Biomedical subjects

A Hamsten

Publications and source records attributed to A Hamsten.

At least 55 records · Page 3Linked to original sources

PubMed2001

Fatty acid binding protein expression in different adipose tissue depots from lean and obese individuals.

AIMS/HYPOTHESIS: This study investigated the expression of adipose tissue fatty acid binding proteins (FABPs) in subcutaneous and visceral human adipose tissue depots from lean and obese individuals. METHODS: Adipocyte lipid binding protein (ALBP) and keratinocyte lipid binding protein (KLBP) expression was quantified by western blot in subcutaneous and omental adipose tissue from 20 obese and 9 lean individuals. RNA expression was quantified by Northern blot in the obese subjects. RESULTS: In the obese subjects, ALBP protein and RNA expression was higher in subcutaneous compared with omental adipose tissue (increases of 31 +/- 14 % and 40 +/- 13 % respectively, both p < 0.05), whereas in the lean group, KLBP protein levels were 32 +/- 9 % lower in subcutaneous fat (p < 0.03). However, the ALBP/KLBP ratio was greater in subcutaneous compared to omental adipose tissue from both lean and obese subjects: increases of 187 +/- 71 % (p = 0.01) and 52 +/- 23 % (p = 0.17) respectively for the protein ratio, and 21 +/- 6 % for RNA (p = 0.01, obese individuals). In lean subjects, insulin concentrations correlated positively with the ALBP/KLBP protein ratio in both depots (both p < or = 0.03). CONCLUSION/INTERPRETATION: There are regional differences in adipose tissue FABP expression, which could be influenced by obesity. However, the ALBP/KLBP ratio is greater in subcutaneous than visceral adipose tissue in lean as well as in obese subjects. Investigation of adipose tissue FABPs could further our understanding of the role of fatty acids in the insulin resistance syndrome.

Actins↗

PubMed2001

Remnant-like lipoprotein particle cholesterol concentration and progression of coronary and vein-graft atherosclerosis in response to gemfibrozil treatment.

Remnant lipoproteins such as chylomicron and very low density lipoprotein (VLDL) remnants have been implicated in the progression of coronary atherosclerosis. Recently, a novel method for the determination of the remnant-like lipoprotein particle cholesterol (RLP-C) concentration was developed based on immunoaffinity-separation of plasma. The compositional characteristics of RLP are strikingly similar to those of postprandially modified VLDL. In addition, the method also detects chylomicron remnants. We investigated the relationship between the plasma RLP-C concentration and the angiographic outcome of the 2-year, randomised, placebo-controlled Lipid Coronary Angiography Trial (LOCAT), which used gemfibrozil as lipid lowering agent. The RLP-C response to gemfibrozil treatment has not been described before. Gemfibrozil reduced the median RLP-C concentration by 34%. The on-treatment RLP-C concentration was significantly associated with the progression of the minimum lumen diameter (MLD) (P<0.004). The plasma levels of RLP-C as well as the change in response to treatment was closely associated with plasma triglycerides and the association between on-treatment RLP-C concentration and progression of MLD was not independent of plasma triglycerides. A significant relation was seen between RLP-C and the occurrence of new lesions in vein grafts. Subjects with one new lesion had an approximately 25% higher on-treatment RLP-C concentration and the four patients showing two new lesions had a 100% higher RLP-C concentration than patients without vein graft stenosis. A total of 19 out of 23 subjects having one new lesion, and all four patients showing two new lesions, were assigned to the placebo group. We conclude that the RLP-C concentration, which is likely to reflect the plasma cholesterol contained in postprandially modified VLDL and chylomicron remnants, is strongly associated with angiographically verified progression of focal coronary atherosclerosis, and that lowering of RLPs prevents vein graft stenosis.

Apolipoproteins↗

PubMed2001

Mild-to-moderate hypertriglyceridemia in young men is associated with endothelial dysfunction and increased plasma concentrations of asymmetric dimethylarginine.

OBJECTIVES: The aim of this study was to investigate endothelial function and common carotid intima-media thickness (IMT) in healthy young men with mild-to-moderate hypertriglyceridemia. Plasma asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor, was measured to further elucidate the mechanisms involved. BACKGROUND: Hypertriglyceridemia is a risk factor for coronary heart disease although the mechanisms behind the increased risk remain to be defined. Acute elevation of plasma triglycerides induced by an intravenous fat load is associated with impaired endothelial function. The results of studies examining acute effects induced by a high-fat meal or effects of chronic hypertriglyceridemia on endothelial function are more inconsistent. METHODS: Flow-mediated vasodilation and nitroglycerin-induced vasodilation of the brachial artery and common carotid IMT were measured noninvasively by ultrasound technique in 15 hypertriglyceridemic (HTG) subjects and 15 matched controls, mean age 34 years. Plasma concentrations of ADMA were measured by high-performance liquid chromatography. RESULTS: Flow-mediated vasodilation was decreased in the HTG group (p < 0.0001), whereas nitroglycerin-induced vasodilation and carotid IMT did not differ significantly. Asymmetric dimethylarginine concentrations were higher in the HTG group (p < 0.05). CONCLUSIONS: Hypertriglyceridemia in young men is associated with endothelial dysfunction and increased plasma concentration of ADMA but not with increased IMT of the common carotid artery. The corollary is that chronic hypertriglyceridemia results in endothelial dysfunction, possibly due to increased ADMA concentration, and that endothelial dysfunction might precede increased IMT among the early manifestations of atherosclerosis.

