ApoE and ApoC-I polymorphisms: association of genotype with cardiovascular disease phenotype in African Americans
2009; Elsevier BV; Volume: 50; Issue: 7 Linguagem: Inglês
10.1194/jlr.p900012-jlr200
ISSN1539-7262
AutoresErdembileg Anuurad, Masayuki Yamasaki, Neil S. Shachter, Thomas A. Pearson, Lars Berglund,
Tópico(s)Liver Disease Diagnosis and Treatment
ResumoApolipoproteins (apo) E and C-I are components of triglyceride (TG)-rich lipoproteins and impact their metabolism. Functional polymorphisms have been established in apoE but not in apoC-I. We studied the relationship between apoE and apoC-I gene polymorphisms and plasma lipoproteins and coronary artery disease (CAD) in 211 African Americans and 306 Caucasians. In African Americans but not in Caucasians, apoC-I H2-carriers had significantly lower total and LDL cholesterol and apoB levels, and higher glucose, insulin, and HOMA-IR levels compared with H1 homozygotes. Differences across CAD phenotypes were seen for the apoC-I polymorphism. African-American H2-carriers without CAD had significantly lower total cholesterol (P < 0.001), LDL cholesterol (P < 0.001), and apoB (P < 0.001) levels compared with H1 homozygotes, whereas no differences were found across apoC-I genotypes for African Americans with CAD. Among African-American apoC-I H1 homozygotes, subjects with CAD had a profile similar to the metabolic syndrome (i.e., higher triglyceride, glucose, and insulin) compared with subjects without CAD. For African-American H2-carriers, subjects with CAD had a pro-atherogenic lipid pattern (i.e., higher LDL cholesterol and apoB levels), compared with subjects without CAD. ApoC-I genotypes showed an ethnically distinct phenotype relationship with regard to CAD and CAD risk factors. Apolipoproteins (apo) E and C-I are components of triglyceride (TG)-rich lipoproteins and impact their metabolism. Functional polymorphisms have been established in apoE but not in apoC-I. We studied the relationship between apoE and apoC-I gene polymorphisms and plasma lipoproteins and coronary artery disease (CAD) in 211 African Americans and 306 Caucasians. In African Americans but not in Caucasians, apoC-I H2-carriers had significantly lower total and LDL cholesterol and apoB levels, and higher glucose, insulin, and HOMA-IR levels compared with H1 homozygotes. Differences across CAD phenotypes were seen for the apoC-I polymorphism. African-American H2-carriers without CAD had significantly lower total cholesterol (P < 0.001), LDL cholesterol (P < 0.001), and apoB (P < 0.001) levels compared with H1 homozygotes, whereas no differences were found across apoC-I genotypes for African Americans with CAD. Among African-American apoC-I H1 homozygotes, subjects with CAD had a profile similar to the metabolic syndrome (i.e., higher triglyceride, glucose, and insulin) compared with subjects without CAD. For African-American H2-carriers, subjects with CAD had a pro-atherogenic lipid pattern (i.e., higher LDL cholesterol and apoB levels), compared with subjects without CAD. ApoC-I genotypes showed an ethnically distinct phenotype relationship with regard to CAD and CAD risk factors. Apolipoprotein (apo) C-I is a constituent of triglyceride (TG)-rich lipoproteins. ApoC-I is reported to inhibit hepatic lipase and to interfere with lipoprotein clearance by the LDL receptor, the LDL receptor-related protein (LRP) and the VLDL receptor (1Conde-Knape K. Bensadoun A. Sobel J.H. Cohn J.S. Shachter N.S. Overexpression of apoC-I in apoE-null mice: severe hypertriglyceridemia due to inhibition of hepatic lipase.J. Lipid Res. 2002; 43: 