Altered particle size distribution of apolipoprotein A-I-containing lipoproteins in subjects with coronary artery disease

Plasma high density lipoproteins (HDL) can be separated into two subpopulations of apolipoprotein A-I-containing particles: those that also contain apoA-II [Lp(AI w AII)] and those that do not [Lp(AI w/o AII)]. These particles were isolated by immunoaffinity chromatography from 17 men (9 normolipidemic (NL), 8 hyperlipidemic (HL) with symptomatic coronary artery disease (CAD), from 17 NL men without any symptoms of CAD (healthy controls), and from 10 NL men with entirely normal coronary arteriograms (CAD-free controls). The distributions of particle size in these two subpopulations were determined by gradient gel electrophoresis and densitometric scanning. Approximately half of the Lp(AI w AII) particles in all subjects were distributed in the 8.2-9.2 nm interval. For patients with CAD, a greater fraction of the particles were small, in the 7.0-8.2 nm interval [33% in CAD vs. 26% in CAD-free controls (P less than 0.01) and 19% in healthy controls (P less than 0.0001)], and a smaller fraction of the particles were in the 9.2-11.2 nm interval (14% in CAD vs. 24% in CAD-free control (P less than 0.002) and healthy control groups (P less than 0.001). The Lp(AI w/o AII) of both control groups were primarily composed of two discrete subpopulations in the 8.2-9.2 nm and the 9.2-11.2 nm intervals. In CAD patients there were fewer particles in the 9.2-11.2 nm size interval (23% in CAD vs. 33% in CAD-free controls (P less than 0.005) and 36% in healthy controls (P less than 0.0001), and more particles in the smallest 7.0-8.2 nm size interval (32% in CAD vs. 23% in CAD-free controls (P less than 0.01) and 18% in healthy controls (P less than 0.001]. Thus, the spectrum of HDL particle sizes in patients with CAD tends to be shifted toward the smaller particle when compared with the two control groups. This was observed in both NL and HL patients with HDL cholesterol (CH) values in the normal range. As a group, CAD patients had lower HDL (42 +/- 7 mg/dl) and HDL2 (6 +/- 4 mg/dl) CH than healthy (HDL: 49 +/- 7, HDL2: 12 +/- 6 mg/dl) and CAD-free (HDL: 51 +/- 9, HDL2: 12 +/- 6 mg/dl) controls. When controls and patients were compared for their frequencies of abnormal HDL CH levels and particle sizes, abnormalities in HDL and HDL2 CH levels were not significantly more frequent (twofold) among CAD patients than among controls.(ABSTRACT TRUNCATED AT 400 WORDS)     

Relationship between CMV infection and coronary heart disease.

Conflicting evidence implicating CMV infection in coronary heart disease (CHD) exists. In this work using serological methods (IgM-CMV by Western blot and IgG-CMV by ELISA) correlation between CMV infection and CHD was not found. On the other hand presence of CMV DNA in atherosclerotic plaques with absence in unchanged vessel indicates possible role of CMV infection in progression of this process.     

Effects of the apolipoprotein(a) size polymorphism on the lipoprotein(a) concentration in 7 ethnic groups

Summary Apolipoprotein(a) [apo(a)] exhibits a genetic size polymorphism explaining about 40% of the variability in lipoprotein(a) [Lp(a)] concentration in Tyroleans. Lp(a) concentrations and apo(a) phenotypes were determined in 7 ethnic groups (Tyrolean, Icelandic, Hungarian, Malay, Chinese, Indian, Black Sudanese) and the effects of the apo(a) size polymorphism on Lp(a) levels were estimated in each group. Average Lp(a) concentrations were highly significantly different among these populations, with the Chinese (7.0mg/dl) having the lowest and the Sudanese (46mg/dl) the highest levels. Apo(a) phenotype and derived apo(a) allele frequencies were also significantly different among the populations. Apo(a) isoform effects on Lp(a) levels were not significantly different among populations. Lp(a) levels were however roughly twice as high in the same phenotypes in the Indians, and several times as high in the Sudanese, compared with Caucasians. The size variation of apo(a) explains from 0.77 (Malays) to only 0.19 (Sudanese) of the total variability in Lp(a) levels. Together these data show (I) that there is considerable heterogeneity of the Lp(a) polymorphism among populations, (II) that differences in apo(a) allele frequencies alone do not explain the differences in Lp(a) levels among populations and (III) that in some populations, e.g. Sudanese Blacks, Lp(a) levels are mainly determined by factors that are different from the apo(a) size polymorphism.     

