Distribution and effect of apo A-IV genotype on plasma lipid and apolipoprotein levels in a Chinese population

OBJECTIVES: Hypertriglyceridaemia has been recognized as an independent risk factor for the development of coronary heart disease. Apolipoprotein A-IV (apo A-IV) plays an important role in the metabolism of TG-rich lipoproteins and HDL. However, the role of the polymorphism of the apo A-IV gene in hyperlipidaemia remains to be fully determined. The impact of the genetic variant in the apolipoprotein A-IV gene on lipid risk factor profiles for coronary heart disease was examined in Chinese patients with type-IV hyperlipoproteinaemia (HTG) and in healthy control individuals. METHODS: We genotyped five polymorphisms in the apo A-IV gene (codon 9, codon 347, codon 360, 3'end VNTR and Msp I sites) by direct sequencing or RFLP analysis in a Chinese population. RESULTS: The genotype frequencies in our results were significantly different from those reported in Caucasians. The polymorphic sites of codon 347 and codon 360, that have been widely studied in Western populations, were not observed in our population. The frequency of the G allele at codon 9 in HTG subjects was higher than that in healthy controls (P < 0.05). Serum apolipoprotein A-I (apo A-I), triglyceride (TG) and low-density lipoprotein cholesterol (LDLC) levels were affected by genotypes of codon 9, Msp I and VNTR polymorphisms, respectively, with some sex-specific effects in the control or HTG group. CONCLUSION: These results suggest that codon 9, Msp I and VNTR polymorphisms in the apo A-IV gene are associated with type-IV hyperlipoproteinaemia in a Chinese population.     

Genetic polymorphism of heparan sulfate proteoglycan (perlecan, HSPG2), lipid profiles and coronary artery disease in the Australian population

Perlecan is one of the three major classes of heparan sulfate proteoglycans (HSPGs) within the cardiovascular system; it interacts with lipid metabolism by binding to lipoprotein lipase (LpL) and apolipoprotein B (apo B) and may be related to vascular disease. We explored interactions between an HSPG2 polymorphism (BamHI marker), and apo B and coronary artery disease (CAD) in patients undergoing coronary angiography. The frequencies of the HSPG2 BamHI +/+, +/-, and -/- genotypes were 4.7, 31.7 and 63.6%, respectively, with a '+' allele frequency of 20.6%. The genotype distribution was in Hardy-Weinberg equilibrium (chi(2)=0.669, P0.05). The +/+homozygotes had the lowest apo B levels (0.74+/-0.06 g/l, n=36) compared to +/- (0.89+/-0.03 g/l, n=241) and -/- (0.93+/-0.02 g/l, n=480) genotypes. Although plasma apo B concentration was the strongest lipid risk factor for significant CAD, the HSPG2 genotypes were not independently associated with the presence of CAD (P=0.640 in males; P=0.224 in females), with significant CAD (P=0.764; P=0.110) or with the number of significantly stenosed coronary arteries (P=0.945; P=0. 335). In Australian Caucasians undergoing coronary angiography the HSPG2 BamHI polymorphism is associated with lower circulating apo B but not with the occurrence or severity of CAD. This may be due to HSPG2-mediated alterations in the HSPG2-apo B-LpL system and requires further exploration.     

Role of genetic factors (CETP gene Taq I B polymorphism and Apo A-I gene Msp I polymorphism) in serum HDL-C levels in women

