-blockers, and apoE genotype. The C variant was also associated with an increased TC/HDL ratio in men. Variance components analysis indicated that allelic variability at nucleotide -204 of the CYP7 gene and polymorphism of the apoE gene accounted for 1 and 5% of the variation of plasma LDL-cholesterol concentrations, respectively. In women, however, there was no relationship between LDL-cholesterol and the A-204C polymorphism but subjects homozygous for the CC genotype had significantly lower triglyceride levels than heterozygotes. Moreover, no significant relationship was found between the A-204C variants and lipoprotein particle diameter or the prevalence of coronary heart disease in both genders. Thus, our results show that the A-204C polymorphism in the CYP7 gene is associated with statistically significant variations in LDL-C and triglyceride concentrations in men and women, respectively, but the cumulative effects of these variations on atherosclerotic risk remain uncertain.—Couture, P., J. D. Otvos, L. A. Cupples, P. W. F. Wilson, E. J. Schaefer, and J. M. Ordovas. Association of the A-204C polymorphism in the cholesterol 7α-hydroxylase gene with variations in plasma low density lipoprotein cholesterol levels in the Framingham Offspring Study. J. Lipid Res. 1999. 40: 1883–1889. Evidence from epidemiologic studies clearly indicates that high plasma concentrations of LDL-cholesterol are associated with an increased risk of developing CHD (1National Cholesterol Education Program Summary of the second report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II).J. Am. Med. Assoc. 1993; 269: 3015-3023Google Scholar). Other major CHD risk factors include age, male gender, arterial hypertension, diabetes, smoking, a familial history of premature CHD disease, and a decreased plasma HDL-cholesterol (2Miller G.J. Miller N.E. Plasma-high-density-lipoprotein concentration and development of ischaemic heart-disease.Lancet. 1975; 1: 16-19Google Scholar, 3Assmann G. Schulte H. Relation of high-density lipoprotein cholesterol and triglycerides to incidence of atherosclerotic coronary artery disease (the PROCAM experience). Prospective Cardiovascular Munster study.Am. J. Cardiol. 1992; 70: 733-737Google Scholar, 4Wilson P.W. D'Agostino R.B. Levy D. Belanger A.M. Silbershatz H. Kannel W.B. Prediction of coronary heart disease using risk factor categories.Circulation. 1998; 97: 1837-1847Google Scholar). Data from family and twin studies have indicated that genetic factors play a major role in the susceptibility to atherosclerosis and that these influences are thought to result from variability in multiple genes, which act in concert to increase susceptibility (5Marenberg M.E. Risch N. Berkman L.F. Floderus B. de Faire U. Genetic susceptibility to death from coronary heart disease in a study of twins.N. Engl. J. Med. 1994; 330: 1041-1046Google Scholar). The influence of genetic variation on lipoprotein levels primarily manifests as decreased HDL-cholesterol and elevated LDL-cholesterol (6Pérusse L. Després J.P. Tremblay A. Leblanc C. Talbot J. Allard C. Bouchard C. Genetic and environmental determinants of serum lipids and lipoproteins in French Canadian families.Arteriosclerosis. 1989; 9: 308-318Google Scholar, 7Rice T. Vogler G.P. Perry T.S. Laskarzewski P.M. Rao D.C. 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Moreover, familial defective apoB and familial hypocholesterolemia in which individuals have abnormal plasma levels of LDL-cholesterol are caused by mutations in the gene encoding apoB (9Myant N.B. Familial defective apolipoprotein B-100: a review, including some comparisons with familial hypercholesterolaemia.Atherosclerosis. 