This prospective study included four dog groups (group A: healthy dogs, groups B: dogs with idiopathic epilepsy under antiepileptic medication (AEM), C: idiopathic epilepsy dogs without AEM administration, D: dogs with structural epilepsy). The purpose of the study was to compare the proteomic profile among the four groups. Samples were analyzed by a quantitative Tandem Mass Tags approach using a Q-Exactive-Plus mass-spectrometer. Identification and relative quantification were performed using Proteome Discoverer, and data were analyzed using R. Gene ontology terms were analyzed based on Canis lupus familiaris database. Data are available via ProteomeXchange with identifier PXD018893. Eighteen proteins were statistically significant among the four groups (P < 0.05). MMP2 and EFEMP2 appeared down-regulated whereas HP and APO-A1 were up-regulated (groups B, D). CLEC3B and PEBP4 were up-regulated whereas APO-A1 was down-regulated (group C). IGLL1 was down-regulated (groups B, C) and up-regulated (group D). EFEMP2 was the only protein detected among the four groups and PEBP4 was significantly different among the epileptic dogs. Western blot and SPARCL immunoassay were used to quantify HP abundance change, validating proteomic analysis. Both, showed good correlation with HP levels identified through proteomic analysis (r = 0.712 and r = 0.703, respectively). SIGNIFICANCE: The proteomic analysis from CSF of dogs with epileptic seizures could reflect that MMP2, HP and APO-A1 may contribute to a blood-brain barrier disruption through the seizure-induced inflammatory process in the brain. MMP2 change may indicate the activation of protective mechanisms within the brain tissue. Antiepileptic medication could influence several cellular responses and alter the CSF proteome composition.

Keywords: Dogs; Idiopathic epilepsy; SPARCL immunoassay; TMT-based proteomics; Western blot.

BACKGROUND

Acne vulgaris is one of the most common skin conditions affecting young adults. The relationship between lipid profile or lipid ratios and acne is not widely reported.

METHODS

A case control study was performed in 90 females with severe acne vulgaris. Lipid profiles were measured, lipid ratios were calculated, and results were compared with 90 age matched healthy controls.

RESULTS

Total cholesterol, LDL-C, HDL-C, Apo A1, though, were significantly higher in patients as compared to healthy controls but all the levels in patients were within normal range so we calculated lipid ratios for TC/HDL, LDL/HDL, TG/HDL, Apo B/Apo A1, Atherogenic index of plasma and found that all the ratios were significantly higher as compared to controls using a t-test. The area under receiver operating characteristic curve was>> 0.7 for all the lipid ratios and sensitivity and specificity were calculated for all the ratios and it was highest for Apo A1/Apo B.

CONCLUSIONS

We suggest using lipid ratios as a screening test in females with acne vulgaris to diagnose dyslipidemia at an early stage but further studies are required to see the effect of treating hyperlipidemia in females with severe acne vulgaris.

The results of the research of early vascular alterations in LDL-R carriers in comparison with those in non-carriers with severe hypercholesterolemia are controversial.

OBJECTIVE

To investigate the difference between severe hypercholesterolemia patients that carry LDL-R defective gene and those that do not have it, in their functional (flow-mediated vasodilation) and structural (intima-media thickness of carotid artery and ankle-brachial index) characteristics of arterial wall.

METHODS

The study included 120 hypercholesterolemic patients. Biochemistry parameters were studied by routine methods. The flow-mediated vasodilation (%FMD), ankle-brachial index (ABI) and intima-media thickness (IMT) of common carotid artery were determined using Hewlett Packard Sonos 5 500; MedicaSoft. IMT.lab was the software programme used in the study.

RESULTS

There was no significant difference between the groups with respect to total cholesterol, LDL, HDL, Apo-B, Apo-A1, cellular adhesion molecules (sICAM-1, sVCAM-1, sP- and sE-selectine). The Apo-B/Apo A1 index differed significantly (t = 11.23, p < 0.001) between the two groups; there was difference even after adjustment for age. There was no significant difference in the endothelial dependent and independent vasodilatation between the examined groups (p>> 0.05). We found a significantly greater carotid IMT and lower ABI in the carriers than the respective parameters in the non-carriers. This significant difference was confirmed after adjustment for age.

CONCLUSIONS

Our data show that LDL-R carriers have a higher carotid IMT and lower ABI than non-carriers, whereas no difference between the groups was found with respect to the level of lipid parameters and %FMD.