2136-2145Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar, 2Windler E. Chao Y. Havel R.J. Regulation of the hepatic uptake of triglyceride-rich lipoproteins in the rat. Opposing effects of homologous apolipoprotein E and individual C apoproteins.J. Biol. Chem. 1980; 255: 8303-8307Abstract Full Text PDF PubMed Google Scholar, 3Quarfordt S.H. Michalopoulos G. Schirmer B. The effect of human C apolipoproteins on the in vitro hepatic metabolism of triglyceride emulsions in the rat.J. Biol. Chem. 1982; 257: 14642-14647Abstract Full Text PDF PubMed Google Scholar–4Jong M.C. van Dijk K.W. Dahlmans V.E. Van der Boom H. Kobayashi K. Oka K. Siest G. Chan L. Hofker M.H. Havekes L.M. Reversal of hyperlipidaemia in apolipoprotein C1 transgenic mice by adenovirus-mediated gene delivery of the low-density-lipoprotein receptor, but not by the very-low-density-lipoprotein receptor.Biochem. J. 1999; 338: 281-287Crossref PubMed Scopus (0) Google Scholar). Overexpression of apoC-I in transgenic mice produces combined hyperlipidemia along with increased postprandial lipemia (5Shachter N.S. Ebara T. Ramakrishnan R. Steiner G. Breslow J.L. Ginsberg H.N. Smith J.D. Combined hyperlipidemia in transgenic mice overexpressing human apolipoprotein Cl.J. Clin. Invest. 1996; 98: 846-855Crossref PubMed Scopus (98) Google Scholar, 6Jong M.C. 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Lipid Res. 2002; 43: 1680-1687Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar). These studies have raised the possibility that apoC-I may play an important role in clinical dyslipidemia and coronary artery disease (CAD).Genetic variability of apolipoprotein E (apoE) is a major determinant of plasma lipoprotein levels (9Mahley R.W. Apolipoprotein E: cholesterol transport protein with expanding role in cell biology.Science. 1988; 240: 622-630Crossref PubMed Scopus (3351) Google Scholar). Furthermore, apoE genotype frequencies differ between African Americans and Caucasians (10Moore R.J. Chamberlain R.M. Khuri F.R. Apolipoprotein E and the risk of breast cancer in African-American and non-Hispanic white women: a review.Oncology. 2004; 66: 79-93Crossref PubMed Scopus (29) Google Scholar, 11de Knijff P. van Duijn C.M. Role of APOE in dementia: a critical reappraisal.Haemostasis. 1998; 28: 195-201PubMed Google Scholar). Variation of apoE genotypes has been strongly and consistently associated with plasma lipid levels and risk of CAD (12Utermann G. Hees M. Steinmetz A. Polymorphism of apolipoprotein E and occurrence of dysbetalipoproteinaemia in man.Nature. 1977; 269: 604-607Crossref PubMed Scopus (524) Google Scholar, 13van Bockxmeer F.M. Mamotte C.D. Apolipoprotein epsilon 4 homozygosity in young men with coronary heart disease.Lancet. 1992; 340: 879-880Abstract PubMed Scopus (186) Google Scholar, 14Stengard J.H. Pekkanen J. Ehnholm C. Nissinen A. Sing C.F. Genotypes with the apolipoprotein epsilon4 allele are predictors of coronary heart disease mortality in a longitudinal study of elderly Finnish men.Hum. Genet. 1996; 97: 677-684Crossref PubMed Scopus (56) Google Scholar, 15Gerdes L.U. Gerdes C. Kervinen K. Savolainen M. Klausen I.C. Hansen P.S. Kesaniemi Y.A. Faergeman O. The apolipoprotein epsilon4 allele determines prognosis and the effect on prognosis of simvastatin in survivors of myocardial infarction: a substudy of the Scandinavian simvastatin survival study.Circulation. 