1993; 104: 1-18Google Scholar, 10Welty F.K. Ordovas J. Schaefer E.J. Wilson P.W.F. Young S.G. Identification and molecular analysis of two apoB gene mutations causing low plasma cholesterol levels.Circulation. 1995; 92: 2036-2040Google Scholar). These disorders, however, are uncommon and account for a small fraction of the genetically determined variation in plasma LDL-cholesterol levels (11Welty F.K. Lahoz C. Tucker K.L. Ordovas J.M. Wilson P.W. Schaefer E.J. Frequency of apoB and apoE gene mutations as causes of hypobetalipoproteinemia in the Framingham Offspring Population.Arterioscler. Thromb. Vasc. Biol. 1998; 18: 1745-1751Google Scholar). In the general population, associations between genetic polymorphisms and interindividual variations of plasma LDL-cholesterol concentrations have been reported, but these relationships seem to be inconsistent or at least influenced by other factors, such as age, gender, diet, and ethnic origin. Specific genetic polymorphisms in LDL receptor, apoB, and microsomal triglyceride transfer protein gene have been studied but their contribution to the population variance in LDL-cholesterol remains controversial (12Humphries S. Coviello D.A. Masturzo P. Balestreri R. Orecchini G. Bertolini S. Variation in the low density lipoprotein receptor gene is associated with differences in plasma low density lipoprotein cholesterol levels in young and old normal individuals from Italy.Arterioscler Thromb. 1991; 11: 509-516Google Scholar, 13Klausen I.C. Hansen P.S. Gerdes L.U. Rudiger N. Gregersen N. Faergeman O. A PvuII polymorphism of the low density lipoprotein receptor gene is not associated with plasma concentrations of low density lipoproteins including Lp(a).Hum. Genet. 1993; 91: 193-195Google Scholar, 14Hansen P.S. Gerdes L.U. Klausen I.C. Gregersen N. Faergeman O. Polymorphisms in the apolipoprotein B-100 gene contributes to normal variation in plasma lipids in 464 Danish men born in 1948.Hum. Genet. 1993; 91: 45-50Google Scholar, 15Gaffney D. Freeman D.J. Shepherd J. Packard C.J. The ins/del polymorphism in the signal sequence of apolipoprotein B has no effect on lipid parameters.Clin. Chim. Acta. 1993; 218: 131-138Google Scholar, 16Karpe F. Lundahl B. Ehrenborg E. Eriksson P. Hamsten A. A common functional polymorphism in the promoter region of the microsomal triglyceride transfer protein gene influences plasma LDL levels.Arterioscler. Thromb. Vasc. Biol. 1998; 18: 756-761Google Scholar, 17Herrmann S.M. Poirier O. Nicaud V. Evans A. Ruidavets J.B. Luc G. Arveiler D. Bao-Sheng C. Cambien F. Identification of two polymorphisms in the promoter of the microsomal triglyceride transfer protein (MTP) gene: lack of association with lipoprotein profiles.J. Lipid Res. 1998; 39: 2432-2435Google Scholar). In fact, only the polymorphism in apoE has been shown to be associated consistently with genetically determined variations in plasma LDL-cholesterol levels (18de Knijff P. van den Maagdenberg A.M. Frants R.R. Havekes L.M. Genetic heterogeneity of apolipoprotein E and its influence on plasma lipid and lipoprotein levels.Hum. Mutat. 1994; 4: 178-194Google Scholar, 20Dallongeville J. Lussier C.S. Davignon J. Modulation of plasma triglyceride levels by apoE phenotype: a meta-analysis.J. Lipid Res. 1992; 33: 447-454Google Scholar). ApoE acts as a ligand for apoB/E receptor uptake and thus plays an essential role in the catabolism of triglyceride-rich lipoproteins such as VLDL and remnants (21Utermann G. Hees M. Steinmetz A. Polymorphism of apolipoprotein E and occurrence of dysbetalipoproteinaemia in man.Nature. 