BACKGROUND AND AIM: Plasma high density lipoprotein cholesterol (HDL-C) levels are determined by a variety of environmental and genetic factors. The cholesteryl ester transfer protein (CETP) and apolipoprotein A-I (Apo A-I) are considered to be associated with HDL-C metabolism. The aim of this study was to investigate the relationship between the CETP gene Taq I B and Apo A-I gene Msp I polymorphisms and plasma lipid levels taking into account environmental factors, and to determine the combined effects of these polymorphisms on HDL-C levels in Japanese women. METHODS AND RESULTS: The study involved 270 Japanese women aged 30-69 years. We found a significant association between the CETP genotypes and HDL-C levels (p=0.0020), which were also associated with the Apo A-I gene (M1) polymorphism. Stepwise multiple regression analysis revealed that both the CETP Taq I B and Apo A-I gene (M1) genotypes were independent predictive variables. The strength of the association between the Apo A-I (M1) subgroup and HDL-C levels was reduced in the subjects with a high Body Mass Index (BMI). The combination of genotypes provided more detailed information about HDL-C levels. The "high risk" combination of the M1+ (M1+/+) and B1B1 genotypes was associated with the lowest HDL-C level (1.52+/-0.36 mmol/L), and the "low risk" combination of the M1- (M1+/- or M1-/-) and B2B2 genotypes was associated with the highest HDL-C levels (2.06+/-0.34 mmol/L). CONCLUSIONS: Our results suggest that the combination of the two polymorphisms influences HDL-C levels in women, and that the association between genetic factors and HDL-C levels is altered by environmental factors. They may also help to detect individuals with low HDL-C levels at high risk for coronary artery syndrome.     

Genetics of apolipoprotein B and apolipoprotein AI and premature coronary artery disease

Increased low-density lipoprotein (LDL) and decreased high-density lipoprotein cholesterol (HDL-C) predict premature coronary artery disease, as do elevated levels of apolipoprotein B or reduced levels of apolipoprotein AI. Probands were studied of families with common genetic forms of dyslipidaemia to determine if apo B or apo AI define genetic groups and if apo B or apo AI levels relate to premature coronary artery disease risk. Elevated apo B was characteristic of familial hypercholesterolaemia, familial combined hyperlipidaemia (FCHL), and was seen in individuals with elevated Lp(a). Normal apo B levels were seen in familial hypertriglyceridaemia and in 'coronary artery disease with low-HDL cholesterol'. Apo AI levels tended to be low in FCHL and were decreased in 'coronary disease with low-HDL cholesterol'. In familial hypertriglyceraemia, even though HDL-C levels were low, normal apo AI and apo B levels were seen in the absence of premature coronary artery disease. Therefore, in genetic dyslipidaemias elevated apo B levels and reduced apo AI levels (or increased apo B/AI ratio) differ and predict premature coronary artery disease.     

DNA polymorphisms of the gene for apolipoprotein B in patients with peripheral arterial disease

We have determined the frequency of DNA polymorphisms of the gene for human apolipoprotein B, detected with XbaI and EcoRI, in 205 patients with documented peripheral arterial disease. Of the patients, 78 have no evidence of disease in the coronary and carotid arteries, 64 have coexisting coronary artery disease but no evidence of carotid artery disease, 26 patients have coexisting carotid artery disease but no evidence of coronary artery disease, and 37 have coexisting coronary and carotid artery disease. Levels of triglycerides, cholesterol and apolipoprotein B were measured for each patient, and RFLP frequency was determined in all the patients. Lipid, lipoprotein and apolipoprotein levels were not significantly different between the different patient groups. Compared with a sample from the clinically well London population, the frequency of the R2 allele of the polymorphism detected with EcoRI, and the frequency of the X1 allele of the XbaI polymorphism was significantly higher in the patient group. The frequency of these alleles was not significantly different in the different patient groups. In patients with only peripheral arterial disease, individuals with the XbaI genotype X1X1 have the lowest and those with the genotype X2X2 have the highest mean levels of serum cholesterol. However, in all other patient groups this trend was reversed (X1X1 highest and X2X2 lowest). Our observations suggest that variation at the apo B locus is one of the factors involved in predisposing an individual to develop arterial disease but does not determine where in the arterial system the disease develops.     

Angiotensin-converting enzyme and apolipoprotein B polymorphisms in coronary artery disease