2000; 101: 1366-1371Crossref PubMed Scopus (223) Google Scholar–16Anuurad E. Rubin J. Lu G. Pearson T.A. Holleran S. Ramakrishnan R. Berglund L. Protective effect of apolipoprotein E2 on coronary artery disease in African Americans is mediated through lipoprotein cholesterol.J. Lipid Res. 2006; 47: 2475-2481Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar). In contrast to apoE, less information is available on apoC-I genetic variation in humans or on their possible contributions to clinically relevant lipoprotein phenotypes. A DNA polymorphism produced by a CGTT insertion 317-bp 5′ to the apoC-I transcription initiation site (apoC-I -317insCGTT) has been described and is at present the only known common apoC-I gene variant (17Smit M. van der Kooij-Meijs E. Woudt L.P. Havekes L.M. Frants R.R. Exact localization of the familial dysbetalipoproteinemia associated HpaI restriction site in the promoter region of the APOC1 gene.Biochem. Biophys. Res. Commun. 1988; 152: 1282-1288Crossref PubMed Scopus (26) Google Scholar, 18Xu Y. Berglund L. Ramakrishnan R. Mayeux R. Ngai C. Holleran S. Tycko B. Leff T. Shachter N.S. A common Hpa I RFLP of apolipoprotein C–I increases gene transcription and exhibits an ethnically distinct pattern of linkage disequilibrium with the alleles of apolipoprotein E.J. Lipid Res. 1999; 40: 50-58Abstract Full Text Full Text PDF PubMed Google Scholar). This polymorphism has been termed the HpaI RFLP, with “H2” designating the insertion allele (and consequent presence of the HpaI DNA restriction enzyme site) and “H1” designating the deletion allele (and absence of the HpaI site). The H1 and H2 alleles of apoC1 have been reported to show an ethnically distinct pattern of linkage disequilibrium with alleles of the adjacent apoE gene (18Xu Y. Berglund L. Ramakrishnan R. Mayeux R. Ngai C. Holleran S. Tycko B. Leff T. Shachter N.S. A common Hpa I RFLP of apolipoprotein C–I increases gene transcription and exhibits an ethnically distinct pattern of linkage disequilibrium with the alleles of apolipoprotein E.J. Lipid Res. 1999; 40: 50-58Abstract Full Text Full Text PDF PubMed Google Scholar, 19Seixas S. Trovoada M.J. Rocha J. Haplotype analysis of the apolipoprotein E and apolipoprotein C1 loci in Portugal and Sao Tome e Principe (Gulf of Guinea): linkage disequilibrium evidence that APOE*4 is the ancestral APOE allele.Hum. Biol. 1999; 71: 1001-1008PubMed Google Scholar–20Cohn J.S. Tremblay M. Boulet L. Jacques H. Davignon J. Roy M. Bernier L. Plasma concentration and lipoprotein distribution of ApoC-I is dependent on ApoE genotype rather than the Hpa I ApoC-I promoter polymorphism.Atherosclerosis. 2003; 169: 63-70Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar). In our prior study of an elderly, multiracial, community-based population, there was a strong association of apo ε3 with the apoC-I H1 allele and of apo ε4 with apoC-I H2 allele in non-Hispanic Caucasians. In contrast, in African-Americans, these associations were significantly weaker, while apo ε2 was closely associated with H2 in both groups (18Xu Y. Berglund L. Ramakrishnan R. Mayeux R. Ngai C. Holleran S. Tycko B. Leff T. Shachter N.S. A common Hpa I RFLP of apolipoprotein C–I increases gene transcription and exhibits an ethnically distinct pattern of linkage disequilibrium with the alleles of apolipoprotein E.J. Lipid Res. 1999; 40: 50-58Abstract Full Text Full Text PDF PubMed Google Scholar). Similar ethnic differences in the genetic association of the two markers were found in a comparison of Portuguese with Africans from Sao Tome e Principe (19Seixas S. Trovoada M.J. Rocha J. Haplotype analysis of the apolipoprotein E and apolipoprotein C1 loci in Portugal and Sao Tome e Principe (Gulf of Guinea): linkage disequilibrium evidence that APOE*4 is the ancestral APOE allele.Hum. Biol. 1999; 