Expressed hypervariable polymorphism of apolipoprotein (a)

Elevated plasma lipoprotein (a) (LP(a] levels are an independent predictor of the development of premature atherosclerosis in humans. The LP(a) particle consists of two disulfide-linked proteins, apolipoprotein (APO) B and APO(a). The APO(a) is a highly glycosylated protein which carries the LP(a) antigen. Genetic polymorphism in the APO(a) molecule has been reported, and, depending on the sensitivity of the method used, 6-11 alleles at the APO(a) structural locus have been documented in the literature. In this investigation, we have used a high-resolution SDS-agarose electrophoresis method followed by immunoblotting to screen APO(a) polymorphism in 54 families with 130 offspring. This method identified a total of 23 different APO(a) isoforms, and their genetic basis was confirmed in families. In addition to the detectable products of 23 APO(a) alleles, the family data predict the existence of a "null" allele. Of the total 270 individuals tested, 209 (77.4%) revealed double-banded phenotypes and 61 (22.6%) revealed single-banded phenotypes. In the unrelated sample of 140 individuals, however, 114 (81.4%) and 26 (18.6%) had double- and single-banded phenotypes, respectively. When the segregation pattern of single-banded phenotypes in the unrelated sample was followed in families, only nine (6.4%) were found to be true homozygotes, and the remaining 17 (12.2%) were classified as heterozygotes for the null allele. Of the 276 possible phenotypes predicted for 23 alleles in a large population, we observed 115 (42%) phenotypes in our restricted sample. On the basis of our results from the family data, we hypothesize the existence of at least 24 alleles, including a null allele, at the APO(a) structural locus.(ABSTRACT TRUNCATED AT 250 WORDS)     

Association between coronary heart disease and the apolipoprotein A-I/C-III/A-IV complex in a Japanese population

Several studies have reported that a variant allele (S₂) of the apolipoprotein (apo) A-I/C-III/A-IV complex is associated with hyperlipoproteinemia in some populations and that the frequency of this allele is two- to fivefold higher in patients with premature coronary heart disease (CHD) than in healthy controls. In the present study in a Japanese population, we were unable to confirm the association of the S₂ allele with either coronary heart disease or elevated serum apo C-III levels, as has been previously reported in Caucasians. No genotype difference was observed among the severity of coronary heart disease, as determined by the number of involved vessels (one, two and three vessel disease), compared to controls. In addition, the frequency of the S₂ allele among Japanese, in both CHD (0.328) and controls (0.369), was quite different from that in many other populations.     

Relationship between a novel polymorphism of the C5L2 gene and coronary artery disease

Background

C5L2 has been demonstrated to be a functional receptor of acylation-stimulating protein (ASP), which is a stimulator of triglyceride synthesis or glucose transport. However, little is known about the variations in the coding region of the C5L2 gene and their association with coronary artery disease (CAD).

