Genetic analysis of a polymorphism in the human apoA-V gene: effect on plasma lipids
2003; Elsevier BV; Volume: 44; Issue: 6 Linguagem: Inglês
10.1194/jlr.m200480-jlr200
ISSN1539-7262
AutoresBradley E. Aouizerat, Medha Kulkarni, David C. Heilbron, Donna J. Drown, Stephen Raskin, Clive R. Pullinger, Mary J. Malloy, John P. Kane,
Tópico(s)Cancer, Lipids, and Metabolism
ResumoRecent discovery and characterization of APOAV suggests a role in metabolism of triglyceride (TG)-rich lipoproteins. Previously, variation at the APOAV locus was shown to modestly influence plasma TGs in normolipidemic samples. The aims of this study were to assess the effects of a polymorphism in APOAV (T-1131C) in terms of its frequency among three dyslipidemic populations and a control population, differences of allele frequency across available ethnic groups, and associations with specific lipoprotein TG and cholesterol compartments. We found a striking elevation in the frequency of the rare allele in a Chinese population (P = 0.0002) compared with Hispanic and European populations. The rare allele of the polymorphism was associated with elevated plasma TG (P = 0.012), VLDL cholesterol (P = 0.0007), and VLDL TG (P = 0.012), LDL TG (P = 0.003), and HDL TG (P = 0.016). Linear regression models predict that possession of the rare allele elevates plasma TG by 21 mg/dl (P = 0.009) and VLDL cholesterol by 8 mg/dl (P = 0.0001), and reduces HDL cholesterol by 2 mg/dl (P = 0.017). The association of the polymorphism with altered lipoprotein profiles was observed in combined hyperlipidemia, hypoalphalipoproteinemia, and hyperalphalipoproteinemia, and in controls.These findings indicate that APOAV is an important determinant of plasma TG and lipoprotein cholesterol, and is potentially a risk factor for cardiovascular disease. Recent discovery and characterization of APOAV suggests a role in metabolism of triglyceride (TG)-rich lipoproteins. Previously, variation at the APOAV locus was shown to modestly influence plasma TGs in normolipidemic samples. The aims of this study were to assess the effects of a polymorphism in APOAV (T-1131C) in terms of its frequency among three dyslipidemic populations and a control population, differences of allele frequency across available ethnic groups, and associations with specific lipoprotein TG and cholesterol compartments. We found a striking elevation in the frequency of the rare allele in a Chinese population (P = 0.0002) compared with Hispanic and European populations. The rare allele of the polymorphism was associated with elevated plasma TG (P = 0.012), VLDL cholesterol (P = 0.0007), and VLDL TG (P = 0.012), LDL TG (P = 0.003), and HDL TG (P = 0.016). Linear regression models predict that possession of the rare allele elevates plasma TG by 21 mg/dl (P = 0.009) and VLDL cholesterol by 8 mg/dl (P = 0.0001), and reduces HDL cholesterol by 2 mg/dl (P = 0.017). The association of the polymorphism with altered lipoprotein profiles was observed in combined hyperlipidemia, hypoalphalipoproteinemia, and hyperalphalipoproteinemia, and in controls. These findings indicate that APOAV is an important determinant of plasma TG and lipoprotein cholesterol, and is potentially a risk factor for cardiovascular disease. Atherosclerosis is the leading cause of morbidity and mortality in both industrialized and developing countries (1Genest Jr., J. McNamara J.R. Ordovas J.M. Jenner J.L. Silberman S.R. Anderson K.M. Wilson P.W. Salem D.N. Schaefer E.J. Lipoprotein cholesterol, apolipoprotein A-I and B and lipoprotein (a) abnormalities in men with premature coronary artery disease.J. Am. Coll. Cardiol. 