The association between angiotensin-converting enzyme (ACE) as well as apolipoprotein B polymorphisms and dyslipidemia and coronary artery disease (CAD) is controversial. We assessed the distribution of ACE insertion and/or deletion, apolipoprotein B signal peptide insertion and/or deletion, and apolipoprotein B XbaI restriction fragment length polymorphisms in 388 nondiabetic patients. We studied 112 patients with angiographically defined asymptomatic CAD or with stable functional classes I and II angina and 139 patients with acute myocardial infarction who were age matched to 137 control subjects. Univariate analysis showed higher prevalence of Xba50% reduction of lumen diameter. Overall, multivariable regression disclosed traditional risk factors and elevated levels of apolipoprotein B for men and reduced levels of apolipoprotein AI for women as independent variables for CAD. After adjustment for the most important subset of risk factors (age, hypertension, hypercholesterolemia, and smoking), apolipoprotein B XbaI polymorphism was disclosed as an independent variable for CAD. Apolipoprotein B XbaI was also selected as an independent variable for acute myocardial infarction after adjusting for age, hypertension, hypercholesterolemia, and smoking. Thus, in addition to traditional coronary risk factors, apolipoproteins B and AI, and apolipoprotein B XbaI polymorphism could be considered predictors of CAD.     

载脂蛋白B基因多态性与心肌梗死的关系

目的研究载脂蛋白B(apoB)基因多态性与心肌梗死发病的关系.方法用聚合酶链反应(PCR)法对65例心肌梗死(MI)患者和60例正常人apoB基因XbaI和MspI两个酶切位点上限制性片段长度多态性(RFLPs)进行检测.结果MI组Xbal酶切位点上X+等位基因频率显著高于对照组,分别为0.092和0.025(P<0.05).MspI酶切点位上M-等位基因相对频率在MI组和对照组之间无明显差异.结论XbaIRFLPs可以作为MI的独立预测指标.     

DNA polymorphisms of the apolipoprotein B gene in patients with premature coronary artery disease

Elevated plasma levels of low density cholesterol and their major apolipoprotein (apo B) are associated with an increased risk of coronary artery disease (CAD). We have examined allele frequencies of restriction fragment length polymorphisms (RFLP) of the apo B gene in 111 male Caucasians with premature CAD (mean age 49 +/- 7 years) and in 122 elderly Caucasian males (mean age, 73 +/- 5 years), free of clinical cardiovascular disease. The rare allele (R1) of the EcoR1 RFLP in exon 29, resulting in an amino acid change (Glu----Lys4154) was seen more frequently in CAD than in controls (0.270 vs 0.207, P less than 0.05). The R1 RFLP and the MspI insertion polymorphisms (MI) within the 3' hypervariable region (HVR) were observed together in 87% and are likely in linkage disequilibrium. The MI RFLP were slightly more frequent in CAD than control (0.239 vs. 0.211, P = 0.08). A second MspI RFLP in exon 26 results in an amino acid change (Arg----Glu3611); the rare allele M2 was seen more frequently in patients than in controls (0.150 vs. 0.057, P less than 0.005). No significant differences in allele frequencies were observed for the Xba1 RFLP in exon 26 (0.500 vs. 0.529, P = ns) or for the PvuII RFLP near the 5' end (P2) (0.105 vs. 0.088, P = ns). No statistically significant differences in lipid, lipoprotein cholesterol or apolipoproteins A-I and B were observed in patients or in controls. Two of the RFLPs examined (R1 and M2) result in changes in amino acid sequence and their allele frequencies are increased in CAD cases when compared with controls. Genetic variability within the apo B gene may thus contribute to cardiovascular risk. The physiological effects of individual mutations within apo B remain to be determined. It is unlikely, however that the single site polymorphisms examined in this study, will impart further information about CAD risk than conventional lipid parameters.     

The Effect of Alcohol Withdrawal on Serum Concentrations of Lp(a), Apolipoproteins A-1 and B, and Lipids

Moderate alcohol consumption is associated with a decreased risk of coronary artery disease. The mechanism of the putative protective effect of alcohol intake, however, remains elusive. Recent studies suggest that a ratio of apolipoprotein A-I/apolipoprotein B and Lp(a) are better indicators of the risk of atherosclerosis than total cholesterol and high density lipoprotein cholesterol. To assess the effect of alcohol on these analytes, we determined the concentration of Lp(a), apolipoprotein A-I, apolipoprotein B, total cholesterol, and high-density lipoprotein cholesterol, and calculated low-density lipoprotein cholesterol in serum of 12 patients meeting DSM-III-R criteria for alcohol dependence at the time of admission for treatment of alcohol withdrawal (before). The analyses were repeated after 4 weeks of supervised abstinence on a locked research unit (after). With abstinence, there was a significant increase in the concentration of Lp(a), the atherogenic index and the ratio of low-density to high-density lipoprotein cholesterol but a significant decrease in total cholesterol, high-density lipoprotein cholesterol, apolipoprotein A-I, and the apolipoprotein A-I/B ratio. Apolipoprotein B and low-density lipoprotein cholesterol showed no significant changes before and after alcohol abstinence. Thus, decreased Lp(a) and increased high-density lipoprotein cholesterol and apolipoprotein A-I may be factors mediating the putative protective effect of alcohol in coronary artery disease.     