71: 1001-1008PubMed Google Scholar).In contrast to the wealth of information on apoE genotypes, the relationship of apoC-I genotypes with CAD has not been addressed. In the current study, we investigated the association between genetic polymorphism of apoE and apoC-I and cardiovascular disease and risk factors across African-American and Caucasian ethnicity. This approach allowed us to assess differences across both CAD phenotypes and apoC-I and apoE genotypes for each ethnic group.MATERIALS AND METHODSSubjectsSubjects were recruited from a patient population scheduled for diagnostic coronary arteriography either at Harlem Hospital Center in New York City or at the Mary Imogene Bassett Hospital in Cooperstown, NY. The clinical characteristics of the study population and the study design, including inclusion and exclusion criteria, have been described previously, and notably, exclusion criteria included use of lipid-lowering drugs (16Anuurad E. Rubin J. Lu G. Pearson T.A. Holleran S. Ramakrishnan R. Berglund L. Protective effect of apolipoprotein E2 on coronary artery disease in African Americans is mediated through lipoprotein cholesterol.J. Lipid Res. 2006; 47: 2475-2481Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar, 21Anuurad E. Lu G. Rubin J. Pearson T.A. Berglund L. ApoE genotype affects allele-specific apo[a] levels for large apo[a] sizes in African Americans: the Harlem-Basset Study.J. Lipid Res. 2007; 48: 693-698Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar). Briefly, a total of 648 patients, 401 men and 247 women, ethnically self-identified as Caucasian (n = 344), African American (n = 232), or Other (n = 72) were enrolled. The present report is based on the findings in 306 Caucasians (201 males, 105 females) and 211 African Americans (123 males, 88 females) in whom lipid levels and apoE and apoC-I genotypes were available. The study was approved by the Institutional Review Boards at Harlem Hospital, the Mary Imogene Bassett Hospital, Columbia University College of Physicians and Surgeons, and University of California Davis, and informed consent was obtained from all subjects.Clinical and biochemical assessmentFasting blood samples were drawn approximately 2–4 h before the catheterization procedure, and serum and plasma samples were stored at −80°C prior to analysis. Serum triglycerides, total and HDL cholesterol, and glucose were determined using standard enzymatic procedures, and LDL cholesterol levels were calculated as described (22McGowan M.W. Artiss J.D. Strandbergh D.R. Zak B. A peroxidase-coupled method for the colorimetric determination of serum triglycerides.Clin. Chem. 1983; 29: 538-542Crossref PubMed Scopus (1065) Google Scholar, 23Allain C.C. Poon L.S. Chan C.S. Richmond W. Fu P.C. Enzymatic determination of total serum cholesterol.Clin. Chem. 1974; 20: 470-475Crossref PubMed Scopus (7272) Google Scholar, 24Warnick G.R. Benderson J. Albers J.J. Dextran sulfate-Mg2+ precipitation procedure for quantitation of high-density-lipoprotein cholesterol.Clin. Chem. 1982; 28: 1379-1388Crossref PubMed Scopus (1807) Google Scholar–25Friedewald 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: 499-502Crossref PubMed Scopus (63) Google Scholar). Homeostasis model assessment–insulin resistance (HOMA-IR) was calculated using the updated model available from the Oxford Centre for Endocrinology and Diabetes (26Levy J.C. Matthews D.R. Hermans M.P. Correct homeostasis model assessment (HOMA) evaluation uses the computer program.Diabetes Care. 1998; 21: 2191-2192Crossref PubMed Scopus (1504) Google Scholar, 27Adler A.I. Levy