We recently observed that, around the time of hatching, chick skeletal muscles synthesize and secrete apolipoprotein A1 (apo-A1) at high rates and that reinitiation of synthesis of this serum protein to high levels occurs in mature chicken breast muscle following surgical denervation (Shackelford, J. E., and Lebherz, H. G. (1983) J. Biol. Chem. 258, 7175-7180; 14829-14833). In the present work we investigate the effect of avian muscular dystrophy on the synthesis of apo-A1 in chicken muscles. The relative rate of synthesis of apo-A1 and levels of apo-A1 RNA in mature dystrophic breast (fast-twitch) muscle were about 6-fold higher than normal, while synthesis of apo-A1 in breast muscles derived from 2-day-old dystrophic chicks was close to normal. These observations suggest that the elevated apo-A1 synthetic rate in mature dystrophic breast muscle results from a failure of the diseased tissue to "shut down" apo-A1 synthesis to the normal level during postembryonic maturation. Apo-A1 synthesis in the "slow-twitch" lateral adductor muscle of dystrophic chickens was found to be normal. Our work is discussed in terms of the apparent similarities between the effects of surgical denervation and muscular dystrophy on the protein synthetic programs expressed by chicken skeletal muscles.

BACKGROUND

The high prevalence, severity, and prematurity of coronary artery disease (CAD) in the Indian population cannot be completely explained by the conventional lipid parameters and the existing lipid indices.

OBJECTIVE

To calculate newly defined advanced atherogenic index (AAI) in premature CAD patients and compare it between cases and controls and Correlate its values with the existing indices.

METHODS

One hundred and twenty premature CAD patients and an equal number of age and sex matched healthy individuals were included in this study. Lipid profile and nonconventional lipid parameters like oxidized Low density lipoprotein (OX LDL), small dense LDL (SD LDL), lipoprotein (a) apolipoprotein B (Apo B), and apolipoprotein A1 (Apo A1) were estimated and their values were used to define AAI and existing lipid indices like AI, lipid tetrad index (LTI) and lipid pentad index (LPI).

RESULTS

The mean age of cases and controls was 37.29 + 4.50 and 36.13 + 3.53 years, respectively. The value of AAI was highly significant in cases (3461.22 ± 45.20) as compared to controls (305.84 ± 21.80). AAI has shown better statistical significance and correlation (P < 0.0001, r = 0.737) as compared to the earlier indices such as AI (P < 0.01, r = 0.52), LTI (P < 0.001, r = 0.677) and LPI (P < 0.001, r = 0.622) in premature CAD. Kolmogorov D statistic and cumulative distribution function plot has shown that AAI can discriminate cases and controls more accurately as compared to the earlier indices.

CONCLUSIONS

Statistically AAI appears to be a better marker of consolidated lipid risk in premature CAD patients as compared to the earlier indices.

Thirty-three patients with coronary heart disease (CHD) and angiographically documented coronary atherosclerosis were studied for the levels of lipids and apolipoproteins B and A1 (apo-B and apo-A1) in the blood plasma and apo-A1 in the preparations of two major subclasses of high density lipoproteins (HDLP)-HDLP2 and HDLP3. It was established that the apo-B/apo-A1 ratio was statistically higher in the group of CHD patients with clinical signs of atherosclerotic damage to the abdominal portion of the aorta and its branches than in CHD patients without clinical manifestations of disseminated atherosclerosis of the abdominal portion of the aorta and its major branches. This parameter may indicate the presence of a more severe atherosclerotic damage in CHD patients. Moreover, the CHD patients with a more extensive atherosclerotic damage displayed a decrease in the cholesterol load of HDLP3 particles in relation to the weight unit of apo-A1 and also in the amount of apo-A1 in HDLP2 which is suggestive of a weakening of the cholesterol-acceptor properties of HDLP3 and an impairment of their transformation into larger HDLP2 particles which transport cholesterol to the liver.

The contribution of major gene and multifactorial effects on variation of plasma apolipoproteins A1 and B has been tested in a large sample of population-based Israeli pedigrees. Our most parsimonious and best fitting model for both apolipoproteins is consistent with Mendelian transmissibility, with significant contribution of major genes (with 2 alleles recessive and dominant within each locus) and polygenes, but neglects effects of common sib environment as well as related intergeneration differences in polygenic effects. Total genetic effects explain 71 and 58% of phenotypic variance of APO-A1 and APO-B levels. The major genes account for about 44 and 32% of the variance in APO-A1 and APO-B, respectively, and the frequency of the recessive alleles determining the high level of apolipoproteins under the study in the Israeli population is in the vicinity of 40% at each locus.