Removal of low-density lipoproteins in patients by extracorporeal immunoadsorption

A new technique called LDL-pheresis was used in patients to lower low-density lipoprotein cholesterol levels. This procedure combines continuous extracorporeal plasma separation with immunoadsorption of low-density lipoprotein on columns containing monospecific antibody to human apolipoprotein B. Six patients underwent a total of 164 procedures without significant side effects or nonspecific protein depletion. Acutely, LDL-pheresis lowered plasma cholesterol levels by removing up to 82 percent of the circulating low-density lipoprotein. Weekly LDL-pheresis combined with a portacaval shunt in a patient with homozygous familial hypercholesterolemia resulted in normalization of plasma cholesterol levels and rapid regression of skin xanthomata. Three of four patients with atherosclerotic coronary artery disease have noted improvement in their angina. LDL-pheresis appears to be a promising new technique capable of safely and efficiently lowering plasma low-density lipoprotein cholesterol levels.     

稳定型冠心病患者血清低密度脂蛋白胆固醇和载脂蛋白B浓度与SYNTAX评分的关系

目的探讨稳定型冠状动脉粥样硬化性心脏病(stable coronary artery disease,SCAD)患者血清低密度脂蛋白胆固醇(low-density lipoprotein cholesterol,LDL-C)和载脂蛋白B浓度与SYNTAX评分的关系。方法回顾性选择2016年1月至2017年12月在宝鸡市中心医院接受冠状动脉造影检查确诊的SCAD患者150例作为研究对象,根据SYNTAX评分结果将患者分为0~22分组(低分组,n=80)、23~32分组(中分组,n=40)和33分以上组(高分组,n=30)。SYNTAX评分与不同临床特征间的相关性采用Spearman相关性分析和多元线性回归分析。结果3组患者血小板分布宽度(platelet distribution width,PDW)、红细胞分布宽度(red cell distribution width,RDW)、纤维蛋白原、总胆固醇、高密度脂蛋白胆固醇(high density lipoprotein-cholesterol,HDL-C)、LDL-C、脂蛋白a、载脂蛋白A1、载脂蛋白B、SYNTAX评分比较,差异有统计学意义(P<0.05)。Spearman相关性分析结果显示,SYNTAX评分与HDL-C、载脂蛋白A1呈负相关(P<0.05),与纤维蛋白原、总胆固醇、LDL-C、PDW、RDW、脂蛋白a、载脂蛋白B呈正相关(P<0.05)。多元线性回归分析结果显示,HDL-C、LDL-C、纤维蛋白原、载脂蛋白B均是影响冠状动脉病变的危险因素(P<0.05)。结论随着血清LDL-C、载脂蛋白B浓度的升高,SCAD患者SYNTAX评分升高,冠状动脉病变严重程度加重。血清LDL-C、载脂蛋白B浓度可作为判断SCAD患者冠状动脉病变严重程度的参考指标。     

Genetic variation in the cholesteryl ester transfer protein and apolipoprotein A-I genes and its relation to coronary heart disease in a Sri Lankan population

The influence of variation in the genes for cholesteryl ester transfer protein and apolipoprotein A-I was investigated in 95 patients with coronary heart disease and 95 matched control subjects of South East Asian extraction. Restriction fragment length polymorphisms (RFLPs) linked to the cholesteryl ester transfer protein gene TaqIA and TaqIB, and to the apolipoprotein A-I gene SstI, were examined to investigate the extent of genetic variation at these loci. None of the alleles defined by these RFLPs were associated with increased coronary risk. Analysis of the data by division of high density lipoprotein-cholesterol levels into tertiles showed a trend of a higher frequency of B1 allele (presence of the TaqIB site) with reduced high density lipoprotein levels. The B1 allele was more frequent in control subjects, with low high density lipoprotein levels (P less than 0.02), but not in coronary heart disease patients. The differences became significant for both groups (P less than 0.05) when the data of non-smokers were analysed separately.     