1992; 19: 792-802Google Scholar). The etiology of coronary artery disease is multifactorial, with both genetic and environmental determinants (2Davignon J. Genest Jr., J. Genetics of lipoprotein disorders.Endocrinol. Metab. Clin. North Am. 1998; 27: 521-550Google Scholar, 3Lusis A.J. Atherosclerosis.Nature. 2000; 407: 233-241Google Scholar). Abnormalities of lipoprotein metabolism are central to the development of atherosclerosis (4Farmer J.A. Gotto Jr., A.M. Dyslipidemia and the vulnerable plaque.Prog. Cardiovasc. Dis. 2002; 44: 415-428Google Scholar, 5Wilson P.W. Castelli W.P. Kannel W.B. Coronary risk prediction in adults (the Framingham Heart Study).Am. J. Cardiol. 1987; 59: 91G-94GGoogle Scholar). Study of premature coronary artery disease has revealed that apolipoproteins are important discriminating factors for distinguishing individuals with coronary artery disease (6McNamara J.R. Campos H. Ordovas J.M. Peterson J. Wilson P.W. Schaefer E.J. Effect of gender, age, and lipid status on low density lipoprotein subfraction distribution. Results from the Framingham Offspring Study.Arteriosclerosis. 1987; 7: 483-490Google Scholar, 7Rosseneu M. Fruchart J.C. Bard J.M. Nicaud V. Vinaimont N. Cambien F. De Backer G. Plasma apolipoprotein concentrations in young adults with a parental history of premature coronary heart disease and in control subjects. The EARS Study. European Atherosclerosis Research Study.Circulation. 1994; 89: 1967-1973Google Scholar, 8Genest J.J. McNamara J.R. Salem D.N. Schaefer E.J. Prevalence of risk factors in men with premature coronary artery disease.Am. J. Cardiol. 1991; 67: 1185-1189Google Scholar). The apolipoprotein gene cluster (APOAI-CIII-AIV) on human chromosome 11q23 is known to harbor at least three genes that affect the metabolism of plasma lipoproteins (9Groenendijk M. Cantor R.M. de Bruin T.W. Dallinga-Thie G.M. The apoAI-CIII-AIV gene cluster.Atherosclerosis. 2001; 157: 1-11Google Scholar). The relationship between variations in the gene cluster and plasma lipids has been studied for nearly two decades (9Groenendijk M. Cantor R.M. de Bruin T.W. Dallinga-Thie G.M. The apoAI-CIII-AIV gene cluster.Atherosclerosis. 2001; 157: 1-11Google Scholar, 10Aouizerat B.E. Allayee H. Bodnar J. Krass K.L. Peltonen L. de Bruin T.W. Rotter J.I. Lusis A.J. Novel genes for familial combined hyperlipidemia.Curr. Opin. Lipidol. 1999; 10: 113-122Google Scholar, 11Karathanasis S.K. Ferris E. Haddad I.A. DNA inversion within the apolipoproteins AI/CIII/AIV-encoding gene cluster of certain patients with premature atherosclerosis.Proc. Natl. Acad. Sci. USA. 1987; 84: 7198-7202Google Scholar, 12Ferns G.A. Galton D.J. Haplotypes of the human apoprotein AI-CIII-AIV gene cluster in coronary atherosclerosis.Hum. Genet. 1986; 73: 245-249Google Scholar). The majority of studies have focused on either apolipoprotein A-I (apoA-I), because of its influence on HDL production, or on apoC-III for its modulation of plasma triglyceride (TG). Recently, study of apoA-IV, an apolipoprotein associated with chylomicron and HDL particles (13Weinberg R.B. Spector M.S. Human apolipoprotein A-IV: displacement from the surface of triglyceride-rich particles by HDL2-associated C-apoproteins.J. Lipid Res. 1985; 26: 26-37Google Scholar), has provided evidence for its role in postprandial lipemia (14Hockey K.J. Anderson R.A. Cook V.R. Hantgan R.R. Weinberg R.B. Effect of the apolipoprotein A-IV Q360H polymorphism on postprandial plasma triglyceride clearance.J. Lipid Res. 2001; 42: 211-217Google Scholar) and coronary artery disease (15Kronenberg F. Stuhlinger M. Trenkwalder E. Geethanjali F.S. Pachinger O. von Eckardstein A. Dieplinger H. Low apolipoprotein A-IV plasma concentrations in men with coronary artery disease.J. Am. Coll. Cardiol. 