J.C. Matthews D.R. Stratton I.M. Hines G. Holman R.R. Insulin sensitivity at diagnosis of Type 2 diabetes is not associated with subsequent cardiovascular disease (UKPDS 67).Diabet. Med. 2005; 22: 306-311Crossref PubMed Scopus (34) Google Scholar).Determination of apoE and apoC-I genotypesApoE genotypes were determined as described previously (16Anuurad E. Rubin J. Lu G. Pearson T.A. Holleran S. Ramakrishnan R. Berglund L. Protective effect of apolipoprotein E2 on coronary artery disease in African Americans is mediated through lipoprotein cholesterol.J. Lipid Res. 2006; 47: 2475-2481Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar, 21Anuurad E. Lu G. Rubin J. Pearson T.A. Berglund L. ApoE genotype affects allele-specific apo[a] levels for large apo[a] sizes in African Americans: the Harlem-Basset Study.J. Lipid Res. 2007; 48: 693-698Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar, 28Hixson 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). Genotypic status for the HpaI apoC-I promoter polymorphism was determined as described by a two-step nested PCR followed by restriction digestion with HpaI and electrophoresis on 1.5% agarose (ultraPure Agarose, Life Technologies, Gaithersburg, MD) (18Xu Y. Berglund L. Ramakrishnan R. Mayeux R. Ngai C. Holleran S. Tycko B. Leff T. Shachter N.S. A common Hpa I RFLP of apolipoprotein C–I increases gene transcription and exhibits an ethnically distinct pattern of linkage disequilibrium with the alleles of apolipoprotein E.J. Lipid Res. 1999; 40: 50-58Abstract Full Text Full Text PDF PubMed Google Scholar).Coronary angiographyTwo readers, who were blinded to patient identity, clinical diagnosis, lipoprotein, and genotype results, recorded the localization and extent of luminal narrowing for 15 segments of the major coronary arteries. Presence of CAD was defined as the presence of at least 50% stenosis in any 1 of 15 coronary artery segments. Of the patients without CAD, the majority (80.5%) had less than 25% stenosis, and of the patients with CAD, 81% had greater than 75% stenosis. A composite cardiovascular score (0–75) was calculated based on determination of presence of stenosis on a scale of 0–5 of 15 predetermined coronary artery segments.StatisticsAnalysis of data was done with SPSS statistical analysis software (SPSS Inc., Chicago, IL). Results were expressed as means ± SD. Triglyceride and insulin levels and cardiovascular composite score were logarithmically transformed to achieve normal distributions. Proportions were compared between groups using χ2 analysis, and Fisher exact test where appropriate. Group means for clinical parameters were compared using one-way ANOVA and post hoc analyses were performed by the Tukey-HSD test. Means for CAD groups were compared using Student’s t-test. Multiple logistic regression analysis was applied to predict the variables that independently and significantly contributed to the dependent variable: the presence of cardiovascular disease. All analyses were two-tailed, and P-values less than 0.05 were considered statistically significant.RESULTSEffect of apoC-I polymorphism on clinical parametersThe effect of apoC-I allele status on lipoprotein, apolipoprotein, and glucose, insulin and HOMA-IR measurements is shown in Table 1. In Caucasians, no effect of apoC-I allele status on any of the clinical parameters was evident. On the other hand, statistically significant effects of the apoC-I polymorphism on clinical parameters were noted in African Americans, with a gradual decrease in total cholesterol levels with increasing number of apoC-I H2 alleles (209 ± 47, 190 ± 41, and 172 ± 39 mg/dl for H1/H1, H1/H2 and H2/H2, respectively; P < 0.001). As seen in the table, essentially the same pattern was found for LDL cholesterol and apoB levels. There was no difference in HDL cholesterol or apoA-I levels across apoC-I genotype. Glucose, insulin, and HOMA-IR levels were significantly higher among African-American apoC-I H2 homozygotes compared with H1 homozygotes or H1/H1 heterozygotes.TABLE 1Clinical characteristics by apoC-I genotype across ethnicityAfrican AmericansCaucasiansCharacteristicsH1/H1 (n = 103)H1/H2 (n = 88)H2/H2 (n = 20)PH1/H1 (n = 191)H1/H2 (n = 101)H2/H2 (n = 14)PTotal cholesterol (mg/dl)209 ± 47190 ± 41aP < 0.05 compared with H1 homozygote subjects.172 ± 39aP < 0.05 compared with H1 homozygote subjects.<0.001193 ± 39200 ± 40191 ± 53NSLDL cholesterol (mg/dl)136 ± 41117 ± 40aP < 0.05 compared with H1 homozygote subjects.101 ± 41aP < 0.05 compared with H1 homozygote subjects.<0.001120 ± 32122 ± 36116 ± 43NSHDL cholesterol (mg/dl)49 ± 1750 ± 1947 ± 16NS40 ± 1241 ± 1239 ± 14NSTriglyceride (mg/dl)117 ± 47116 ± 55122 ± 72NS170 ± 90196 ± 117174 ± 74NSApoA-I (mg/dl)132 ± 31129 ± 29126 ± 27NS121 ± 22124 ± 24113 ± 20NSApoB (mg/dl)143 ± 42126 ± 37aP < 0.05 compared with H1 homozygote subjects.113 ± 40aP < 0.05 compared with H1 homozygote subjects.0.001133 ± 32138 ± 40130 ± 41NSGlucose (mg/dl)122 ± 56113 ± 42146 ± 81bP < 0.05 compared with H1/H2 heterozygote subjects.0.048128 ± 61138 ± 69105 ± 23NSInsulin (μU/ml)22 ± 2718 ± 2030 ± 26bP < 0.05 compared with H1/H2 heterozygote subjects.0.03526 ± 3530 ± 4820 ± 17NSHOMA-IR2.6 ± 2.42.4 ± 2.54.2 ± 3.3a,bP < 0.05 compared with H1/H2 heterozygote subjects.0.0113.5 ± 4.33.5 ± 4.82.6 ± 2.1NSData are means ± SD. Apo, apolipoprotein; HOMA-IR, homeostasis model assessment–insulin resistance; NS, not significant. P values were calculated using one-way ANOVA and post hoc analyses were performed with the Tukey-HSD test for two independent samples. Values for triglycerides, insulin and HOMA-IR were logarithmically transformed before analyses. Nontransformed values are shown in the table.a P < 0.05 compared with H1 homozygote subjects.b P < 0.05 compared with H1/H2 heterozygote subjects. Open table in a new tab Clinical parameters by CAD across ApoC-I genotypeWe next evaluated the impact of apoC-I genotype on the same clinical parameters in patients with two different clinical phenotypes, presence or absence of CAD (Table 2). In doing so, we were able to undertake two different comparisons. First, a comparison across apoC-I genotypes provided information for a given phenotype (presence or absence of CAD). Second, a comparison within a given genotype (H1 homozygotes or H2-carriers) allowed a comparison across phenotypes (e.g., presence or absence of CAD).TABLE 2Clinical characteristics by CAD across ApoC-I genotype in Caucasians and African AmericansWithout CADWith CADH1/H1H1/H2, H2/H2PH1/H1H1/H2, H2/H2PAfrican Americansn = 59n = 55n = 41n = 50 Total cholesterol (mg/dl)206 ± 41173 ± 38<0.001215 ± 56200 ± 40bP < 0.05 compared with H1/H2, H2/H2 across CAD status.NS LDL cholesterol (mg/dl)134 ± 35102 ± 37<0.001141 ± 49126 ± 39bP < 0.05 compared with H1/H2, H2/H2 across CAD status.NS HDL cholesterol (mg/dl)50 ± 1651 ± 19NS48 ± 1748 ± 17NS Triglyceride (mg/dl)109 ± 44101 ± 39NS128 ± 51aP < 0.05 compared with H1/H1 across CAD status.130 ± 69bP < 0.05 compared with H1/H2, H2/H2 across CAD status.NS ApoA-I (mg/dl)136 ± 32131 ± 30NS127 ± 27125 ± 27NS ApoB (mg/dl)138 ± 37112 ± 34<0.001152 ± 48134 ± 36bP < 0.05 compared with H1/H2, H2/H2 across CAD status.NS Glucose (mg/dl)112 ± 36111 ± 43NS136 ± 