Methodology/Principal Findings

We identified a novel single nucleotide polymorphism (SNP), 698C>T (P233L), in exon 2 using a polymerase chain reaction direct-sequencing method. This nucleotide change causes the amino-acid order from proline to leucine at codon 233. We examined the role of this SNP for CAD using two independent case–control studies: one was in the Han population (492 CAD patients and 577 control subjects) and the other was in the Uygur population (319 CAD patients and 554 control subjects). Heterozygote carriers of the 698CT genotype were more frequent among CAD patients than among controls not only in the Han population (7.3% versus 1.7%) but also in the Uygur population (4.7% versus 1.6%). The odds ratio (OR) for carriers of the 698CT genotype for CAD was 4.484 (95% confidence interval (CI): 2.197–9.174) in the Han group and 2.989 (95% CI: 1.292–6.909) in the Uygur population. After adjustment of confounding factors such as sex, age, smoking, alcohol consumption, hypertension, diabetes, as well as serum levels of triglyceride, total cholesterol, high-density lipoprotein, the difference remained significant in the Han group (P<0.001, OR = 6.604, 95% CI: 2.776–15.711) and in the Uygur group (P = 0.047, OR = 2.602, 95% CI: 1.015–6.671).

Conclusion/Significance

The 698CT genotype of C5L2 may be a genetic maker of CAD in the Han and Uygur population in western China.     

Relationship between hemorheology and Glu(298)Asp polymorphism of endothelial nitric oxide synthase gene in patients with coronary artery disease

This study aimed to investigate the relationship between endothelial nitric oxide synthase Glu(298)Asp gene polymorphism and hemorheological parameters. Red blood cell (RBC) deformability, aggregation were measured using an ectacytometry, whole blood, plasma viscosities were determined by a viscometer. Restriction fragment length polymorphism was used to detect polymorphism. Plasma nitrite, nitrate concentrations were determined by Griess method. The genotype distribution of the control group was as follows: 50 (67.5%) GG, 21 (28.4%) GT, 3 (4.1%) TT. A 48 (57.8%) of the patients with CAD had GG, 28 (33.7%) GT, 7 (8.5%) of them TT genotype. RBC aggregation index of CAD patients with G allele was higher and t½ lower compared to controls carrying the same allele. The amplitude of RBC aggregation of healthy subjects with T allele, who are under increased cardiovascular risk was lower compared to control subjects with G allele. The results of this study indicate that, alterations in RBC aggregation seem to be a consequence of CAD, more than being a preexisting cause. Additionally, some compensatory mechanisms by causing decrements in RBC aggregation, may help regulation of circulation in healthy individuals with high cardiovascular risk.     

Relationship between chromosomal polymorphism and wing size in a natural population of Drosophila subobscura

Chromosomal polymorphism and wing size (as a measure of body size) were analysed simultaneously in two samples of Drosophila subobscura from Barcelona, Spain. The very rich chromosomal polymorphism of this species makes it difficult to detect the relationship of this polymorphism with any phenotypical character. However, a positive significant regression of wing size on the percentage of the autosome length with standard arrangement was found. Furthermore, for each polymorphic chromosome, except for the J chromosome, an association between the most frequent arrangements and wing size was observed. This trend, which was the same in the two samples, was that expected according to the latitudinal clines of both characters.     

ApoA-I related DNA polymorphism in humans with coronary heart disease

Summary A genetic analysis of atherosclerotic patients as well as healthy subjects using an apoA-I gene specific probe confirmed that an EcoRI restriction fragment length polymorphism is related to the development of atherosclerosis. Three subjects with severe coronary heart disease were found to be homozygous for a 6.5 kb fragment hybridizing to the apoA-I probe. In the atherosclerotic patient group 44% were heterozygous for this fragment, compared to 9.5% in the control group. The distribution of genotypes in the atherosclerotic and control groups was signficantly different. Among the heterozygous subjects, specific differences were found after digestion of their DNA with Bam HI restriction endonuclease.     

