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• W2128185415 abstract "Atherosclerosis is the major cause of coronary artery disease (CAD), and oxidized LDL (oxLDL) is believed to play a key role in the initiation of the atherosclerotic process. Recent studies show that inflammation and autoimmune reactions are also relevant in atherosclerosis. In this study, we examined the association of antibodies against oxLDL (anti-oxLDL) with the severity of CAD in 558 Women's Ischemia Syndrome Evaluation (WISE) study samples (465 whites; 93 blacks) determined by coronary stenosis (<20%, 20%–49%, >50% stenosis). We also examined the relationship of anti-oxLDL with serum lipid levels and nine candidate genes including APOE, APOH, APOA5, LPL, LRP1, HL, CETP, PON1, and OLR1. IgM anti-oxLDL levels were significantly higher in the >20% stenosis group than in the ≥20% stenosis group in whites (0.69 ± 0.02 vs. 0.64 ± 0.01, respectively; P = 0.02). IgM anti-oxLDL levels correlated significantly with total cholesterol (r2= 0.01; P = 0.03) and LDL cholesterol (r2= 0.017; P = 0.004) in whites. Multiple regression analysis revealed a suggestive association of LPL/S447X single-nucleotide polymorphism (SNP) with both IgG anti-oxLDL (P = 0.02) and IgM anti-oxLDL (P = 0.07), as well as between IgM anti-oxLDL and the OLR1/3′UTR SNP (P = 0.020). Our data suggest that higher IgM anti-oxLDL levels may provide protection against coronary stenosis and that genetic variation in some candidate genes are determinants of anti-oxLDL levels. Atherosclerosis is the major cause of coronary artery disease (CAD), and oxidized LDL (oxLDL) is believed to play a key role in the initiation of the atherosclerotic process. Recent studies show that inflammation and autoimmune reactions are also relevant in atherosclerosis. In this study, we examined the association of antibodies against oxLDL (anti-oxLDL) with the severity of CAD in 558 Women's Ischemia Syndrome Evaluation (WISE) study samples (465 whites; 93 blacks) determined by coronary stenosis (<20%, 20%–49%, >50% stenosis). We also examined the relationship of anti-oxLDL with serum lipid levels and nine candidate genes including APOE, APOH, APOA5, LPL, LRP1, HL, CETP, PON1, and OLR1. IgM anti-oxLDL levels were significantly higher in the >20% stenosis group than in the ≥20% stenosis group in whites (0.69 ± 0.02 vs. 0.64 ± 0.01, respectively; P = 0.02). IgM anti-oxLDL levels correlated significantly with total cholesterol (r2= 0.01; P = 0.03) and LDL cholesterol (r2= 0.017; P = 0.004) in whites. Multiple regression analysis revealed a suggestive association of LPL/S447X single-nucleotide polymorphism (SNP) with both IgG anti-oxLDL (P = 0.02) and IgM anti-oxLDL (P = 0.07), as well as between IgM anti-oxLDL and the OLR1/3′UTR SNP (P = 0.020). Our data suggest that higher IgM anti-oxLDL levels may provide protection against coronary stenosis and that genetic variation in some candidate genes are determinants of anti-oxLDL levels. Coronary artery disease (CAD) is a multifactorial chronic disease caused by atherosclerosis. Although the initiation and progression of atherosclerosis depends largely on genetic factors and life style factors, the underlying cellular and molecular mechanism remains unclear. Accumulating data suggest that oxidized low-density lipoprotein (oxLDL) plays an important role in the development and progression of atherosclerosis (1Witztum J.L. Steinberg D. Role of oxidized low density lipoprotein in atherogenesis.J. Clin. Invest. 1991; 88: 1785-1792Crossref PubMed Scopus (2474) Google Scholar, 2Ohashi R. Mu H. Yao Q. Chen C. Atherosclerosis: immunopathogenesis and immunotherapy.Med. Sci. Monit. 