2000; 36: 751-757Google Scholar). While variations in the APOAI-CIII-AIV gene cluster have been reported to influence several dyslipidemic states (16Aouizerat B.E. Allayee H. Cantor R.M. Dallinga-Thie G.M. Lanning C.D. de Bruin T.W. Lusis A.J. Rotter J.I. Linkage of a candidate gene locus to familial combined hyperlipidemia: lecithin:cholesterol acyltransferase on 16q.Arterioscler. Thromb. Vasc. Biol. 1999; 19: 2730-2736Google Scholar, 17Allayee H. Aouizerat B.E. Cantor R.M. Dallinga-Thie G.M. Krauss R.M. Lanning C.D. Rotter J.I. Lusis A.J. de Bruin T.W. Families with familial combined hyperlipidemia and families enriched for coronary artery disease share genetic determinants for the atherogenic lipoprotein phenotype.Am. J. Hum. Genet. 1998; 63: 577-585Google Scholar, 18Dallinga-Thie G.M. van Linde-Sibenius Trip M. Rotter J.I. Cantor R.M. Bu X. Lusis A.J. de Bruin T.W. Complex genetic contribution of the Apo AI-CIII-AIV gene cluster to familial combined hyperlipidemia. Identification of different susceptibility haplotypes.J. Clin. Invest. 1997; 99: 953-961Google Scholar, 19Surguchov A.P. Page G.P. Smith L. Patsch W. Boerwinkle E. Polymorphic markers in apolipoprotein C-III gene flanking regions and hypertriglyceridemia.Arterioscler. Thromb. Vasc. Biol. 1996; 16: 941-947Google Scholar, 20Rotter J.I. Bu X. Cantor R.M. Warden C.H. Brown J. Gray R.J. Blanche P.J. Krauss R.M. Lusis A.J. Multilocus genetic determinants of LDL particle size in coronary artery disease families.Am. J. Hum. Genet. 1996; 58: 585-594Google Scholar), the recent characterization of the proximal apoA-V provides evidence for a significant role in the modulation of levels of lipids and lipoproteins (21Pennacchio L.A. Olivier M. Hubacek J.A. Cohen J.C. Cox D.R. Fruchart J.C. Krauss R.M. Rubin E.M. An apolipoprotein influencing triglycerides in humans and mice revealed by comparative sequencing.Science. 2001; 294: 169-173Google Scholar). The apoA-V gene (APOAV) was recently discovered by comparative sequencing of the APOAI-CIII-AIV gene region (21Pennacchio L.A. Olivier M. Hubacek J.A. Cohen J.C. Cox D.R. Fruchart J.C. Krauss R.M. Rubin E.M. An apolipoprotein influencing triglycerides in humans and mice revealed by comparative sequencing.Science. 2001; 294: 169-173Google Scholar). Pennacchio and colleagues, by construction of both knockout and human transgenic murine models for apoA-V, established its role in modulating plasma TG, a major risk factor for coronary artery disease (21Pennacchio L.A. Olivier M. Hubacek J.A. Cohen J.C. Cox D.R. Fruchart J.C. Krauss R.M. Rubin E.M. An apolipoprotein influencing triglycerides in humans and mice revealed by comparative sequencing.Science. 2001; 294: 169-173Google Scholar). Employing four single-nucleotide polymorphisms (SNPs) revealed during sequence analysis, significant associations were found between both plasma TG and VLDL mass in two independent human genetic-association studies (21Pennacchio L.A. Olivier M. Hubacek J.A. Cohen J.C. Cox D.R. Fruchart J.C. Krauss R.M. Rubin E.M. An apolipoprotein influencing triglycerides in humans and mice revealed by comparative sequencing.Science. 2001; 294: 169-173Google Scholar). The minor allele of each of three SNPs, in linkage disequilibrium, was associated with 20–30% higher plasma TG than among individuals homozygous for the major allele. There was no association with a genetic marker in the adjacent apoC-III gene, which is known to also modulate plasma TG (21Pennacchio L.A. Olivier M. Hubacek J.A. Cohen J.C. Cox D.R. Fruchart J.C. Krauss R.M. Rubin E.M. An apolipoprotein influencing triglycerides in humans and mice revealed by comparative sequencing.Science. 