75aP < 0.05 compared with H1/H1 across CAD status.124 ± 47NS Insulin (μU/ml)20 ± 3118 ± 18NS25 ± 2324 ± 26NS HOMA-IR2.1 ± 1.52.4 ± 2.3NS3.4 ± 3.2aP < 0.05 compared with H1/H1 across CAD status.3.1 ± 3.1NSCaucasiansn = 76n = 52n = 110n = 60 Total cholesterol (mg/dl)187 ± 39195 ± 41NS198 ± 40203 ± 41NS LDL cholesterol (mg/dl)114 ± 29120 ± 34NS126 ± 35aP < 0.05 compared with H1/H1 across CAD status.125 ± 39NS HDL cholesterol (mg/dl)42 ± 1443 ± 12NS39 ± 11aP < 0.05 compared with H1/H1 across CAD status.40 ± 12NS Triglyceride (mg/dl)157 ± 93168 ± 90NS179 ± 88aP < 0.05 compared with H1/H1 across CAD status.218 ± 127bP < 0.05 compared with H1/H2, H2/H2 across CAD status.0.038 ApoA-I (mg/dl)124 ± 24125 ± 22NS119 ± 20122 ± 26NS ApoB (mg/dl)124 ± 29136 ± 46NS141 ± 34aP < 0.05 compared with H1/H1 across CAD status.139 ± 35NS Glucose (mg/dl)118 ± 64130 ± 58NS134 ± 59137 ± 74NS Insulin (μU/ml)22 ± 2734 ± 60NS29 ± 4022 ± 19NS HOMA-IR2.9 ± 3.53.2 ± 5.1NS3.8 ± 4.73.3 ± 3.7NSApo, apolipoprotein; CAD, coronary artery disease; HOMA-IR, homeostasis model assessment–insulin resistance. Data are means ± SD. P values calculated using Student’s t-test. Values for triglycerides, insulin and HOMA-IR were logarithmically transformed before analyses. Nontransformed values are shown.a P < 0.05 compared with H1/H1 across CAD status.b P < 0.05 compared with H1/H2, H2/H2 across CAD status. Open table in a new tab In the first comparison (i.e., apoC-I genotypes in patients with or without CAD), African-American H2-carriers without CAD had significantly lower total cholesterol (P < 0.001), LDL cholesterol (P < 0.001), and apoB (P < 0.001) levels compared with H1 homozygotes. However, no significant difference were seen across apoC-I genotypes for African Americans with CAD. There was no significant difference between Caucasian apoC-I H1 homozygotes and H2-carriers without CAD, whereas triglyceride levels were higher in Caucasian H2-carriers with CAD (P < 0.05).In the second comparison, we found significant differences for a number of parameters for a given apoC-I genotype (H1 homozygotes or H2-carriers) across CAD status among African Americans. As seen in Table 2 and highlighted for lipid components in Fig. 1, African-American apoC-I H1 homozygotes with CAD had significantly higher triglyceride (P < 0.05), glucose (P < 0.05), and HOMA-IR (P < 0.05) levels compared with patients with the same genotype without CAD. In contrast, African-American apoC-I H2-carriers with CAD had significantly higher total cholesterol (P = 0.001), LDL cholesterol (P < 0.05) and apoB (P = 0.001) levels compared with patients with the same genotype without CAD. These results suggest that parameters associated with the metabolic syndrome (triglyceride, insulin, and glucose) differed across CAD status for H1 homozygotes, whereas H2-carriers with CAD had a more pronounced pro-atherogenic lipid pattern (higher levels of total and LDL cholesterol, triglycerides, and apoB) compared with the same genotype without CAD. For Caucasians, the pattern was different. Caucasian apoC-I H1 homozygotes with CAD had a pro-atherogenic lipid phenotype (i.e., higher LDL cholesterol, triglyceride, and apoB levels, and lower HDL cholesterol levels) compared with subjects carrying the same genotype without CAD. The only significant difference among apoC-I H2-carriers was a higher triglyceride level for subjects with CAD.Prevalence of apoC-I and apoE genotypeIn our previous study in a different population, we observed linkage disequilibrium between apoE and apoC-I genotypes (18Xu Y. Berglund L. Ramakrishnan R. Mayeux R. Ngai C. Holleran