Intrapartum asphyxia modifies lipoprotein cholesterol distribution with possible repercussions related to membrane structures and its metabolic functions. We have studied plasma lipid profile and plasma lipoproteins cholesterol distribution in cord blood from 115 newborn infants and 72 pregnant women at delivery.

CONCLUSIONS

newborn infants with perinatal asphyxia (n, 48; pHua less than 7.20) have a higher cord blood triglyceridemia and lower plasma HDL-cholesterol, associated to high significant concentrations of atherogenic ratios (CT/HDLc, LDLc/HDLc) than normal newborn infants (n, 67; pHua = 7.20) [TG, 54.81 +/- 2.96 mg/dl vs 45.74 +/- 2.10 mg/dl (p less than 0.005); CT/HDLc, 24.00 +/- 1.30 mg/dl vs 29.62 +/- 1.12 mg/dl (p less than 0.05); LDLc/HDLc, 1.38 +/- 0.10 vs 1.07 +/- 0.06 (p less than 0.01)]. The highest triglycemia and atherogenic ratios in the acidotic newborn infants reveal deep changes in "esterified cholesterol/binding proteins" system, whereon "Apo A1-LCAT-Apo D" molecular complex binding HDL participate. More studies must be done to understand well this phenomenology. Furthermore, at delivery, pregnant women, that their newborn infants suffer an intrapartum hypoxia, had lower lipidemia than those who had newborn infants with intrapartum physiological stress.

OBJECTIVE

To investigate the disorder of lipid metabolism in type 2diabetic patients. To assessed the association of cholesterol and apolipoprotein with derangement of glucose metabolism.

METHODS

The levels of TC, TG, HDL-C, LDL-C, Apo A1, Apo A2, Apo AB48, Apo B100 and Apo E were all measured in 60 type 2 diabetic patients and 60 healthy controls. The differences of these clinical indicators in the two groups have been compared. Correlation analysis, multiple regression analysis have been applied in this paper.

RESULTS

The levels of TC, TG, LDL-C were significantly higher( P < 0. 01) and the level of HDL-C was significantly lower( P < 0. 01) in patients with type 2 diabetes which indicating a lipid metabolic abnormalities. The levels of Apo A2, Apo B100, Apo E were significantly higher in type 2 diabetic patients than those in control group. Multiple regression analysis showed that Apo B100, Apo B48, LDL-C, TG were the main factors of FBG level. It was showed that apolipoproteins, especially Apo B, isassociated with glucose metabolism disorder.

CONCLUSIONS

T2 DM patients are obviously associated with abnormal lipid metabolism, and the apolipoproteins may play an important role in derangement of glucose metabolism.

Serum apolipoprotein B (apo B) levels were found to be significantly (p < 0.001) higher in the 27 patients with combined hyperlipidemia (144 m./dl +/- 27.6) than in the 17 normal weight normolipidemic control subjects (92 mg/dl +/- 20.6; X +/- SD). When compared to apolipoprotein A1 (apo A1) levels obtained in controls (168.5 mg/dl +/- 28.4), hyperlipidemic subjects displayed a moderate yet significant (p < 0.02) decrease of this apolipoprotein (140 mg/dl +/- 24.2). Serum apo B levels were significantly (p < 0.001) correlated with serum cholesterol concentrations and also, to a lesser degree (p < 0.01), with serum cholinesterase activity. A highly significant correlation (p < 0.001) between apo A1 and HDL cholesterol levels was also noted. The decrease ofHDL cholesterol occurring in hyperlipidemic men (-30%) was however more accentuated than the decrease of apo A1 (-18%) suggesting an enhanced transfer of cholesterol esters from HDL to VLDL and LDL. It is considered that the determination of apolipoproteins may be useful not only for the detection of risk factors for atherosclerosis, but also for a better insight concerning the mechanisms involved in the development of an atherogenic dyslipidemia.