The association between CD14 gene C-260T polymorphism and coronary heart disease risk: a meta-analysis

Monocyte differentiation antigen CD14 is considered an important cell-activating mediator of inflammatory responses that may result in atherosclerosis, coronary heart disease (CHD), thrombus formation, and myocardial infarction (MI). A common C-260T polymorphism in the promoter of the CD14 gene, the trans-membrane receptor of lipopolysaccharides, has been inconsistently associated with CHD. To investigate this inconsistency, we performed a meta-analysis of 28 studies involving a total of 13,335 CHD cases and 7,979 controls for C-260T of the CD14 gene to evaluate the effect of CD14 on genetic susceptibility for CHD. An overall random effects odds ratio of 1.24 (95 % CI: 1.12–1.36, P < 10^?5) was found for T allele. Significant results were also observed using dominant (OR = 1.34, 95 % CI: 1.17–1.54, P < 10^?4) or recessive genetic model (OR = 1.25, 95 % CI: 1.10–1.41, P = 0.0004). There was strong evidence of heterogeneity (P < 10^?5), which largely disappeared after stratification by ethnicity. After stratified by ethnicity, significant results were found in East Asians; whereas no significant associations were found among Caucasians and other ethnic populations in all genetic models. In the stratified analysis according to sample size, CHD endpoints, and HWE status, significantly increased risks for the polymorphism were found in all genetic models. In conclusion, our results indicate that the CD14 C-260T polymorphism is a risk factor of CHD, especially in East Asians. However, additional very large-scale studies are warranted to confirm our results.     

颈动脉内-中膜厚度及踝肱指数与冠心病的相关性研究

目的:通过研究颈动脉内-中膜厚度(carotid Intimal medial thickness cIMT)及踝肱指数(ankle-brachial index,ABI)与冠心痛患者的相关性,探讨动脉硬化和动脉粥样硬化之间的相关性.方法:本研究入选264例在本院行冠脉造影的患者,按冠脉造影的结果分为对照组和冠心痛组,冠心痛组根据冠脉病变程度进一步分为单支、双支、多支病变组.所有入选者在冠脉造影前用日本ALOKAα 7超声检测cIMT,用日本科林无创动脉硬化测定仪测量两侧ABI.结果:冠心痛组cIMT明显高于对照组,踝臂指数明显低于对照组,差异有统计学意义(P＜0.05);冠状动脉病变程度分析中:cIMT随着冠脉病变程度加重均有增高趋势,其中多支病变、双支病变组cIMT和颈动脉斑块积分均高于单支病变组、对照组,单支病变组cIMT和颈动脉斑块积分也明显高于对照组:ABI却随着冠脉病变程度加重均有降低趋势,多支病变组ABI均低于双支、单支痛变组和对照组,双支、单支痛变组ABI也明显低于对照组,差异有统计学意义(P＜0.05).结论:cIMT和ABI与冠心痛密切相关,在一定程度上可以预测冠心痛冠脉病变程度.     

The prevalence of overweight and obesity among Croatian hospitalized coronary heart disease patients

The aim of this article was to investigate the prevalence of overweight and obesity using selected anthropometric variables in a sample of hospitalized coronary heart disease (CHD) patients in Croatia (N = 1,298). Prevalence of overweight and obesity in surveyed patient population was high: 48.2% of participants were overweight and 28.6% were obese according to their body mass index; measured through waist-to-hip ratio 54.5% of participants were centrally obese. These data on prevalences of overweight, obesity and central obesity show that although there are some reassuring trends, there is still considerable amount of work to be done if the prevalence of this cardiovascular risk factor is to be reduced further among Croatian CHD patients. While the prevalence of obesity seems to be on the decline, the prevalence of overweight is rising, which may be just an early warning sign of an incoming wave of obesity epidemic in future years.     