S. Tycko B. Leff T. Shachter N.S. A common Hpa I RFLP of apolipoprotein C–I increases gene transcription and exhibits an ethnically distinct pattern of linkage disequilibrium with the alleles of apolipoprotein E.J. Lipid Res. 1999; 40: 50-58Abstract Full Text Full Text PDF PubMed Google Scholar). In the present study, the prevalence of apoC-I genotype differed between Caucasians and African Americans. Caucasians had higher H1 and lower H2 allele frequency and, consequently, a higher frequency of H1/H1 and H1/H2 genotypes (P = 0.002 and P = 0.038, respectively), while African Americans had significantly higher prevalence of H2/H2 (P = 0.041). An association of apoC-I allele status with apoE allele status was observed for both ethnic groups. Apo ε3 homozygotes (genotype E3/E3), the major genotype group in both ethnicities, was strongly associated with apoC-I H1/H1 in Caucasians, while the association was less pronounced among African Americans (P < 0.001) (Table 3). Thus, only 6 of the 193 (3%) Caucasian apo ε3 homozygosity carried the apoC-I H2-allele, whereas 18 of 77 (23%) African-American apo ε3 homozygotes were apoC-I H2-carriers, all being H1/H2 heterozygotes. Conversely, only 2 of the 69 (3%) Caucasian apo ε4-carriers (apo E3/E4 and E4/E4) were apoC-I H1 homozygotes, while the corresponding number for African Americans was substantially higher [40 of 87 apo ε4-carriers (46%)].TABLE 3ApoC-I genotype by apoE genotypeApoC-I genotypeApoE genotypeEthnicityH1/H1H1/H2H2/H2E2/E2African Americans01 (50%)1 (50%)Caucasians003 (100%)E2/E4African Americans2 (13%)8 (53%)5 (34%)Caucasians1 (14%)2 (29%)4 (57%)E2/E3African Americans2 (7%)23 (77%)5 (16%)Caucasians1 (3%)33 (97%)0E3/E3African Americans59 (77%)18 (23%)0Caucasians187 (97%)5 (3%)1 (0%)E3/E4African Americans35 (46%)32 (42%)9 (12%)Caucasians2 (3%)61 (97%)0E4/E4African Americans5 (45%)6 (55%)0Caucasians006 (100%)TotalAfrican Americans103 (49%)88 (42%)20 (9%)Caucasians191 (62%)101 (33%)14 (5%)Apo, apolipoprotein. Values represent number of subjects; values in parentheses are percentages of each group. Open table in a new tab Clinical parameters by CAD across ApoC-I genotype in African-American apo ε4-carriersAs the apoC-I genotype showed a less pronounced pattern of linkage disequilibrium with apoE genotypes in African Americans, we next compared the relation between apoC-I genotypes and clinical parameters across CAD in African-American apo ε4-carriers (Table 4). As for the entire group, African-American ε4-carriers without CAD had higher total and LDL cholesterol and apoB levels among apoC-I H1 homozygotes, while no significant differences were seen across apoC-I genotypes for subjects with CAD. When comparing intra-genotype differences across CAD phenotype, glucose and HOMA-IR was higher among apoC-I H1 homozygotes with CAD compared with subjects without CAD. In contrast, apoC-I H2-carriers with CAD had higher total and LDL cholesterol levels compared with the same genotypes without CAD (Table 4).TABLE 4Clinical characteristics of African Americans across ApoE and ApoC-I genotypesWithout CADWith CADAfrican Americans apo ε4H1/H1 (n = 23)H1/H2, H2/H2 (n = 24)PH1/H1 (n = 17)H1/H2, H2/H2 (n = 23)PTotal cholesterol (mg/dl)211 ± 39180 ± 370.008234 ± 65209 ± 48bP < 0.05 compared with H1/H2, H2/H2 across CAD status.NSLDL-C (mg/dl)141 ± 36111 ± 350.006158 ± 55137 ± 48bP < 0.05 compared with H1/H2, H2/H2 across CAD status.NSHDL-C (mg/dl)48 ± 1049 ± 19NS49 ± 1447 ± 18NSTG (mg/dl)109 ± 43100 ± 39NS134 ± 42127 ± 69NSApoA-I (mg/dl)130 ± 23123 ± 24NS132 ± 24120 ± 28NSA
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