2004; 10: RA255-RA260PubMed Google Scholar). OxLDL, generated by the action of reactive oxygen species, is taken up by macrophages, which develop into foam cells. Autoantibodies against oxLDL (anti-oxLDL) are found in both atherosclerotic lesions and plasma (3Witztum J.L. The oxidation hypothesis of atherosclerosis.Lancet. 1994; 344: 793-795Abstract PubMed Scopus (1261) Google Scholar), and thus, the state of oxidative stress might be measured by serum oxLDL antibody levels (4Suzuki K. Ito Y. Wakai K. Kawado M. Hashimoto S. Toyoshima H. Kojima M. Tokudome S. Hayakawa N. Watanabe Y. Serum oxidized low-density lipoprotein levels and risk of colorectal cancer: a case-control study nested in the Japan Collaborative Cohort Study.Cancer Epidemiol. Biomarkers Prev. 2004; 13: 1781-1787PubMed Google Scholar). The serum levels of anti-oxLDL have been reported to predict the progression of carotid and coronary atherosclerosis (5Lehtimaki T. Lehtinen S. Solakivi T. Nikkila M. Jaakkola O. Jokela H. Yla-Herttuala S. Luoma J.S. Koivula T. Nikkari T. Autoantibodies against oxidized low density lipoprotein in patients with angiographically verified coronary artery disease.Arterioscler. Thromb. Vasc. Biol. 1999; 19: 23-27Crossref PubMed Scopus (185) Google Scholar, 6Inoue T. Uchida T. Kamishirado H. Takayanagi K. Hayashi T. Morooka S. Clinical significance of antibody against oxidized low density lipoprotein in patients with atherosclerotic coronary artery disease.J. Am. Coll. Cardiol. 2001; 37: 775-779Crossref PubMed Scopus (93) Google Scholar, 7Salonen J.T. Yla-Herttuala S. Yamamoto R. Butler S. Korpela H. Salonen R. Nyyssonen K. Palinski W. Witztum J.L. Autoantibody against oxidised LDL and progression of carotid atherosclerosis.Lancet. 1992; 339: 883-887Abstract PubMed Scopus (1199) Google Scholar, 8Puurunen M. Manttari M. Manninen V. Tenkanen L. Alfthan G. Ehnholm C. Vaarala O. Aho K. Palosuo T. Antibody against oxidized low-density lipoprotein predicting myocardial infarction.Arch. Intern. Med. 1994; 154: 2605-2609Crossref PubMed Google Scholar). Published studies assessing the relationship between anti-oxLDL antibodies and atherosclerosis severity by different methods have yielded inconsistent results (6Inoue T. Uchida T. Kamishirado H. Takayanagi K. Hayashi T. Morooka S. Clinical significance of antibody against oxidized low density lipoprotein in patients with atherosclerotic coronary artery disease.J. Am. Coll. Cardiol. 2001; 37: 775-779Crossref PubMed Scopus (93) Google Scholar, 9Rossi G.P. Cesari M. De Toni R. Zanchetta M. Maiolino G. Pedon L. Ganzaroli C. Maiolino P. Pessina A.C. Antibodies to oxidized low-density lipoproteins and angiographically assessed coronary artery disease in white patients.Circulation. 2003; 108: 2467-2472Crossref PubMed Scopus (53) Google Scholar, 10van de Vijver L.P. Steyger R. van Poppel G. Boer J.M. Kruijssen D.A. Seidell J.C. Princen H.M. Autoantibodies against MDA-LDL in subjects with severe and minor atherosclerosis and healthy population controls.Atherosclerosis. 1996; 122: 245-253Abstract Full Text PDF PubMed Scopus (95) Google Scholar, 11Sherer Y. Tenenbaum A. Praprotnik S. Shemesh J. Blank M. Fisman E.Z. Harats D. George J. Levy Y. Peter J.B. Coronary artery disease but not coronary calcification is associated with elevated levels of cardiolipin, beta-2-glycoprotein-I, and oxidized LDL antibodies.Cardiology. 2001; 95: 20-24Crossref PubMed Scopus (63) Google Scholar, 12Tornvall P. Waeg G. Nilsson J. Hamsten A. Regnstrom J. Autoantibodies against modified low-density lipoproteins in coronary artery disease.Atherosclerosis. 