Post-hoc analysis on the CD14 C(-260)T promoter polymorphism and coronary heart disease

Functional C(-260)--> T polymorphism in the promoter of the CD14 gene has been reported to be associated with coronary heart disease (CHD). The functional role of the polymorphism, however, is still a matter of debate, since several studies have not proved its effect on clinical outcomes associated with atherosclerosis. Cardiovascular-related morbidity and mortality was assessed in a post-hoc approach four years after baseline characterization of patients (male/female n = 36/32) with angiographically proven coronary heart disease. CD14 C(-260)--> T promoter genotype was determined at baseline. Seventeen out of 20 CHD patients with non-lethal cardiovascular events carried at least one T-allele. CD14 T-260 allele carriers have a 3.59-fold (95 % confidence interval: 1.11-6.75) increased risk for non-lethal cardiovascular events (Kaplan-Meier plot: log rank test p = 0.029). All patients with lethal outcomes (n = 6) were also T-allele carriers. Multivariate logistic regression analysis among CHD patients including age, established risk factors and the C(-260)--> T polymorphism as covariates and non-lethal events as a dependent variable confirmed the independent prospective effect of the T-allele on cardiovascular outcomes in this subset. Further evidence is provided for the role of CD14 C(-260)--> T promoter polymorphism as a genetic susceptibility marker of atherosclerosis in patients with an advanced clinical course of the disease. Due to the small sample size and post-hoc character of the study large-scale prospective studies that monitor patients with proven CHD are needed to confirm these findings.     

Neuromedin beta: P73T polymorphism in overweight and obese subjects

Neuromedin beta (NMB) is a member of the bombesin-like peptide family expressed in brain, gastrointestinal tract, pancreas, adrenals and adipose tissue. The aim of our study was to compare the frequency of P73T polymorphism in overweight and obese patients (37 men: age 50.6+/-11.7 years, BMI 41.1+/-7.8 kg/m(2); 255 women: age 49.0+/-11.9 years, BMI 37.9+/-6.8 kg/m(2)) with that of healthy normal weight subjects (51 men: age 28.2+/-7.1 years, BMI 22.3+/-2.0 kg/m(2); 104 women: age 29.1+/-9.1 years, BMI 21.5+/-1.9 kg/m(2)) and to investigate the polymorphism's influence on anthropometric, nutritional and psychobehavioral parameters in overweight/obese patients both at the baseline examination and at a control visit carried out 2.5 years later, regardless of the patient s compliance with the weight reduction program. No significant differences in the genotype distribution were demonstrated between normal weight and overweight/obese subjects. Male T allele non-carriers compared to T allele carriers had higher energy (p=0.009), protein (p=0.018) and fat (p=0.002) intakes and hunger score (p=0.015) at the beginning of treatment. Male T allele non-carriers had a more favorable response to weight management at the follow-up, as they exhibited a significant reduction in waist circumference, energy intake and depression score as well as a significant increase in dietary restraint. No significant differences between carriers and non-carriers were demonstrated in women at the baseline examination. Both female T allele carriers and non-carriers demonstrated similar significant changes in nutritional parameters and in restraint score at the follow-up. Nevertheless, only female non-carriers showed a significant decrease in the hunger score.     

Differences in apolipoprotein(a) polymorphism in West Greenland Eskimos and Caucasian Danes

Summary Previous studies in Greenland suggest that death rates from ischemic heart disease [IHD] are lower in Eskimos than in Danes and other Caucasian populations. This has been explained by a high intake of n-3 polyunsaturated fatty acids with beneficial effects on blood lipids and hemostasis. In other populations, lipoprotein(a) [Lp(a)] is associated with IHD, plasma concentrations of Lp(a) being genetically determined to a major extent. We have compared Lp(a) concentrations and apo(a) phenotypes in 120 Greenlandic Eskimos with those in 466 Danish men. The median Lp(a) concentration in Eskimos (8.7mg/dl;[95% CI 6.5–10.7]) was not significantly different from that in Danes (6.3mg/dl; [95% CI 5.2–7.0]), whereas the 90th percentile was significantly higher among Danes: 46.36mg/dl; [95% Cl 43.0–54.3] vs. 27.6mg/dl [95% CI 20.7–36.9]. In 20% of the Danes, but in only 8% of the Eskimos (P = 0.009), the concentration of Lp(a) exceeded 30mg/dl. The difference is probably explained by a low frequency of the low molecular weight apo(a) phenotypes among Eskimos, since the apo(a) isoforms F and B were absent, and the S1 and S2 types were present in only 3.3% of Eskimos. In contrast, these apo(a) isoforms were present in 26.6% of the Danes in either single-band or double-band phenotypes. The pattern of apo(a) polymorphism found in this study could provide part of a genetic explanation for the putative low rates of IHD in Eskimo populations.     