Using microbeam to irradiate human-hamster hybrid A(L) cells with defined number of a particles in a highly localized spatial region, this paper showed that cytoplasmic irradiation induced very little toxicity. For example, the cell killing by 4 a particle traversal through the cytoplasm was about 10%, and about 70% cells survived after their cytoplasm was irradiated with 32 a particles. In contrast, the survival fractions for nuclear irradiation at the same doses were 35% and less than 1% respectively. Mutation induction showed that while nuclear irradiation induced 3-4-fold more CD59 (-) mutants than cytoplasmic irradiation at equivalent particle traversal, at an equitoxic dose level of 90% survival, the latter exposure mode induced 3.3-fold more mutants than nuclear irradiation. Moreover, using multiplex PCR to analyze five marker genes on chromosome 11 (WT, CAT, PTH, APO-A1 and RAS), the results showed that the majority of mutants induced by cytoplasmic irradiation had retained all of the marker genes analyzed. By comparison, the proportion of mutants suffering loss of additional chromosomal markers increased with increasing number of particle traversal through nuclei.

Org OD 14 is a synthetic steroid which in animal bioassays displays oestrogenic as well as very weak androgenic-anabolic properties. Earlier studies have shown that it alleviates oestrogen-deficiency symptoms and retards osteoporosis. OD 14 can be administered continuously with little effect on the endometrium. The aim of this study was to evaluate the effect of OD 14 on apolipoprotein A1 (Apo-A1), the major protein constituent of the high-density lipoprotein (HDL) fraction, as compared with that of oestradiol valerate (E2V) and a placebo. Twenty-two women, who had been oophorectomized when undergoing surgical treatment for stage IB or IIA cervical carcinoma, were given OD 14 2.5 mg/day, a placebo, and E2V 2 mg/day for a period of 6 wk in each case using a double-blind, cross-over method. Serum Apo-A1 was determined by electro-immunoassay after each treatment period. There was a marked decrease in Apo-A1 after OD 14 as compared with the levels seen after the placebo and E2V. This decrease is interpreted as evidence of a strong androgenic influence by OD 14. In epidemiological studies low levels of Apo-A1 have been associated with a higher incidence of atherosclerosis and cardiovascular disease. Long-term treatment with OD 14 might therefore be hazardous in this respect.

Bilayer micellar complexes of the human plasma apolipoprotein A1 with dimyristoyl phosphatidylcholine were prepared under kinetically controlled conditions. Detergent-like properties of Apo A1 in the complexes were expressed in terms of delta SA1 parameter (surface area of mixed micelle per an Apo A1 molecule). Analysis of our and earlier published data showed the correlation of the delta SA1 parameter with the stoichiometry of complexes. Changes of detergent-like properties were caused by cross-linking or proteolysis of Apo A1.

To analyze the alteration of lipid profile and inflammatory markers in the serum of patients with gouty arthritis (GA), the levels of serum lipid profile, C-reactive protein (CRP), and erythrocyte sedimentation rates (ESRs) were measured in the serum of 69 gout patients, 35 patients with rheumatoid arthritis (RA), 23 patients with ankylosing spondylitis (AS)/spondyloarthropathy (SpA), and 25 patients with osteoarthritis (OA). The serum levels of apoprotein A1 (Apo-A1) were significantly decreased in patients with gout when compared with RA, AS/SpA, and OA patients. The serum levels of CRP were significantly increased in gouty patients when compared with RA, AS/SpA, and OA patients. Furthermore, the serum levels of ESR were significantly increased in patients with gout compared to patients with OA. Correlation analysis indicated that the levels of Apo-A1 were negatively correlated with serum ESR and CRP (r = -0.475, P < .001; r = -0.380, P = .001, respectively) in the patients with GA. Taken together, this study gives us a better understanding of the relationships between serum lipid profile and inflammatory markers in gout patients.

Inhibition of human immunodeficiency virus (HIV) entry into target human cells is considered as a critical strategy for preventing HIV infection. Conformational shifts of the HIV-1 envelope glycoprotein (gp120) facilitates the attachment of the virus to target cells, therefore gp120 remains an attractive target for antiretroviral therapy development. Compound 18A has been recently identified as a broad-spectrum anti-HIV inhibitor. It was proposed that 18A disrupts rearrangements of V1/V2 region in gp120; however, the precise mechanism by which 18A interferes with the inherent motion of V1/V2 domain remains obscure. In this report, we elaborate on the binding mode of compound 18A to the closed conformation of a soluble cleaved gp120 and further examine the dynamic motion of V1/V2 region in both gp120 and the gp120-18A complex via all-atom molecular dynamics simulations. In this work, comparative molecular dynamic analyses revealed that 18A makes contact with Leu179, Ile194, Ile424, Met426 W427, E370 and Met475 in the main hydrophobic cavity of the unliganded gp120 and disrupts the restructuring of V1/V2 domain observed in apo gp120. The unwinding of α1 and slight inversion of β2 in gp120 leads to the shift of VI/V2 domain away from the V3 N-terminal regions and toward the outer domain. Stronger contacts between Trp425 and Trp112 rings may contribute to the reduced flexibility of α1 observed upon 18A binding thereby inhibiting the shifts of the V1/V2 region. Binding of 18A to gp120: (1) decreases the overall flexibility of the protein and (2) inhibits the formation a gp120 conformation that closely ressembles a CD4-bound-like conformation. Information gained from this report not only elaborates on important dynamic features of gp120, but will also assist with the future designs of potent gp120 inhibitors as anti-HIV.