1977; 269: 604-607Google Scholar). The molecular basis of apoE polymorphism can be traced to two amino acid changes and, taken together, the three common isoforms of apoE (E2, E3, and E4) would account for 5–20% of the genetically determined variation in plasma LDL-cholesterol concentrations. Thus, the major genetic determinants of plasma LDL-cholesterol concentrations still remain to be determined. In a recent study, the common functional polymorphism in the promoter region of the CYP7 gene has been shown to be associated with significant variations in plasma LDL-cholesterol levels (22Wang J. Freeman D.J. Grundy S.M. Levine D.M. Guerra R. Cohen J.C. Linkage between cholesterol 7 alpha-hydroxylase and high plasma low-density lipoprotein cholesterol concentrations.J Clin Invest. 1998; 101: 1283-1291Google Scholar). This transversion referred to as C-278A (22Wang J. Freeman D.J. Grundy S.M. Levine D.M. Guerra R. Cohen J.C. Linkage between cholesterol 7 alpha-hydroxylase and high plasma low-density lipoprotein cholesterol concentrations.J Clin Invest. 1998; 101: 1283-1291Google Scholar) is located 204 bp upstream of the transcription start site (23Wang D.P. Chiang J.Y. Structure and nucleotide sequences of the human cholesterol 7 alpha-hydroxylase gene (CYP7).Genomics. 1994; 20: 320-323Google Scholar, 24Nishimoto M. Noshiro M. Okuda K. Structure of the gene encoding human liver cholesterol 7 alpha-hydroxylase.Biochim. Biophys. Acta. 1993; 1172: 147-150Google Scholar). CYP7 plays a major role in cholesterol metabolism by catalyzing the first and rate-limiting step in bile acid synthesis in the liver. However, data from the general population with regard to the effect of this common CYP7 variant on lipid and lipoprotein levels, as well as heterogeneity and possibly atherogenecity of the three major lipoprotein classes, are clearly missing. The purpose of the current study, therefore, was to examine the frequency, phenotypic effect on lipoprotein levels, and lipoprotein subclass profiles as well as potential modulation of CHD risk in the Framingham Offspring Study by the A-204C polymorphism in the CYP7 gene. Subjects were participants in the Framingham Offspring Study, a long-term prospective evaluation of risk factors of cardiovascular disease in which participants are the offspring of the subjects of the Framingham Heart Study and their spouses. The details of the design and methods of the Framingham Offspring Study have been presented elsewhere (25Feinleib M. Kannel W.B. Garrison R.J. McNamara P.M. Castelli W.P. The Framingham Offspring Study. Design and preliminary data.Prev. Med. 1975; 4: 518-525Google Scholar). Starting in 1971, a total of 5124 subjects were enrolled (26Kannel W.B. Feinleib M. McNamara P.M. Garrison R.J. Castelli W.P. An investigation of coronary heart disease in families. The Framingham offspring study.Am. J. Epidemiol. 1979; 110: 281-290Google Scholar). Lipid, lipoprotein, and apoprotein measurements as well as DNA, and information on CHD risk factors were available for 1139 men and 1191 women who attended the 4th and 5th examination visits of the Framingham Offspring Study conducted between 1987 and 1995. Nearly all subjects were Caucasians. Data on smoking, blood pressure, height, weight, and diabetes were obtained on these subjects as previously described (26Kannel W.B. Feinleib M. McNamara P.M. Garrison R.J. Castelli W.P. An investigation of coronary heart disease in families. The Framingham offspring study.Am. J. Epidemiol. 1979; 110: 281-290Google Scholar, 27Dawber T.R. Meadors G.F. Moore R. Epidemiological approach to heart disease: The Framingham Study.Am. J. Public Health. 1951; 41: 279-286Google Scholar). CHD cases were adjudicated up to 1994, by criteria established for the analysis of Framingham Offspring Study, as described elsewhere (28Cupples L.A. Gagnon D.R. Kannel W.B. Long- and short-term risk of sudden coronary death.Circulation. 