2003; 167: 347-353Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar) partly because the two antibodies of oxLDL (IgM and IgG) have different mechanistic functions in the atherosclerosis pathway. While IgM antibodies inhibit macrophage uptake of oxLDL (13Horkko S. Bird D.A. Miller E. Itabe H. Leitinger N. Subbanagounder G. Berliner J.A. Friedman P. Dennis E.A. Curtiss L.K. Monoclonal autoantibodies specific for oxidized phospholipids or oxidized phospholipid-protein adducts inhibit macrophage uptake of oxidized low-density lipoproteins.J. Clin. Invest. 1999; 103: 117-128Crossref PubMed Scopus (474) Google Scholar, 14Oksjoki R. Kovanen P.T. Lindstedt K.A. Jansson B. Pentikainen M.O. OxLDL-IgG immune complexes induce survival of human monocytes.Arterioscler. Thromb. Vasc. Biol. 2006; 26: 576-583Crossref PubMed Scopus (41) Google Scholar), oxLDL and IgM immune complexes induce accumulation of macrophages (14Oksjoki R. Kovanen P.T. Lindstedt K.A. Jansson B. Pentikainen M.O. OxLDL-IgG immune complexes induce survival of human monocytes.Arterioscler. Thromb. Vasc. Biol. 2006; 26: 576-583Crossref PubMed Scopus (41) Google Scholar). Genetic factors may also affect the association of oxLDL levels with atherosclerosis. While a number of candidate genes have been associated with CAD risk (15Winkelmann B.R. Hager J. Genetic variation in coronary heart disease and myocardial infarction: methodological overview and clinical evidence.Pharmacogenomics. 2000; 1: 73-94Crossref PubMed Scopus (55) Google Scholar), their possible associations with oxLDL parameters have not been studied extensively. The present study was designed to (1) investigate the separate associations of IgM and IgG anti-oxLDL with stenosis severity in the well-characterized cohort of Women's Ischemic Syndrome Evaluation (WISE) study, and to (2) examine the association between anti-oxLDL levels and genetic variation in selected candidate genes, including the apolipoprotein E (APOE), apolipoprotein H (APOH), apolipoprotein 5 (APOA5), lipoprotein lipase (LPL), low-density lipoprotein receptor related protein-1 (LRP1), hepatic lipase (HL), cholesteryl ester transfer protein (CETP), paraoxonase (PON1 and PON2), and oxLDL receptor 1 (OLR1) genes. These candidate genes are actively involved in the lipoprotein metabolism pathway, and thus variations in these genes might have significant impact on the levels of anti-oxLDL. Study subjects were collected as part of the WISE study. Detailed information on the study has been described elsewhere (16Chen Q. Reis S.E. Kammerer C.M. McNamara D.M. Holubkov R. Sharaf B.L. Sopko G. Pauly D.F. Merz C.N. Kamboh M.I. Association between the severity of angiographic coronary artery disease and paraoxonase gene polymorphisms in the National Heart, Lung, and Blood Institute-sponsored Women's Ischemia Syndrome Evaluation (WISE) study.Am. J. Hum. Genet. 2003; 72: 13-22Abstract Full Text Full Text PDF PubMed Scopus (107) Google Scholar, 17Merz C.N. Kelsey S.F. Pepine C.J. Reichek N. Reis S.E. Rogers W.J. Sharaf B.L. Sopko G. The Women's Ischemia Syndrome Evaluation (WISE) study: protocol design, methodology and feasibility report.J. Am. Coll. Cardiol. 1999; 33: 1453-1461Crossref PubMed Scopus (278) Google Scholar). Briefly, female patients were recruited during their clinical examination at one of the four clinical centers (University of Alabama at Birmingham; Allegheny University of the Health Sciences at Pittsburgh; University of Florida at Gainesville; and University of Pittsburgh). Recruitment criteria included (1) ≥18 years of age; (2) presence of chest pain or other symptoms suggestive of myocardial ischemia; (3) clinically indicated coronary angiography; and (4) the ability to give informed written consent. Major exclusion criteria were: pregnancy, cardiomyopathy, contraindications to