2001; 294: 169-173Google Scholar). Taken together, these data indicate that APOAV polymorphisms may serve as important prognostic indicators for susceptibility to hypertriglyceridemia. A recent report of increased plasma TG, associated with an upstream APOAV promoter polymorphism in two independent Caucasian populations, suggests that APOAV may contribute to certain dyslipidemic states (21Pennacchio L.A. Olivier M. Hubacek J.A. Cohen J.C. Cox D.R. Fruchart J.C. Krauss R.M. Rubin E.M. An apolipoprotein influencing triglycerides in humans and mice revealed by comparative sequencing.Science. 2001; 294: 169-173Google Scholar). Moreover, variations in APOAV may have varying impacts in different ethnic groups. Therefore, we elected to assess the frequency of the same polymorphism in APOAV in three dyslipidemic groups and a control population. We also tested for variations in allele frequency in three ethnic groups. The impact of this variation on lipoprotein composition and body mass index (BMI) was examined. A significant difference in minor allele frequency was detected in Chinese in comparison with Hispanic and European populations. Whereas we detected no preferential association with any of the three dyslipidemic phenotypes, the minor APOAV allele was associated with elevated plasma TG, VLDL TG, LDL TG, and HDL TG, strikingly elevated VLDL cholesterol, and marginally depressed HDL cholesterol. In addition, linear regression analysis of lipid parameters yielded regression models permitting estimates of adjusted means for plasma TG, VLDL cholesterol, and HDL cholesterol, conditioned on minor allele carrier status. This study was a retrospective analysis of the prevalence of the APOAV T-1131C intragenic SNP among three dyslipidemic population samples recruited without bias toward ethnicity. They were selected from the University of California, San Francisco (UCSF) Genomic Resource in Arteriosclerosis (22Pullinger C.R. Hennessy L.K. Chatterton J.E. Liu W. Love J.A. Mendel C.M. Frost P.H. Malloy M.J. Schumaker V.N. Kane J.P. Familial ligand-defective apolipoprotein B. Identification of a new mutation that decreases LDL receptor binding affinity.J. Clin. Invest. 1995; 95: 1225-1234Google Scholar), a population-based study of atherosclerotic heart disease, using the following criteria: 1) individuals with the combined hyperlipidemia phenotyped as having plasma total cholesterol (TC) >200 mg/dl, total plasma TG >200 mg/dl, LDL cholesterol >130 mg/dl, and VLDL cholesterol >30 mg/dl; 2) individuals with hypoalphalipoproteinemia were identified as having HDL cholesterol less than the tenth percentile for their age and gender (23Program L.R.C. Population Studies Data Book: Vol. I, The Prevalence Study. U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health (NIH publication number 80-1527), Washington, DC1980Google Scholar) and TG 140 mm Hg and/or diastolic blood pressure >90 mm Hg and/or taking antihypertensive medication. Blood was drawn after a 10 h fast for ultracentrifugal separation of the d < 1.006 g/cm3 and d > 1.006 g/cm3 fractions (26Havel R.J. Eder A.H. Bragdon J.M. The distribution and chemical composition of ultracentrifugally separated lipoproteins in human serum.J. Clin. Invest. 1955; 34: 1345-1363Google Scholar). HDL cholesterol was measured after precipitation of apoB-containing lipoproteins with dextran sulfate and magnesium (27Warnick G.R. Benderson J. Albers J.J. Dextran sulfate-Mg2+ precipitation procedure for quantitation of high-density-lipoprotein cholesterol.Clin. Chem. 1982; 28: 1379-1388Google Scholar). Cholesterol and TG levels were measured in plasma and in lipoprotein fractions by either automated fluorescence method (28Rush, K., L. Leon, and J. Turrell. 