XbaⅠpolymorphisms of apolipoprotein B gene:Another risk factor of gallstone formation after radical gastrectomy

AIM:To prospectively investigate the association between the XbaⅠpolymorphisms of apolipoprotein B (APOB)gene and gallstone formation following gastrectomy.METHODS:The study was conducted between January 2005 and December 2006.A total of 186 gastric cancer patients who had undergone radical gastrectomy were grouped according to XbaⅠpolymorphisms of APOB gene(X+X-group,n=24 and X-X-group,n =162)and compared.The XbaⅠpolymorphisms of APOB gene were detected by polymerase chain reaction-restriction fragment len...     

Insight into a bad omen for white men: coronary artery disease--the Bogalusa Heart Study

Clinical experience of diagnostic and interventional procedures, including cardiac surgery, indicates a greater prevalence of coronary heart disease in white men than in other race-gender groups. Studies of children and young adults in the Bogalusa Heart Study have provided evidence that might account for this race-gender contrast. A variety of anthropometric and metabolic parameters influencing serum lipid and lipoprotein levels places white boys and young white men selectively at high risk for the development of atherosclerotic coronary artery disease. Obesity and greater central body fat, subtle aberrations in carbohydrate-lipid metabolic relations and variability in sex hormone profiles appear to underlie a trend to adverse lipoprotein changes in white men. A lower high-density lipoprotein cholesterol level and apolipoprotein A-l at puberty and a dramatic increase of low-density lipoprotein cholesterol are seen in young white men; such adverse changes identify them to be at greater risk. It is noteworthy that children whose fathers had myocardial infarction tend to be white. These children also have relatively high ratios of apolipoprotein B/apolipoprotein A-l and apolipoprotein B/low-density lipoprotein cholesterol. Studies of risk factors in children emphasize their importance in the early natural history of coronary artery disease. These findings show the need for beginning prevention of adult heart disease in childhood.     

Small, dense lipoprotein particles and reduced paraoxonase-1 in patients with the metabolic syndrome

The presence of the metabolic syndrome (World Health Organization definition) and its association with lipoprotein abnormalities suggestive of greater susceptibility to oxidative stress have been analyzed in patients with angiographically defined coronary artery disease. The odds ratio for the presence of the metabolic syndrome was significantly higher in coronary artery disease-positive patients (P < 0.001). The metabolic syndrome was also associated with more severe coronary disease (P < 0.01). Patients with the metabolic syndrome had significantly decreased low-density lipoprotein-cholesterol/apolipoprotein B and high-density lipoprotein-cholesterol/apolipoprotein AI ratios, indicative of the presence of small, dense lipoprotein particles. The syndrome was also associated with reduced concentrations and activities of the antioxidant enzyme, paraoxonase-1. The metabolic syndrome is characterized by smaller, denser lipoprotein particles that increase their susceptibility to oxidative modifications and diminished serum paraoxonase-1, which is a major determinant of the antioxidant capacity of high-density lipoproteins. These may be contributory factors to the increased presence and severity of coronary disease in such patients.     

Apolipoproteins A-I and B as predictors of angiographically defined coronary artery disease