Although coronary stenting reduces the incidence of post-angioplasty restenosis, it remains a problem. The influence of lipoproteins on the development of atherosclerosis has been demonstrated but their role in restenosis is controversial. Contradictory results have been published on the subject of the influence of the APO E genotype. In an initial study, the authors showed a closer correlation between Lp (a) and coronary artery disease in women than in men. A sub-group of women who underwent angioplasty and whose lipid profile had been well established, was analysed with respect to APO E alleles. The 59 patients who underwent angioplasty included 35 single, 20 twin and 4 triple vessel diseases. Control coronary angiography was performed in 40 of these women. A telephonic interview was carried out between 12 and 22 months after dilatation on the whole population. The apolipoproteins A1, B, Lp (a) and Lp A1 were measured by immunological, turbidimetric or electroimmunological techniques. The APO E genotyping was performed with the Inno-Lipa kit. The results showed 18 angiographic restenoses (Group A), 20 coronary artery disease without restenosis (Group B), 41 without angiographic (20) or clinical (21) restenosis (Group C). In Group A, the Lp (a) was well above the threshold value of 0.30 g/l. The e4 allele was associated with the highest values of total and LDL cholesterol fractions. There was no significant difference between the APO E genotype of the different groups or with respect to the severity of lesions. The authors conclude that if the e4 is more commonly associated with high LDL-cholesterol and Lp (a), its role in the process of restenosis remains unproven. A greater number of patients is required and further studies are desirable to determine the inflammatory and/or immunological mechanisms through which APO E could influence restenosis.

The efficacy of pravastatin as reducing plasma cholesterol, LDL-CH and Apo B is widely proved. Other molecules within the Apolipoprotein family are recently emerging to have a predictive and/or causative role in atherosclerosis such as particularly Lp(a). The aim of this study was to evaluate the effects of pravastatin therapy in patients affected by primary hypoercholesterolemia on apoprotein and Lp(a) plasma levels. We investigated the effects of pravastatin on 15 patients, seven female and eight male patients, mean age 50.23 +/- 17.2 (range 21-71 years) with primary hypercholesterolemia, of which 7 patients affected by familial hypercholesterolemia and 8 patients by polygenic hypercholesterolemia, were selected. Five weeks after suspension of lipid-lowering drugs and on a normocaloric-fat diet, were given 20 mg pravastatin/day for 12 weeks. The following parameters were measured basally, on the 6th week and the 12th week on pravastatin therapy and after five weeks from drug withdrawal: cholesterol (CH), triglicerides (TG), high density and low density lipoprotein cholesterol (HDL-CH and LDH-CH) measured enzymatically, apoproteins A1, B, C2, C3, E measured radial immunodiffusion technique (RID) and Lp(a), measured as apoprotein(a) with immunoradiometric assay (RIA). Our data confirm pravastatin efficacy in decreasing CH (from 305.6 +/- 43.4 mg/dl to 266.2 +/- 47.7 mg/dl, p < 0.01) LDL-CH (from 223.9 +/- 56.4 mg/dl to 187.2 +/- 59.8 mg/dl, p < 0.01) and Apo B (from 170.4 +/- 27.5 to 152.4 +/- 25.2, p < 0.02); non influence was observed on HDL-CH and apoproteins A1, C2, E and Lp(a). Pravastatin determined a significant increase only on Apo C3 (from 8.35 +/- 2.7 to 10.3 +/- 3.1, p < 0.04). The above data confirm the beneficial effect of pravastatin in greatly decreasing CH and LDL-CH considered as major risk factors for coronary artery disease, but also point to a role of pravastatin in regulating the apoproteins equilibrium, an aspect that surely merits further studies.