provocative diagnostic testing, New York Heart Association class IV congestive heart failure, recent myocardial infarction, significant valvular or congenital heart disease, and recent coronary angioplasty or coronary bypass surgery. As previously described (18Sharaf B.L. Pepine C.J. Kerensky R.A. Reis S.E. Reichek N. Rogers W.J. Sopko G. Kelsey S.F. Holubkov R. Olson M. for the WISE Study Group Detailed angiographic analysis of women with suspected ischemic chest pain (pilot phase data from the NHLBI-sponsored Women's Ischemia Syndrome Evaluation [WISE] Study Angiographic Core Laboratory).Am. J. Cardiol. 2001; 87: 937-941Abstract Full Text Full Text PDF PubMed Scopus (212) Google Scholar), patients were divided into three groups based on their angiographic CAD severity. Patients with <20% stenosis in all coronary arteries were labeled the normal group, having minimal stenosis (227 whites, 48 blacks); women with ≥1 stenosis of between 20% and 49% were considered to have mild stenosis (150 whites, 27 blacks); and women with ≥1 stenosis of ≥50% were considered to have severe stenosis (206 whites, 45 blacks). In addition, we also analyzed a measure of overall CAD severity using a score that was developed to account for severity of stenosis, adjusting for partial and complete col­laterals, and lesion location (18Sharaf B.L. Pepine C.J. Kerensky R.A. Reis S.E. Reichek N. Rogers W.J. Sopko G. Kelsey S.F. Holubkov R. Olson M. for the WISE Study Group Detailed angiographic analysis of women with suspected ischemic chest pain (pilot phase data from the NHLBI-sponsored Women's Ischemia Syndrome Evaluation [WISE] Study Angiographic Core Laboratory).Am. J. Cardiol. 2001; 87: 937-941Abstract Full Text Full Text PDF PubMed Scopus (212) Google Scholar). Coefficients of variation for the angiographic measurements ranged from 3.8%–6.3% (18Sharaf B.L. Pepine C.J. Kerensky R.A. Reis S.E. Reichek N. Rogers W.J. Sopko G. Kelsey S.F. Holubkov R. Olson M. for the WISE Study Group Detailed angiographic analysis of women with suspected ischemic chest pain (pilot phase data from the NHLBI-sponsored Women's Ischemia Syndrome Evaluation [WISE] Study Angiographic Core Laboratory).Am. J. Cardiol. 2001; 87: 937-941Abstract Full Text Full Text PDF PubMed Scopus (212) Google Scholar). Table 1 presents a comparison of lipid profile and other parameters among the three stenoses groups in the WISE sample. Informed consent was obtained from each subject, and the study was approved by the Institutional Review Board.TABLE 1Patient characteristics based upon the stenosis of coronary arteries in the WISE sample% of stenosis≥1 in the epicardial coronary arteryCharacteristic<20%20%–49%≥50%PWhite women(n = 185)(n = 114)(n = 166)Mean age (years) ± SEM53.9 ± 0.7658.5 ± 1.0063.1 ± 0.92<0.0001Mean BMI (kg/m ) ± SEM29.5 ± 0.5028.8 ± 0.5628.6 ± 0.460.19Former smoker N (%)53 (28.8)35 (30.7)66 (39.7)—Current smoker N (%)28 (15.2)28 (24.5)27 (16.3)0.03Alcohol use within previous 6 months N (%)28 (15.1)24 (21.0)19 (11.7)0.11Lipid-lowering drug intakeStatin N (%)20 (10.8)44 (38.6)67 (40.4)<0.0001Other N (%)2 (1.0)8 (7.0)9 (5.4)0.02Family history of CAD N (%)117 (63.9)76 (67.8)110 (67.5)0.71History of hypertension N (%)79 (42.7)65 (57.0)98 (59.7)0.003History of diabetes N (%)19 (10.3)19 (16.7)61 (36.7)<0.0001Menopause N (%)136 (73.9)99 (87.6)148 (90.2)<0.0001Mean total cholesterol (mg/dl) ± SEM193.5 ± 2.93196.2 ± 4.09188.0 ± 3.220.21Mean LDL cholesterol (mg/dl) ± SEM111.1 ± 2.51110.9 ± 3.39105.2 ± 3.000.09Mean triglycerides (mg/dl) ± SEM144.3 ± 6.87152.2 ± 9.31162.8 ± 6.430.006Mean HDL cholesterol (mg/dl) ± SEM54.8 ± 0.8853.4 ± 1.2450.6 ± 0.780.002Black women(n = 39)(n = 21)(n = 34)Mean age (years) ± SEM50 ± 