Understanding coronary heart disease as a consequence of defective regulation of apolipoprotein B metabolism.

Further understanding of the causative link between plasma lipids and coronary heart disease will come from a deeper appreciation of the impact of lipoprotein heterogeneity on the processes of atherosclerosis and thrombosis. It is now widely appreciated that remnants of triglyceride-rich lipoproteins, IDL and specific LDL subfractions may have a role in atherogenesis disproportionate to the plasma concentrations of these species. Elucidation of the factors that control the distribution of subfractions within the spectrum of apolipoprotein B-containing lipoproteins is underway but far from complete. Important influences are the rate and nature of lipoproteins secreted from the liver, the extent of remodelling by lipid exchange and lipolysis in the circulation and the affinity of the various particles for cell surface receptors.     

Carbohydrate intake is correlated with biomarkers for coronary heart disease in a population of overweight premenopausal women

The associations between macronutrient intake and plasma parameters associated with increased risk for coronary heart disease (CHD) were evaluated in 80 overweight premenopausal women. We hypothesized that higher carbohydrate intake would be associated with a more detrimental plasma lipid profile. Dietary data were collected using a validated food frequency questionnaire (FFQ). Plasma total cholesterol (TC), triglycerides (TGs), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) were determined from two fasting blood samples. In addition, selected apolipoproteins (apo) and LDL peak size were measured. Values for TC, TG and HDL were not in the range of risk classification; however, the mean values of LDL-C, 2.7 +/- 0.7 mmol/L, were higher than the current recommendations. Carbohydrate intake was positively associated with TG and apo C-III (P < .01) concentrations, and negatively associated with LDL diameter (P < .01). Participants were divided into low (<53% of energy) or high (> or = 53% energy) carbohydrate intake groups. Individuals in the <53% carbohydrate group consumed more cholesterol and total fat, but also had higher intake of polyunsaturated and monounsaturated fatty acids (SFAs). In contrast, subjects in the > or =53% group consumed higher concentrations of glucose and fructose than those in the low-carbohydrate (LC) group. In addition, subjects consuming <53% carbohydrate had lower concentrations of LDL-C and apo B (P < .01) and a larger LDL diameter (P < .05) than the > or =53% group. These results suggest that the lower LDL-C in the LC group may be related to both the amount of carbohydrate and the type of fatty acids consumed by these subjects.     

Association between angiotensin-converting enzyme gene polymorphism and coronary artery disease

An insertion/deletion (I/D) polymorphism in the gene for angiotensin-converting enzyme (ACE) is associated with myocardial infarction and other cardiac pathology. There is evidence for a role of the renin-angiotensin system in cell growth and in the repair of damaged arterial walls, so the ACE gene is postulated to be a candidate gene affecting the important clinical problem of coronary artery disease (CAD). In view of the clinical importance of the ACE as a major marker of cardiovascular diseases, we investigated the I/D polymorphism of the ACE gene in Turkish CAD patients in comparison with control subjects to evaluate a possible association between CAD and the gene encoding ACE. Polymerase chain reaction, restriction fragment length polymorphism, and agarose gel electrophoresis techniques were used to determine the ACE genotype in 58 subjects. The frequencies of ACE D and ACE I allele among the patients with CAD were 62.26% and 37.73 % and in the control subjects were 49.3% and 50.76%, respectively. The greater frequency of deletion allele (D) was in the CAD group than in the control subjects was significant (P < 0.01).