1970. Automated simultaneous cholesterol and triglyceride determinations on the Autoanalyser II instrument: Advances in automated analysis. Technicon International Congress. 1970.Google Scholar) or automated chemical analysis (29Kane J.P. Malloy M.J. Ports T.A. Phillips N.R. Diehl J.C. Havel R.J. Regression of coronary atherosclerosis during treatment of familial hypercholesterolemia with combined drug regimens.JAMA. 1990; 264: 3007-3012Google Scholar). LDL cholesterol was calculated as the difference of the content of the LDL cholesterol plus HDL cholesterol fraction (d > 1.006 g/cm3) and the plasma HDL cholesterol. Standards were provided by the Centers for Disease Control (Atlanta, GA). Genomic DNA was prepared from whole blood obtained from patients in the Lipid Clinic of UCSF (22Pullinger C.R. Hennessy L.K. Chatterton J.E. Liu W. Love J.A. Mendel C.M. Frost P.H. Malloy M.J. Schumaker V.N. Kane J.P. Familial ligand-defective apolipoprotein B. Identification of a new mutation that decreases LDL receptor binding affinity.J. Clin. Invest. 1995; 95: 1225-1234Google Scholar). The presence or absence of the polymorphism (rs662799) 1,131 bp upstream of the transcription start site (T-1131C) of the APOAV gene was determined as described previously (21Pennacchio L.A. Olivier M. Hubacek J.A. Cohen J.C. Cox D.R. Fruchart J.C. Krauss R.M. Rubin E.M. An apolipoprotein influencing triglycerides in humans and mice revealed by comparative sequencing.Science. 2001; 294: 169-173Google Scholar), when it was given the arbitrary designation "SNP3." Briefly, site-specific primers were used to amplify a 187 bp region of DNA by PCR encompassing the polymorphism. The penultimate base of the 3′ oligonucleotide was changed to incorporate an MseI site (TTAA) in the common allele. Next, 10 units of the enzyme MseI in 15 μl of buffer was added directly to the PCR products and incubated at 37°C for 3 h. The products were resolved on 5% polyacrylamide gels and visualized using ethidium bromide and UV light. The SAS (2000, 2001) system for statistical analysis was used, principally procedures Regression and general linear model (GLM) for linear regression models, and LOGISTIC for logistic regression models (30SAS Institute, Inc. 2000. SAS/STAT User's Guide. Version 8. SAS Institute, Inc., Cary, NC.Google Scholar, 31SAS Institute, Inc. 2001. SAS/STAT Software: Changes and Enhancements, Release 8.2. SAS Institute, Inc., Cary, NC.Google Scholar). On screened predictors, possible subset regression models were ranked by the Cp criterion (32Mallows C.L. Some comments on Cp.Technometrics. 1973; 15: 661-675Google Scholar). Power transformations of response variables were selected using a SAS macro implementing the methods of Box and Cox (33Box G.E.P. Cox D.R. An analysis of transformations (with discussion).J. R. Stat. Soc. 1964; 143: 383-430Google Scholar). Transformations of potential predictor variables were examined to maximize the explanatory power of the overall model (by maximizing the F statistic). One transformation among a small set (square, square root, log, reciprocal, reciprocal squared) was selected that best met these aims, ignoring trivial improvements. Selected interaction effects and covariate-adjusted means of the transformed responses for levels of categorical factors were tested using procedure GLM. Interaction effects with P < 0.10 were retained. Expected means on the untransformed scale were estimated using the "smearing" method (34Duan N. Smearing estimate: A nonparametric retransformation method.J. Am. Stat. Assoc. 