2.0057.3 ± 2.0056.8 ± 1.990.01Mean BMI (kg/m ) ± SEM31.4 ± 1.0132.3 ± 1.1931.5 ± 1.060.91Former smoker N (%)12 (30.7)7 (33.3)10 (29.4)—Current smoker N (%)9 (23.1)4 (19.0)12 (35.3)0.67Alcohol use within the previous 6 months N (%)5 (12.8)4 (19.0)4 (11.8)0.73Lipid-lowering drug intakeStatin N (%)6 (15.4)8 (38.1)12 (35.3)0.08Other N (%)0 (0)1 (4.8)0 (0)0.17Family history of CAD N (%)25 (65.8)11 (57.9)20 (64.5)0.84History of hypertension N (%)27 (69.2)17 (80.9)31 (91.2)0.06History of diabetes N (%)11 (28.2)8 (38.1)17 (51.5)0.13Menopause N (%)26 (66.7)17 (80.9)27 (79.4)0.34Mean total cholesterol (mg/dl) ± SEM175.3 ± 7.36187.2 ± 6.04197.6 ± 7.960.02Mean LDL cholesterol (mg/dl) ± SEM100.6 ± 5.17104.9 ± 5.93114.9 ± 7.440.14Mean triglycerides (mg/dl) ± SEM87.8 ± 9.46106.6 ± 11.4147.9 ± 15.7<0.0001Mean HDL cholesterol (mg/dl) ± SEM54.4 ± 2.1361.0 ± 2.7551.7 ± 1.990.45BMI, body mass index; SEM, standard error of the mean. Open table in a new tab BMI, body mass index; SEM, standard error of the mean. Sera from 465 white and 93 black women in the WISE study were available to measure IgG and IgM anti-oxLDL. IgG and IgM autoantibodies against native and malondialdehyde-modified LDL (MDA-LDL) were assayed in sera by ELISA, as described elsewhere (19Chen Q. Reis S.E. Kammerer C. Craig W.Y. LaPierre S.E. Zimmer E.L. McNamara D.M. Pauly D.F. Sharaf B. Holubkov R. Genetic variation in lectin-like oxidized low-density lipoprotein receptor 1 (LOX1) gene and the risk of coronary artery disease.Circulation. 2003; 107: 3146-3151Crossref PubMed Scopus (78) Google Scholar, 20Craig W.Y. Poulin S.E. Nelson C.P. Ritchie R.F. ELISA of IgG antibody to oxidized low-density lipoprotein: effects of blocking buffer and method of data expression.Clin. Chem. 1994; 40: 882-888Crossref PubMed Scopus (52) Google Scholar), with the modification that sodium azide was omitted from the wash buffer. Data were calculated as the difference in antibody binding between MDA-LDL and native LDL and then expressed as a percentage of the value of the plasma pool. The gene fragments containing each genetic polymorphism of a selected candidate gene were amplified by PCR, followed by restriction enzyme digestion for genotyping screening. Detailed methods are described elsewhere for the SNPs APOA-5/T−1131C (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: 169-173Crossref PubMed Scopus (802) Google Scholar) APOE E2/E3/E4 polymorphism (22Kamboh M.I. Aston C.E. Hamman R.F. The relationship of APOE polymorphism and cholesterol levels in normoglycemic and diabetic subjects in a biethnic population from the San Luis Valley, Colorado.Atherosclerosis. 1995; 112: 145-159Abstract Full Text PDF PubMed Scopus (105) Google Scholar), APOH/V247L and W316S (23Kamboh M.I. Manzi S. Mehdi H. Fitzgerald S. Sanghera D.K. Kuller L.H. Atson C.E. Genetic variation in apolipoprotein H (beta2-glycoprotein I) affects the occurrence of antiphospholipid antibodies and apolipoprotein H concentrations in systemic lupus erythematosus.Lupus. 1999; 8: 742-750Crossref PubMed Scopus (47) Google Scholar), CETP/Taq1B (24Boekholdt S.M. Sacks F.M. Jukema J.W. Shepherd J. Freeman D.J. McMahon A.D. Cambien F. Nicaud V. de Grooth G.J. Talmud P.J. Cholesteryl ester transfer protein TaqIB variant, high-density lipoprotein cholesterol levels, cardiovascular risk, and efficacy of pravastatin treatment: individual patient meta-analysis of 13,677 subjects.Circulation. 