1992; 85: I11-I18Google Scholar). CHD included the presence of myocardial infarction, angina pectoris, coronary insufficiency, and coronary death. Subjects taking a lipid-lowering medication were included for the calculation of the CHD prevalence at exam 5. Plasma was isolated from blood drawn into EDTA tubes after a 12–14 h fast and stored at -70°C for later determination of apolipoproteins and lipoprotein subspecies. Plasma total cholesterol, HDL-cholesterol, and triglyceride levels were measured as previously described (29Lipid Research Clinic Program The Coronary Primary Prevention Trial: design and implementation.J. Chronic Dis. 1979; 14: 1250-1257Google Scholar). LDL-cholesterol concentrations were estimated with the equation of Friedewald, Levy, and Fredrickson (30Friedewald W.T. Levy R.I. Fredrickson D.S. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge.Clin. Chem. 1972; 18: 499-502Google Scholar). The within and between run coefficients of variation for lipid measurements were all less than 5% (31McNamara J. Schaefer E. Automated enzymatic standardized lipid analyses for plasma and lipoprotein fractions.Clin. Chim. Acta. 1987; 166: 1-8Google Scholar). Plasma levels of apoA-I and apoB were measured by non-competitive enzyme-linked immunosorbent assay, using affinity-purified polyclonal antibodies (32Schaefer E. Ordovas J. Metabolism of apolipoproteins A-I, A-II, and A-IV.Methods Enzymol. 1986; 129: 420-443Google Scholar, 33Ordovas J.M. Peterson J.P. Santaniello P. Cohn J.S. Wilson P.W. Schaefer E.J. Enzyme-linked immunosorbent assay for human plasma apolipoprotein B.J. Lipid Res. 1987; 28: 1216-1224Google Scholar). Plasma lipoprotein concentrations and subclasses distributions were also determined by proton NMR spectroscopy as described elsewhere (34Otvos J.D. Jeyarajah E.J. Bennett D.W. Krauss R.M. Development of a proton nuclear magnetic resonance spectroscopic method for determining plasma lipoprotein concentrations and subspecies distributions from a single, rapid measurement.Clin. Chem. 1992; 38: 1632-1638Google Scholar). The 10 lipoprotein subclass categories used were the following: large VLDL and remnants (40–220 nm), intermediate VLDL (31–40 nm), small VLDL (27–31 nm), large LDL (21.3–27.0 nm), intermediate LDL (19.8–21.2), small LDL (18.3–19.7 nm), large HDL (8.8–13.0 nm), intermediate HDL (7.8–8.8 nm), and small HDL (7.3–7.7 nm). Levels of VLDL subclasses are expressed in units of triglyceride (mg/dL), and those of LDL and HDL subclasses in units of cholesterol (mg/dL). LDL and HDL subclass distributions determined by gradient gel electrophoresis and NMR have also been shown to be closely correlated (35Otvos J.D. Measurement of lipoprotein subclass profile by nuclear magnetic resonance.in: Rifai N. Warnick G.R. Dominiczak M.H. Handbook of Lipoprotein Testing. AACC press, Washington, DC1997: 497-508Google Scholar). Genomic DNA was isolated from peripheral blood leucocytes by standard methods (36Miller S.A. Dykes D.D. Polesky H.F. A simple salting out procedure for extracting DNA from human nucleated cells.Nucleic Acids Res. 1988; 16: 1215Google Scholar). CYP7 genotyping was performed as previously described (22Wang J. Freeman D.J. Grundy S.M. Levine D.M. Guerra R. Cohen J.C. Linkage between cholesterol 7 alpha-hydroxylase and high plasma low-density lipoprotein cholesterol concentrations.J Clin Invest. 