1983; 78: 605-610Google Scholar). Two-group comparisons of means of untransformed variables used the Wilcoxon two-sample test. For multiple comparisons between factor levels, Bonferroni-corrected P values are reported. Report of a modest impact by the APOAV locus on plasma TG in two normolipidemic samples prompted our study of the effect of this locus in dyslipidemia. Based on the prediction that APOAV variation would be associated with dyslipidemia, particularly in the TG and cholesterol compartments of lipoproteins, we screened patients from the Lipid Clinic at UCSF and control subjects (35Pullinger C.R. Hennessy L.K. Chatterton J.E. Liu W.Q. Love J.A. Mendel C.M. Frost P.H. Malloy M.J. Schumaker V.N. Kane J.P. Familial ligand-defective apolipoprotein B. Identification of a new mutation that decreases LDL receptor binding affinity.J. Clin. Invest. 1995; 95: 1225-1234Google Scholar) for an APOAV polymorphism previously associated with elevated TG (21Pennacchio L.A. Olivier M. Hubacek J.A. Cohen J.C. Cox D.R. Fruchart J.C. Krauss R.M. Rubin E.M. An apolipoprotein influencing triglycerides in humans and mice revealed by comparative sequencing.Science. 2001; 294: 169-173Google Scholar). The clinical characteristics of the four sample populations are described in Table 1. In addition to elevated BMI, individuals with combined hyperlipidemia displayed significantly elevated VLDL TG, LDL TG, and HDL TG, and depressed HDL cholesterol. Individuals with hypoalphalipoproteinemia displayed significantly elevated BMI, TC, VLDL cholesterol, VLDL-TG, LDL cholesterol, and LDL-TG, while the HDL-TG compartment was significantly depressed. Individuals with hyperalphalipoproteinemia presented significantly elevated TC, VLDL cholesterol, VLDL-TG, LDL cholesterol, and LDL-TG.TABLE 1Clinical characteristics of the study population for lipid analysesVariableControlCombined HyperlipidemiaHypoalphalipoproteinemiaHyperalphalipoproteinemiaNumber191167 75 194Female (%)6250 44aP < 0.05 (Bonferroni corrected) for comparison of mean or percentage versus normal value. 48aP < 0.05 (Bonferroni corrected) for comparison of mean or percentage versus normal value.Age (years)51 ± 16 43 ± 18aP < 0.05 (Bonferroni corrected) for comparison of mean or percentage versus normal value. 44 ± 18 54 ± 15TC207 ± 33 317 ± 75 238 ± 72aP < 0.05 (Bonferroni corrected) for comparison of mean or percentage versus normal value. 285 ± 77aP < 0.05 (Bonferroni corrected) for comparison of mean or percentage versus normal value.TG124 ± 68 339 ± 302 189 ± 118 184 ± 218VLDL cholesterol15 ± 15 60 ± 42 31 ± 32aP < 0.05 (Bonferroni corrected) for comparison of mean or percentage versus normal value. 28 ± 45aP < 0.05 (Bonferroni corrected) for comparison of mean or percentage versus normal value.VLDL-TG66 ± 61 218 ± 104aP < 0.05 (Bonferroni corrected) for comparison of mean or percentage versus normal value. 130 ± 114aP < 0.05 (Bonferroni corrected) for comparison of mean or percentage versus normal value. 107 ± 149aP < 0.05 (Bonferroni corrected) for comparison of mean or percentage versus normal value.LDL cholesterol131 ± 29 209 ± 53 166 ± 57aP < 0.05 (Bonferroni corrected) for comparison of mean or percentage versus normal value. 178 ± 73aP < 0.05 (Bonferroni corrected) for comparison of mean or percentage versus normal value.LDL-TG34 ± 12 82 ± 203aP < 0.05 (Bonferroni corrected) for comparison of mean or percentage versus normal value. 48 ± 21aP < 0.05 (Bonferroni corrected) for comparison of mean or percentage versus normal value. 45 ± 26aP < 0.05 (Bonferroni corrected) for comparison of mean or percentage versus normal value.HDL cholesterol60 ± 19 44 ± 13aP < 0.05 (Bonferroni corrected) for comparison of mean or percentage versus normal value. 