2005; 111: 278-287Crossref PubMed Scopus (303) Google Scholar), HL/C−514T (25Zhang C. Lopez-Ridaura R. Rimm E.B. Rifai N. Hunter D.J. Hu F.B. Interactions between the −514C->T polymorphism of the hepatic lipase gene and lifestyle factors in relation to HDL concentrations among US diabetic men.Am. J. Clin. Nutr. 2005; 81: 1429-1435Crossref PubMed Scopus (37) Google Scholar), OLR1/3′ untranslated region (UTR) C/T (19Chen Q. Reis S.E. Kammerer C. Craig W.Y. LaPierre S.E. Zimmer E.L. McNamara D.M. Pauly D.F. Sharaf B. Holubkov R. Genetic variation in lectin-like oxidized low-density lipoprotein receptor 1 (LOX1) gene and the risk of coronary artery disease.Circulation. 2003; 107: 3146-3151Crossref PubMed Scopus (78) Google Scholar), LPL/S447X and HindIII G/T (26Liu A. Li L. Cao W. Shan S. Lu J. Guo X. Hu Y. [The association of S447X and Hind III polymorphism in the lipoprotein lipase gene with dyslipidemia of the metabolic syndrome in patients with essential hypertension].Zhonghua yixue yichuanxue zazhi. 2005; 22: 151-157Google Scholar), LRP1/A216V (27Schweer D. Jacobsen M. Ziegler A. Jakel S. Oertel W.H. Sommer N. Hemmer B. No association of three polymorphisms in the alpha-2-macroglobulin and lipoprotein related receptor genes with multiple sclerosis.J. Neuroimmunol. 2001; 118: 300-303Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar), and PON1/Q192R, L55M and PON2/S311C (16Chen Q. Reis S.E. Kammerer C.M. McNamara D.M. Holubkov R. Sharaf B.L. Sopko G. Pauly D.F. Merz C.N. Kamboh M.I. Association between the severity of angiographic coronary artery disease and paraoxonase gene polymorphisms in the National Heart, Lung, and Blood Institute-sponsored Women's Ischemia Syndrome Evaluation (WISE) study.Am. J. Hum. Genet. 2003; 72: 13-22Abstract Full Text Full Text PDF PubMed Scopus (107) Google Scholar). All continuous variables, including anti-oxLDL and lipid levels, were tested for distribution normality prior to analysis. To reduce the non-normality, in particular, total cholesterol and LDL cholesterol were transformed using a square root transformation, and triglycerides and HDL cholesterol were transformed using a natural logarithm transformation. All outliers (±4 standard deviations) were removed prior to statistical analyses, and 0–6 values were removed for each variable. All analyses were performed separately for whites and blacks. Stepwise linear regression analysis was used to identify significant covariates for IgG anti-oxLDL and IgM anti-oxLDL (assuming an overall 10% level of significance). The potential covariates considered included age, body mass index, statins, drug use history, history of using other lipid-lowering agents, smoking, alcohol use, family history of CAD, history of hypertension, history of diabetes, menopause, and serum lipid levels. Due to the small number of blacks (n = 34), the possible association between the antibody levels and genetic variations was tested in whites only. Based on power calculations, with a sample size of 465 individuals, we would have 80% power at a P level of <0.05 to detect genotypic mean differences of ≥0.07 for IgG or IgM anti-oxLDL levels. Pearson's correlation coefficients were calculated to determine significant relationships between the adjusted anti-oxLDL variables and lipid levels. All analyses were performed using R version 2.0.1 software (R Foundation for Statistical Computing, Vienna, Austria). Table 2 presents the pairwise correlations (r and P values) between the measurements of anti-oxLDL antibodies and all potential covariates available. Each covariate was examined for its association separately. In whites, the IgM antibody levels were positively correlated with total (r2= 0.01, P = 0.03) and LDL (r2= 0.017, P = 0.004) cholesterol, and cigarette smoking (r2= 0.014, P = 0.007), and negatively correlated with age (r2= 0.012, P = 0.02). White women with diabetes also had lower IgG antibody levels than nondiabetic women (P = 0.04). Among black women, only cigarette