Apolipoprotein A-I and B concentrations were measured in 502 patients undergoing diagnostic cardiac catheterization to assess the predictive power of apolipoproteins B and A-I to discriminate between patients with coronary artery disease and those with normal coronary arteries as defined by coronary arteriography. The strength of the associations was compared with that of the associations between traditional risk factors (eg, smoking status, cholesterol levels) and coronary artery disease. The study population consisted of 154 women (mean age, 62.9 years) and 348 men (mean age, 59.6 years). The apolipoprotein A-I concentration averaged (+/- SD) 124 +/- 25 mg/dL and the apolipoprotein B concentration, 98 +/- 24 mg/dL. In all cases, the apolipoprotein measures showed a larger univariate difference between the "normal" (no coronary artery disease) group (66 patients) and the group with coronary artery disease (436 patients) than did the corresponding standard lipoprotein measures. The variable with the strongest association with coronary artery disease was the ratio of apolipoprotein A-I to apolipoprotein B, followed by apolipoprotein B level. These findings were confirmed using logistic regression, adjusting for other coronary artery disease risk factors. Fasting status did not affect apolipoprotein A-I or B concentrations. We conclude that the use of apolipoprotein A-I and B concentrations gives additional information to that supplied by lipoprotein measures to help predict the presence of coronary artery disease. Since traditional lipid measures may be changed by a meal, apolipoproteins A-I and B might be more useful measures when the fasting status of a patient is in question.     

Gene Polymorphisms for PAI-1 Are Associated with the Angiographic Extent of Coronary Artery Disease

Localized regulation of fibrinolytic protein gene expression is associated with the histologic extent of atherosclerosis. This regulation may be dependent on the presence of certain fibrinolytic protein gene polymorphisms. The relationship between the plasminogen activator inhibitor (PAI)-1 HindIII and the tissue plasminogen activator (t-PA) EcoR1 gene polymorphisms and the extent of coronary artery disease (CAD) were investigated in 49 Caucasian patients with symptomatic CAD. There was a strong association between PAI-1, but not t-PA, gene polymorphisms and the extent of CAD detected by coronary angiography. Patients homozygous for the presence or absence of the PAI-1 HindIII (1/1, 2/2 PAI-1) gene polymorphisms had a significantly greater extent of CAD (number of diseased vessels) than patients with the respective heterozygous forms (vs. 1/2 PAI-1, P = 0.05). Stepwise ordinal multiple regression analysis of classic CAD risk factors and fibrinolytic protein genotypes indicated that only the PAI-1 genotypes were predictive of the extent of angiographic CAD (P = 0.019). Analysis of variance between classic risk factors and fibrinolytic protein genotypes identified an association between t-PA genotypes and a history of prior infarction or stroke. Fibrinolytic gene polymorphisms for PAI-1 are associated with the extent of CAD in symptomatic patients and with certain risk factors for coronary atherosclerosis.     

Relationship of Xba1 and EcoR1 polymorphisms of apolipoprotein-B gene to dyslipidemia and obesity in Asian Indians in North India.

BACKGROUND: Genetic investigation of dyslipidemia and obesity prevalent in the Indian population form the basis of this study. METHODS AND RESULTS: The frequency of restriction fragment length polymorphisms (Xba1 and EcoR1) of the apolipoprotein-B gene was investigated in a case-control study of 30 hyperlipidemic and 40 normolipidemic subjects. By univariate analysis, old age, higher body mass index, waist-hip ratio and sum of four skinfolds were found to be significantly associated with hyperlipidemia. The frequencies of X- and E+ alleles of the apolipoprotein-B gene were significantly higher in North Indians in the state of New Delhi (0.83 and 0.91, respectively) as compared to the observations made in Caucasians in previous studies, but was similar to the frequency reported in Indians settled in Singapore and the UK. There were no significant differences in the allele or genotype frequencies of either Xba1 or EcoR1 polymorphisms between the hyperlipidemic and normolipidemic groups. On multiple logistic regression analysis considering body mass index, waist-hip ratio, percentage body fat and genotypes as independent variables, no association was observed between the apolipoprotein-B genotypes and serum lipid components. Further, there were no associations between apolipoprotein-B polymorphisms and generalized obesity (as assessed by body mass index, sum of four skinfolds, and percentage total body fat) and abdominal obesity (as measured by waist circumference and waist-hip ratio). CONCLUSIONS: We conclude that apolipoprotein-B (Xba1 and EcoR1) polymorphisms do not appear to influence serum lipid levels and parameters of generalized andregional obesity in the study sample.     