1998; 101: 1283-1291Google Scholar). To compare men and women who participated in the study, we used chi-square tests for categorical measures and two-sample t test for continuous measures. We estimated the allele frequency of the C allele and apoE alleles with the chromosome counting method and used a chi-square test to compare it in men and women. To evaluate the relationship between the CYP7 genotypes (AA, AC, and CC) and lipid levels, we used analysis of covariance techniques which accounted for the familial relationships among the members of the study (mostly siblings and cousins). We used two approaches to accomplish these analyses. First, we used a repeated measures approach which assumed an exchangeable correlation structure among all members of a family, using PROC MIXED in SAS. As this approach does not accurately represent the true correlation structure within these pedigrees, we also used a measured genotype approach (37Boerwinkle E. Utermann G. Simultaneous effects of the apolipoprotein E polymorphism on apolipoprotein E, apolipoprotein B, and cholesterol metabolism.Am. J. Hum. Genet. 1988; 42: 104-112Google Scholar) as implemented in SOLAR, a variance component analysis computer package for quantitative traits measured in pedigrees of arbitrary size (38Almasy L. Blangero J. Multipoint quantitative-trait linkage analysis in general pedigrees.Am. J. Hum. Genet. 1998; 62: 1198-1211Google Scholar). The latter approach fully accounts for the different types of relationships within a pedigree in performing an analysis of variance on the defined genotypes. In these analyses, we used several different models to adjust for potential confounders. First, we obtained essentially crude results which accounted only for the family structure; second, we adjusted for age, BMI, smoking, alcohol consumption, beta-blockers, and menopausal status and hormonal replacement therapy in women. In our final analysis, we added apoE genotypes to the model with E2/E2 and E2/E3 in one group, E3/E4 and E4/E4 in a second group, and E3/E3 as the reference group. Subjects with apoE2/E4 genotypes, of which there were very few, were excluded. We analyzed a total of 2330 subjects (1139 males and 1191 females) who participated in the Framingham Offspring Study and who had lipid values available off lipid lowering medication. The demographic, genotypic, and biochemical characteristics of the participants according to gender are presented in Table 1. There was no significant difference in the frequency of the C allele between men and women and the distribution of alleles was consistent with Hardy-Weinberg equilibrium. The mean age of men and women at examination was 52.1 and 51.4 years, respectively. BMI, alcohol consumption, plasma LDL-cholesterol, total apoB, triglycerides as well as glucose levels were significantly higher in men compared with women and HDL, HDL2, and HDL3-cholesterol as well as apoA-I concentrations were significantly higher in female participants. Although a similar proportion of men and women were smokers, male subjects smoked more cigarettes per day than the female subjects and over half of the female participants (54.9%) were post-menopausal. Moreover, the apoE genotype distribution was similar in men and women (P = 0.3570).TABLE 1.Demographic, genotypic, and biochemical characteristics of FOS participants according to genderVariableMenWomenPn (Total)11391191AA (%)434 (38.1)411 (34.5)AC (%)535 (47.0)589 (49.5)CC (%)170 (14.9)191 (16.0)C Allele frequency0.3840.4080.1940ApoE alleles223222940.3570E2 (%)154 (6.9)184 (8.0)E3 (%)1811 (81.1)1839 (80.2)E4 (%)267 (12.0)271 (11.8)Age (years)52.1 ± 10.151.4 ± 9.80.1033BMI (kg/m2)27.7 ± 3.926.0 ± 5.30.0001TC (mg/dL)202 ± 37203 ± 390.7521LDL-C (mg/dL)133 ± 33126 ± 35<0.0001HDL-C (mg/dL)43.6 ± 11.455.6 ± 14.90.0001HDL2-C (mg/dL)5.3 ± 3.79.7 ± 5.80.0001HDL3-C (mg/dL)38.4 ± 8.946.0 ± 11.00.0001TG (mg/dL)135 ± 99108 ± 830.0001ApoA-I (g/L)135 ± 24154 ± 310.0001ApoB (g/L)102 ± 2495 ± 25<0.0001TC/HDL-C4.94 ± 1.533.92 ± 1.410.0001Glucose (mg/dL)98 ± 2793 ± 240.0001Alcohol (ounces/week)4.0 ± 5.21.8 ± 2.60.0001Cigarette/day6.0 ± 12.84.7 ± 10.30.0070Post-menopausal (%)—54.9On estrogen Rx (%)aIncludes hormonal replacement therapy and the use of oral contraceptives.