smoking was found to be significantly associated with IgG anti-oxLDL (r2= 0.044, P = 0.04). These significant covariates were included in the subsequent general linear regression analysis models to test the association between anti-oxLDL antibody levels and CAD severity (measured categorically as CAD stenosis groups and by a severity score), as well as the association between the antibody levels and genotypic variations.TABLE 2Correlation between anti-oxLDL measures and various potential covariates in the WISE sampleWhite women (n = 465)Black women (n = 93)CovariateIgGIgMIgGIgMPotential covariatesrP valuerP valuerP valuerP valueTotal cholesterol0.020.620.100.030.090.360.070.48Triglycerides0.010.81−0.030.480.130.210.060.57HDL cholesterol−0.040.430.0070.88−0.040.69−0.050.66LDL cholesterol0.030.530.130.0040.070.510.090.36Statins drug use0.070.120.00090.98−0.020.86−0.030.79Other lipid lowering agents−0.030.550.010.75−0.140.18−0.150.15Cigarette smoking0.050.260.120.0070.210.040.190.05Alcohol use0.060.200.030.460.020.87−0.0090.93Family history of CAD0.020.650.0080.860.010.92−0.100.36History of hypertension0.010.740.0050.900.060.59−0.020.81History of diabetes−0.090.04−0.060.17−0.140.18−0.150.15Body mass index0.0040.930.020.67−0.130.22−0.100.35Age0.0090.85−0.110.02−0.040.70−0.080.41Menopause−0.0050.91−0.040.35−0.090.40−0.150.14 Open table in a new tab The relationship between the anti-oxLDL antibody levels and the severity of stenosis is presented in Table 3. Because the IgM anti-oxLDL antibody levels were similar in the 20%–49% and >50% stenosis groups, for the purpose of statistical analysis, we combined these two groups to compare with the <20% stenosis group. After adjusting for the effects of age, smoking, and total and LDL cholesterol levels, IgM anti-oxLDL antibody levels remained slightly but significantly higher in the <20% stenosis group than in the >20% stenosis groups (0.69 ± 0.02 vs. 0.64 ± 0.02, respectively; P = 0.03). After adjusting for history of diabetes, no significant association was found between IgG anti-oxLDL levels and stenosis severity. Finally, no significant association was observed between IgM or IgG anti-oxLDL level and severity of stenosis in black subjects. In contrast, we found no significant relationship between the angiographic severity score and IgM or IgG anti-oxLDL antibody levels (P = 0.41 and 0.88, respectively).TABLE 3Mean anti-oxLDL antibody levels among coronary stenosis groupsStenosis of ≥1 in epicardial coronary arteryAntibody<20%20–49%≥50%PWhite women(n = 185)(n = 114)(n = 166)IgG anti-oxLDL0.65 ± 0.010.64 ± 0.020.65 ± 0.020.84IgM anti-oxLDL0.69 ± 0.020.64 ± 0.020.64 ± 0.020.02Black women(n = 39)(n = 21)(n = 34)IgG anti-oxLDL0.69 ± 0.030.65 ± 0.030.75 ± 0.040.15IgM anti-oxLDL0.65 ± 0.030.61 ± 0.050.70 ± 0.040.41Data show adjusted means ± standard deviations (SD) of anti-oxLDL antibody levels (%M-L) among coronary stenosis groups, where %M-L is the difference in antibody binding between MDA-LDL and native LDL expressed as a percentage of the value of the plasma pool.ANOVA P values adjusting for total and LDL cholesterol, history of smoking, and age. Open table in a new tab Data show adjusted means ± standard deviations (SD) of anti-oxLDL antibody levels (%M-L) among coronary stenosis groups, where %M-L is the difference in antibody binding between MDA-LDL and native LDL expressed as a percentage of the value of the plasma pool. ANOVA P values adjusting for total and LDL cholesterol, history of smoking, and age. The results of association analyses between adjusted anti-oxLDL antibody levels and various candidate gene polymorphisms are summarized in Table 4. A significant association (P = 0.02) was observed for IgM