Relationship of angiographically defined coronary artery disease to serum lipoproteins and apolipoproteins in young survivors of myocardial infarction

The relationship of serum lipoprotein and apolipoprotein concentrations to angiographically determined coronary artery disease was investigated in 105 consecutive male survivors of myocardial infarction under the age of 45. Concentrations and composition of lipoproteins, lipid indexes, and nonlipid risk factors (tobacco consumption, hypertension, reduced glucose tolerance, and obesity) were related to a recently developed scoring system for semiquantitative estimation of diffuse coronary atheromatosis, as well as to the number and severity of significant coronary artery stenoses. The concentrations of cholesterol in very low-density lipoprotein (VLDL), low-density lipoprotein (LDL), and high-density lipoprotein (HDL), in combination with serum triglyceride or VLDL triglyceride level, comprised the best set of independent discriminatory lipid variables between patients and control subjects. In the patients, LDL cholesterol and apolipoprotein B levels showed strong relationships to the extent and severity of coronary atheromatosis but not to the number and severity of distinct coronary stenoses. HDL2 cholesterol concentration correlated inversely with the coronary atheromatosis score, whereas other variables reflecting HDL concentration and composition or VLDL lipids were not independently related to any of the coronary scores. The LDL triglyceride level, an index of intermediate-density lipoprotein (IDL) accumulation, was significantly correlated to the coronary atheromatosis score in univariate analysis. Nonlipid risk factors were correlated neither to coronary atheromatosis nor to severity of stenoses. Stepwise multiple regression analyses of data adjusted for age, cumulative tobacco consumption, and weight indicated that 18% of the variation in the coronary atheromatosis score could be accounted for by levels of apolipoprotein B. Addition of other lipoprotein variables or the nonlipid variables hypertension and glucose tolerance did not significantly increase the value of R2. When ratios of lipoprotein lipids and apolipoproteins were included in the regression model, the highest multiple correlation coefficient was obtained with the LDL/HDL cholesterol ratio alone (R2 = .22). The present data demonstrate the importance of elevated LDL cholesterol and apolipoprotein B concentrations for the development of coronary atheromatosis in young male survivors of myocardial infarction. The lack of correlations between the levels of lipoprotein lipids and serum apolipoproteins and the severity of coronary stenoses suggests that mechanisms other than disturbances of lipoprotein metabolism may be involved in the progression of more advanced coronary lesions.     

Increased atherosclerosis in mice lacking apolipoprotein A-I attributable to both impaired reverse cholesterol transport and increased inflammation

To test the hypothesis that apolipoprotein A-I (apoA-I) functions specifically to inhibit atherosclerosis independent of the level of high-density lipoprotein cholesterol (HDL-C) by promoting both reverse cholesterol transport and HDL antiinflammatory function in vivo, we established a murine atherosclerosis model of apoA-I deficiency in which the level of HDL-C is well maintained. ApoA-I-/- mice were crossed with atherosclerosis susceptible low-density lipoprotein receptor-/-/apobec-/- (LA) mice to generate LA mice with apoA-I+/+, apoA-I+/-, and apoA-I-/- genotypes. There were no major differences in the amounts of non-HDL-C and HDL-C in the plasma between different apoA-I genotypes. A significant inverse relationship was observed, however, between apoA-I gene dose and atherosclerosis in both female and male mice. Compared with LA-apoA-I+/+ mice, serum from LA-apoA-I-/- mice had a significantly reduced capacity to function as an acceptor of ABCA1- and SR-BI-mediated cellular cholesterol efflux, and also had markedly reduced lecithin cholesterol acyltransferase activity. In addition, LA-apoA-I-/- mice had significantly reduced macrophage-derived cholesterol esterification and reverse cholesterol transport in vivo. There was significantly reduced plasma paraoxonase (PON-1) activity, impaired HDL vascular antiinflammatory function, and increased basal levels of monocyte chemotactic protein-1 in the plasma of LA-apoA-I-/- mice compared with LA-apoA-I+/+ mice. In LA-apoA-I-/- mice, there was also greater induction of some, but not all, inflammatory cytokines and chemokines in response to intraperitoneal injection of lipopolysaccharide than in LA-apoA-I+/+ mice. We conclude that apoA-I inhibits atherosclerosis by promoting both macrophage reverse cholesterol transport and HDL antiinflammatory function, and that these anti-atherogenic functions of apoA-I are largely independent of the plasma level of HDL-C in this mouse model.