Purpose: Risk stratification in chronic systolic heart failure (HF) is critical to identify the patients who may benefit from advanced therapies. We aimed identifying new biomarkers to improve prognosis evaluation and help to better understand HF physiopathology.

Experimental design: Prognostic evaluation was performed in 198 patients with chronic systolic HF: 99 patients who died from cardiovascular cause within 3 years were individually matched for age, sex, and HF etiology (ischemic vs. not) with 99 patients who were alive after 3 years of HF evaluation. We performed a proteomic profiling of 15 apolipoproteins: Apo-A1, -A2, -A4, -B100, -C1, -C2, -C3, -C4, -D, -E, -F, -H, -J, -L1 and -M using LC-MRM-MS.

Results: In univariate analysis, the levels of Apo-B100 and -L1 were significantly lower and the levels of Apo-C1, -J and -M were significantly higher in patients who died from cardiovascular cause as compared with patients alive. In the final statistical model, Apo-C1, Apo-J and Apo-M improved individually the prediction of cardiovascular death. Ingenuity pathway analysis indicated these 3 Apo in a network associated with lipid metabolism, atherosclerosis signaling and RXR activation.

Conclusions: Proteomic profiling of apolipoproteins using LC-MRM-MS might be useful in clinical practice for risk stratification of HF patients. This article is protected by copyright. All rights reserved.

Keywords: apolipoproteins; biomarkers; diseases; heart; heart failure; proteomics; risk stratification.

Dyslipoproteinemia is involved in the origin of arteriosclerosis by changing the architecture of the coronary artery wall and therefore represents an important factor in the development of coronary artery disease (CAD). High-density lipoprotein (HDL) and apolipoprotein-A1 (Apo A1) serve as protection against the origin and development of coronary obstructive disease. The aims of this study were to evaluate the relations among the plasma lipids, their fraction Apo A1, HDL, and positive coronary arteriography, and to estimate their importance as markers of the degree of coronary lesions. The study included 101 subjects, 77 men and 24 women, aged 35 to 75 years, mean age = 55.7 years. The subjects were divided into 2 groups: 1 group--CAD with positive coronary arteriography (n = 70), and the other group--CAD with negative coronary arteriography (n = 31). According to the anatomic localization of atherosclerotic lesion, the first group of subjects was divided into 1-vessel (n = 26), 2-vessel (n = 20), and multiple-vessel lesion (n = 24) subgroups. The results show a significant difference in Apo A1 and Apo A1/Apo B (p<0.005) in the 2- and multiple-vessel disease in relation to the control group, while subject significance was not proved for 1-vessel disease. A positive correlation and significance for HDL as well as cholesterol ratio/HDL (p<0.05) was noted for 1- and multiple-vessel disease, while a negative correlation was noted for 2-vessel disease in relation to the control group. This study stressed the diagnostic significance in determining Apo A1 and Apo A1/Apo B1 as better predictors than HDL cholesterol in evaluating coronary lesion severity. Dyslipoproteinemia, namely, the level of lipoproteins of low density, plays an important role in the pathogenesis of arteriosclerosis and the development of CAD.

The authors studied the effect of anaprilin monotherapy (dose: 160-200 mg/daily for 10 months) on the level of atherogenic apolipoproteins (apo A, apo B) and fractions of plasma cholesterol in 34 patients with ischemic heart disease, stable exertion angina pectoris (class 2-3). It was established that changes in the plasma lipid and apoprotein spectrum result in an increase of apo B, decrease of apo 1, increase of apo B/apo A1, decrease of high-density lipoprotein cholesterol (HDLCS) and a different dynamics of HDLCS/apo A1. The established changes in the lipid metabolism are of atherogenic character.