anti-oxLDL levels and OLR1 genotypes. The OLR1/3′UTR single-nucleotide polymorphism (SNP) showed gene dosage effects on the IgM antibody levels, with the lowest value in the TT genotype (mean = 0.64 ± 0.02), the highest value in the CC genotype (mean = 0.65 ± 0.02), and an intermediate value in the TC genotype (mean = 0.71 ± 0.02). As the XX genotype of the LPL/S447X SNP was uncommon among our subjects (n = 5), we combined XX and SX genotypes to compare with the SS wild-type genotype. The LPL/S447X SNP showed significant association with IgG anti-oxLDL (P = 0.02) and borderline association with IgM anti-oxLDL (P = 0.07) (Table 4). While 447X allele carriers had higher IgM antibody levels than SS homozygotes (0.72 ± 0.03 and 0.65 ± 0.01, respectively), the reverse trend was observed for the IgG antibody level (0.71 ± 0.02 vs. 0.93 ± 0.01). Association analyses were also carried out to determine whether these polymorphisms were significantly correlated with stenosis severity; however, no significant results were discovered (data not shown).TABLE 4P values for associations between adjusted anti-oxLDL antibody levels and genetic polymorphisms in white womenGenetic polymorphismIgG % M-LIgM % M-LAPOH/V247L0.960.12PON2/S311C0.210.66PON1/Q192R0.220.44PON1/L55M0.230.17APOE/E2/E3/E40.850.14APOH/W316S0.310.41OLR1/3′UTR C/T0.580.02LRP1/A216V0.620.85LPL/S447X0.020.07LPL/Hind III G/T0.580.69CETP/Taq1B0.340.14HL/C−514T0.370.62APOA5/T−1131C0.300.87%M-L is the difference in antibody binding between MDA-LDL and native LDL expressed as a percentage of the value of the plasma pool. Open table in a new tab %M-L is the difference in antibody binding between MDA-LDL and native LDL expressed as a percentage of the value of the plasma pool. It has been suggested that progression of atherosclerosis is modified by an immune reaction trigged by different immunogens (3Witztum J.L. The oxidation hypothesis of atherosclerosis.Lancet. 1994; 344: 793-795Abstract PubMed Scopus (1261) Google Scholar, 28Wick G. Schett G. Amberger A. Kleindienst R. Xu Q. Is atherosclerosis an immunologically mediated disease?.Immunol. Today. 1995; 16: 27-33Abstract Full Text PDF PubMed Scopus (381) Google Scholar, 29Libby P. Hansson G.K. Involvement of the immune system in human atherogenesis: current knowledge and unanswered questions.Lab. Invest. 1991; 64: 5-15PubMed Google Scholar, 30George J. Harats D. Gilburd B. Shoenfeld Y. Emerging cross-regulatory roles of immunity and autoimmunity in atherosclerosis.Immunol. Res. 1996; 15: 315-322Crossref PubMed Scopus (29) Google Scholar, 31Steinberg D. Parthasarathy S. Carew T.E. Khoo J.C. Witztum J.L. Beyond cholesterol. Modifications of low-density lipoprotein that increase its atherogenicity.N. Engl. J. Med. 1989; 320: 915-924Crossref PubMed Google Scholar, 32Xu Q. Wick G. The role of heat shock proteins in protection and pathophysiology of the arterial wall.Mol. Med. Today. 1996; 2: 372-379Abstract Full Text PDF PubMed Scopus (142) Google Scholar), with oxLDL as the major immunogen for such reaction (3Witztum J.L. The oxidation hypothesis of atherosclerosis.Lancet. 1994; 344: 793-795Abstract PubMed Scopus (1261) Google Scholar, 31Steinberg D. Parthasarathy S. Carew T.E. Khoo J.C. Witztum J.L. Beyond cholesterol. Modifications of low-density lipoprotein that increase its atherogenicity.N. Engl. J. Med. 1989; 320: 915-924Crossref PubMed Google Scholar). In animal studies, immunization with modified LDL results in an increased titer of antibodies against MDA-LDL and suppression of atherosclerosis (33Palinski W. Miller E. Witztum J.L. Immunization of low density lipoprotein (LDL) receptor-deficient" @default.
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