36 ± 8 76 ± 20HDL-TG18 ± 6 22 ± 9aP < 0.05 (Bonferroni corrected) for comparison of mean or percentage versus normal value. 15 ± 5aP < 0.05 (Bonferroni corrected) for comparison of mean or percentage versus normal value. 22 ± 14BMI24 ± 4 27 ± 6aP < 0.05 (Bonferroni corrected) for comparison of mean or percentage versus normal value. 28 ± 6aP < 0.05 (Bonferroni corrected) for comparison of mean or percentage versus normal value. 25 ± 4BMI, body mass index; TC, total cholesterol; TG, triglyceride. Values are expressed as mean ± SD, except for Female (%). All lipoprotein parameters are expressed in mg/dl. Boldface values correspond to variables used to define each clinical population.a P < 0.05 (Bonferroni corrected) for comparison of mean or percentage versus normal value. Open table in a new tab BMI, body mass index; TC, total cholesterol; TG, triglyceride. Values are expressed as mean ± SD, except for Female (%). All lipoprotein parameters are expressed in mg/dl. Boldface values correspond to variables used to define each clinical population. Overall, the genotype frequency for individuals carrying the minor allele (CC homozygotes + CT heterozygotes) at T-1131C was 0.295. Genotype frequencies were analyzed to assess effects of clinical population, gender, and ethnicity. Chinese (n = 85) and Hispanics (n = 34) were compared with Europeans (n = 443). Because of unacceptably diminished sample size when clinical population, gender, and ethnicity were cross-tabulated, CC+CT was not analyzed with respect to all three factors simultaneously. Instead, separate analyses were carried out with respect to 1) ethnicity and gender and 2) clinical population and gender within the European group. In the first of these analyses, we found significant differences in minor allele frequencies (CC+CT) among the predominant ethnic groups (P < 0.0003) represented in the study sample. No significant gender (P = 0.62) or interaction effects (P = 0.17) were observed. In multiple comparisons with Europeans, CC+CT was significantly higher for Chinese (P = 0.0002). Table 2 displays CC+CT by ethnic category.TABLE 2Genotype frequencies for carriers of the minor allele within the study populationaGenotype frequency within major ethnic groups.EthnicityCT+CCNChinese0.47185Hispanic0.23534European0.253443a Genotype frequency within major ethnic groups. Open table in a new tab In the analysis of CC+CT versus clinical population and gender within the European group, we found no significant difference in minor allele carrier frequency between the four clinical groups (P = 0.85), nor were any significant gender (P = 0.93) or interaction (P = 0.099) effects evident. Because of the prior hypothesis that genotype frequencies might differ between populations, as well as the nonsignificance of gender effects, CC+CT was reanalyzed with respect to clinical population only (P = 0.92). There were no significant multiple comparisons with the control population. Table 3 displays minor allele carrier frequency versus clinical population within the European group and within the total study population.TABLE 3Genotype frequency within clinical populations, within the European group and overallEuropeanOverallClinical PopulationCT+CCnCT+CCnControl0.2401710.330191Combined hyperlipidemia0.2741450.323167Hypoalphalipoproteinemia0.259660.24075Hyperalphalipoproteinemia0.2421800.258194 Open table in a new tab Given the weakly significant interaction effect (P = 0.099) noted above, the analysis of minor allele carrier frequency among clinical population and gender was examined further for exploratory purposes. Among the three multiple
Referência(s)