—12.4Results are listed as means ± SD.a Includes hormonal replacement therapy and the use of oral contraceptives. Open table in a new tab Results are listed as means ± SD. Table 2 shows that, in men and women, the three genotypic groups were equivalent with respect to age and BMI. A total of 18 linear regressions were performed to test for potential associations of the CYP7 promoter polymorphism with lipid and apoprotein profiles. In men, the C variant was associated with higher plasma concentrations of total and LDL-cholesterol and this association remained significant after adjustment for familial relationship, age, BMI, smoking, alcohol intake, the use of beta-blockers, and apoE genotype. The C variant was also associated with an increased TC/HDL ratio in men. Moreover, there were no significant associations between the CYP7 polymorphism and variations in HDL-cholesterol and its subfractions, triglycerides, apoA-I, and apoB. In women, no relationship was found between LDL-cholesterol and the A-204C polymorphism but subjects homozygous for the CC genotype had significantly lower triglyceride levels compared with heterozygotes. This association remained significant after adjustment for covariates.TABLE 2.Plasma levels of lipids, lipoproteins, and apolipoproteins of FOS subjects according to CYP7 genotypes at nucleotide −204VariableAAACCCPaAfter adjustment for familial relationship.PbAfter adjustment for familial relationship, age, BMI, smoking, alcohol intake and the use of beta-blockers (menopausal status and estrogen therapy in women).PcAfter adjustment for familial relationship, age, BMI, smoking, alcohol intake, use of beta-blockers (menopausal status and estrogen therapy in women) and apoE.Menn434535170Age (years)51.4 ± 10.252.3 ± 9.953.1 ± 10.80.1291BMI (kg/m2)27.8 ± 3.927.6 ± 3.927.5 ± 3.90.6964TC (mg/dL)199 ± 33204 ± 39204 ± 380.06300.09140.0496LDL-C (mg/dL)129 ± 30135 ± 36135 ± 330.0292dSignificant difference between the AC and AA groups.0.0314dSignificant difference between the AC and AA groups.0.0125dSignificant difference between the AC and AA groups.HDL-C (mg/dL)43.6 ± 10.343.3 ± 11.744.6 ± 13.00.47990.26020.2383HDL2-C (mg/dL)5.4 ± 3.55.2 ± 3.75.6 ± 4.20.37060.21400.1881HDL3-C (mg/dL)38.3 ± 7.938.2 ± 9.339.0 ± 10.10.29640.34360.3281TG (mg/dL)136 ± 96137 ± 103130 ± 950.51580.26330.2327ApoA-I (g/L)136 ± 22134 ± 25136 ± 260.25040.12270.2070ApoB (g/L)101 ± 23102 ± 25103 ± 250.45180.47830.2024TC/HDL-C4.81 ± 1.335.05 ± 1.684.91 ± 1.490.0219dSignificant difference between the AC and AA groups.0.0104dSignificant difference between the AC and AA groups.0.0054dSignificant difference between the AC and AA groups.Womenn411589191Age (years)50.9 ± 10.051.4 ± 9.652.4 ± 10.10.2180BMI (kg/m2)26.0 ± 5.526.0 ± 5.225.7 ± 5.00.6819TC (mg/dL)203 ± 38203 ± 39202 ± 410.79370.54230.2619LDL-C (mg/dL)126 ± 36126 ± 34125 ± 370.90650.71500.5063HDL-C (mg/dL)55.3 ± 14.455.3 ± 15.057.5 ± 15.20.16520.42580.6166HDL2-C (mg/dL)9.4 ± 5.59.7 ± 5.910.1 ± 5.90.36660.57250.7931HDL3-C (mg/dL)45.9 ± 10.545.6 ± 11.047.4 ± 11.70.15690.37370.5080TG (mg/dL)107 ± 68113 ± 9896 ± 530.0363eSignificant difference between the AC and CC groups.0.0145eSignificant difference between the AC and CC groups.0.0218eSignificant difference between the AC and CC groups.ApoA-I (g/L)153 ± 30153 ± 29157 ± 360.28180.57950.9030ApoB (g/L)96 ± 2695 ± 2594 ± 260.77320.58900.5654TC/HDL-C3.92 ± 1.353.97 ± 1.493.75 ± 1.240.15170.16760.1769Results are listed as means ± SD.a After adjustment for familial relationship.b After adjustment for familial relationship, age, BMI, smoking, alcohol intake and the use of beta-blockers (menopausal status and estrogen therapy in women).c After adjustment for familial relationship, age, BMI, smoking, alcohol intake, use of beta-blockers (menopausal status and estrogen therapy in women) and apoE.d Significant difference between the AC and AA groups.e Significant difference between the AC and CC groups. Open table in a new tab Results are listed as means ± SD. Potential associations of the CYP7 promoter polymorphism with variations in lipoprotein subclass profiles and lipoprotein particle size were also investigated. Lipoprotein subclass profiles were characterized using automated NMR spectroscopy. As shown in Table 3, after adjustment for familial relationship and other covariables, female subjects homozygous for the CC genotype have significantly lower levels of intermediate VLDL and LDL than women carrying the AC genotype. In men, no significant relationships have been found between the CYP7 polymorphism and lipoprotein subfraction profiles. Table 4 shows the lipoprotein particle size according to CYP7 genotype. In both genders, there was no significant relationship between genotype of the A-204C polymorphism and VLDL, LDL, and HDL particle diameter.TABLE 3.Lipoprotein subclass distributions of FOS subjects according to CYP7 genotypes at nucleotide −204VariableAAACCCPaAfter adjustment for familial relationship.PbAfter adjustment for familial relationship, age, BMI, smoking, alcohol intake, and the use of beta-blockers (menopausal status and estrogen therapy in women).PcAfter adjustment for familial relationship, age, BMI, smoking, alcohol intake, use of beta-blockers (menopausal status and estrogen therapy in women) and apoE.MenVLDLLarge10.0 ± 16.510.7 ± 19.010.2 ± 18.90.90150.68090.6208Intermediate73.3 ± 60.775.2 ± 64.967.5 ± 61.90.37360.19980.2063Small20.3 ± 12.320.7 ± 13.420.8 ± 14.50.81790.83130.7109LDLLarge69.2 ± 33.669.7 ± 33.770.6 ± 32.60.51920.68120.6355Intermediate36.3 ± 25.137.1 ± 23.837.2 ± 26.20.40380.43040.2741Small31.7 ± 26.133.6 ± 25.532.7 ± 23.40.74130.67090.6953HDLLarge14.5 ± 11.314.8 ± 12.415.4 ± 13.00.63170.56200.5362Intermediate21.5 ± 6.521.2 ± 6.721.2 ± 6.80.42050.33830.2093Small8.6 ± 5.18.6 ± 5.38.6 ± 5.40.94460.91830.9060WomenVLDLLarge5.5 ± 13.36.6 ± 18.34.3 ± 7.40.76270.84410.8820Intermediate48.3 ± 44.653.5 ± 54.842.3 ± 44.30.0112dSignificant difference between the AC and CC groups.0.0103dSignificant difference between the AC and CC groups.0.0081dSignificant difference between the AC and CC groups.Small21.9 ± 13.722.4 ± 13.021.3 ± 12.30.63940.58890.5289LDLLarge85.6 ± 34.782.0 ± 31.985.7 ± 36.30.77060.76060.5164Intermediate30.7 ± 24.032.5 ± 24.228.6 ± 23.80.0449dSignificant difference between the AC and CC groups.0.0318dSignificant difference between the AC and CC groups.0.0218dSignificant difference between the AC and CC groups.Small18.8 ± 19.217.9 ± 18.022.1 ± 18.50.52630.61330.4911HDLLarge30.7 ± 16.230.8 ± 16.732.5 ± 16.70.56940.87300.9277Intermediate20.7 ± 6.420.9 ± 6.920.1 ± 7.20.29540.23420.2061Small5.4 ± 4.65.6 ± 4.85.5 ± 4.50.94650.94520.8724Results are listed as means ± SD.a After adjustment for familial relationship.b After adjustment for familial relationship, age, BMI, smoking, alcohol intake, and the use of beta-blockers (menopausal status and estrogen therapy in women).c After adjustment for familial relationship, age, BMI, smoking, alcohol intake, use of beta-blockers
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