Elevated plasma levels of apolipoprotein A1 (APO-A1) and high-density lipoprotein cholesterol (HDL-C) are important protective factors for atherosclerosis and coronary heart disease. Using the data on plasma concentrations of APO-A1, and HDL-C particles HDL2-C and HDL3-C in 970 Israeli individuals belonging to 228 pedigrees, we tested the hypothesis that a major locus influencing interindividual variation in APO-A1 levels also controls interindividual variation in HDL3-C and HDL2-C levels. Univariate and bivariate complex segregation analyses, as implemented in two statistical packages (MAN-3 and PAP-4.0) were applied to test the hypothesis. The results of the analysis clearly indicated the possibility of major gene involvement in the determination of plasma concentration variation of each of the 3 study variables. The results provide strong evidence in support of our hypothesis that HDL3-C genetic variation fully depends on the APO-A1 major locus. In particular, environmental and sporadic models were strongly rejected (P < 0.001) in bivariate analysis. The hypothesis of no pleiotropic effect of the putative APO-A1 locus on HDL3-C transmission was also unequivocally rejected (P < 0.001), while the bivariate Mendelian model was accepted (P>> 0.05). The results of bivariate analysis of APO-A1 effect on HDL2-C were not clear. They indicated the possibility of the existence of slight genetic covariation between the two variables, and as yet we were unable to decipher the mode of covariation with the applied models.

For quantitative traits associated with risk to complex diseases, such as heart disease, single major locus models are likely to be too simplistic. Currently, researchers have begun to use oligogenic models of inheritance, but the resolving power of these models remains to be determined. As the major apoprotein of high density lipoprotein (HDL), apolipoprotein A1 (apo-A1) is generally accepted as a protective factor for coronary artery disease. Although familial aggregation of apo-A1 levels has been reported, the mode of inheritance of apo-A1 remains ill defined. In the present study, we conducted a segregation analysis comparing a series of one-locus and two-locus univariate models for apo-A1 levels in a sample of 137 families ascertained through probands undergoing elective, diagnostic coronary angiography. A two-locus Mendelian model fit these data significantly better than any one-locus model. The incorporation of the second major locus into the model of inheritance leads to a significant improvement in the fit, and a significant decrease of the residual heritability. The best-fitting model included two loci with a reciprocal pattern of epistasis generating 4 distinct genotypic distributions. Taken together, these two major loci account for 58% of the variance of adjusted apo-A1 levels. This demonstration of a second major locus controlling apo-A1 levels may explain the equivocal results obtained from previous studies. This two-locus model may be more powerful for linkage analysis to map one or both of these quantitative trait loci.

A procedure for the quantitation of non-enzymatically glycated apolipoprotein A1 (GApoA1) was developed and optimized. Glycated total protein was separated from plasma using m-aminophenyl-boronate affinity chromatography. Apolipoprotein A1 present in the glycated and non-glycated fractions of each sample was determined by rate nephelometry, and the percent glycated apo A1 calculated. The measuring range of the assay was 0.5-8.0% GApoA1. The within- and between-run CV's were less than 5.2 and 7.9%, respectively, and recoveries were greater than 92%. Free glucose did not affect the results. In a group of female non-insulin diabetic subjects the mean GApoA1 was 3.8 +/- 1.6% (mean +/- SD). In non-diabetic subjects the mean level of GApoA1 was 2.1 +/- 0.8% (mean +/- SD).

Objective: We examined the relationships of apolipoprotein A1 (ApoA1), ApoB levels and ApoB/A1 ratio with blood pressure (BP) in Chinese adults with coronary artery disease (CAD).

Methods: This cross-sectional study included 4921 adults with CAD. SBP, DBP, serum ApoA1 and ApoB levels were measured. The associations between Apo and BP were assessed by analyses of covariance.

Results: Serum ApoA1 was inversely associated with BP, whereas ApoB and the ApoB/A1 ratio exhibited positive associations with BP. For all subjects, a higher ApoA1 level was associated with lower SBP. Subjects in the fourth quartile for ApoA1 exhibited - 2.85 and - 2.63% lower DBP and mean arterial pressure (MAP), respectively than those in the third quartile. In contrast, higher ApoB and ApoB/A1 ratios were associated with higher SBP, DBP and MAP. The mean differences between ApoB quartiles 4 and 1 were 1.54% for SBP, 2.92% for DBP and 2.29% for MAP. The mean differences between the ApoB/A1 ratio quartiles 4 and 1 were 1.94% for SBP, 3.53% for DBP and 2.80% for MAP. In analyses stratified by gender, graded and inverse associations of ApoA1 with SBP, DBP and MAP were observed in both men and women, but positive associations were observed for ApoB and the ApoB/A1 ratio. Path analysis showed that BMI mediated the associations between ApoB and the ApoB/A1 ratio and SBP.

Conclusions: In general, serum ApoA1 was inversely associated with BP in persons with CAD. In contrast, serum ApoB and the ApoB/A1 ratio were positively associated with BP, and these associations were mediated by BMI.