Adult↗

PubMed2001

LDL immunization induces T-cell-dependent antibody formation and protection against atherosclerosis.

Atherosclerosis is an inflammatory disease, and the involvement of immune mechanisms in disease progression is increasingly recognized. Immunization with oxidized low density lipoprotein (LDL) decreases atherosclerosis in several animal models. To explore humoral and cellular immune reactions involved in this protection, we immunized apolipoprotein E knockout mice with either homologous plaque homogenates or homologous malondialdehyde (MDA)-LDL. Immunization with both these antigen preparations reduced lesion development. The plaques contained immunogen(s) sharing epitopes on MDA-LDL, MDA-very low density lipoprotein, and oxidized cardiolipin. This shows that a T-cell-dependent antibody response was associated with protection against atherosclerosis. The protection was associated with specific T-cell-dependent elevation of IgG antibodies against MDA-LDL and oxidized phospholipids, and the increased titers of IgG antibodies were correlated with decreased lesion formation and lower serum cholesterol levels.

Animals↗

PubMed2001

Allele-specific regulation of matrix metalloproteinase-7 promoter activity is associated with coronary artery luminal dimensions among hypercholesterolemic patients.

An enhanced expression of matrix metalloproteinase (MMP)-7 has previously been demonstrated in atherosclerotic and aneurysmal tissue. Because perturbed regulation of MMP-7 may influence the development of these diseases, we searched the MMP-7 promoter for functional polymorphisms. An A to G substitution at position -181 (-181 A/G) and a C to T substitution at position -153 (-153 C/T) with frequencies of 0.50 and 0.10, respectively, were identified. Allele-specific associations were studied in 350 patients undergoing percutaneous transluminal coronary angioplasty. Hypercholesterolemic patients carrying the -181G allele or the -153T allele had smaller reference luminal diameters before percutaneous transluminal coronary angioplasty. Reverse transcription-polymerase chain reaction demonstrated that expression of MMP-7 was confined to differentiated U937 cells. Northern blot analysis could not detect an effect of native or oxidatively modified low density lipoprotein on MMP-7 expression. Thus, the limitation of allele-specific effects on vessel wall remodeling to hypercholesterolemic patients may be secondary to lipid-mediated accumulation of MMP-7-expressing monocyte-derived macrophages within the vessel wall. Both polymorphisms influenced the binding of nuclear proteins. Furthermore, in transient transfection studies, the combination of the 2 rare alleles conferred an increased promoter activity. In conclusion, the present study identified and characterized 2 common polymorphisms in the promoter region of the MMP-7 gene that are functional in vitro and seem to influence coronary arterial dimensions in hypercholesterolemic patients with manifest coronary artery disease.

Adult↗

PubMed2001

Transcriptional regulation of plasminogen activator inhibitor type 1 gene by insulin: insights into the signaling pathway.

Impairment of the fibrinolytic system, caused primarily by increases in the plasma levels of plasminogen activator inhibitor (PAI) type 1, are frequently found in diabetes and the insulin-resistance syndrome. Among the factors responsible for the increases of PAI-1, insulin has recently attracted attention. In this study, we analyzed the effects of insulin on PAI-1 biosynthesis in HepG2 cells, paying particular attention to the signaling network evoked by this hormone. Experiments performed in CHO cells overexpressing the insulin receptor indicate that insulin increases PAI-1 gene transcription through interaction with its receptor. By using inhibitors of the different signaling pathways evoked by insulin-receptor binding, it has been shown that the biosynthesis of PAI-1 is due to phosphatidylinositol (PI) 3-kinase activation, followed by protein kinase C and ultimately by mitogen-activated protein (MAP) kinase activation and extracellular signal-regulated kinase 2 phosphorylation. We also showed that this pathway is Ras-independent. Transfection of HepG2 cells with several truncations of the PAI-1 promoter coupled to a CAT gene allowed us to recognize two major response elements located in the regions between -804 and -708 and between -211 and -54. Electrophoretic mobility shift assay identified three binding sites for insulin-induced factors, all colocalized with putative Sp1 binding sites. Using supershifting antibodies, the binding of Sp1 could only be confirmed at the binding site located just upstream from the transcription start site of the PAI-1 promoter. A construct comprising four tandem repeat copies of the -93/-62 region of the PAI-1 promoter linked to CAT was transcriptionally activated in HepG2 cells by insulin. These results outline the central role of MAP kinase activation in the regulation of PAI-1 induced by insulin.

Base Sequence↗

PubMed2001

Circulating immune complexes induced by food proteins implicated in precocious myocardial infarction.

BACKGROUND: Circulating immune complexes (CIC) are frequently found in postinfarction patients. The constituents of these CIC are mostly unknown. AIM: The objective of the current study was to assess whether CIC containing alimentary proteins and antibodies against these proteins are implicated in precocious myocardial infarction (MI). METHODS: Seventy-six survivors (67 men and 9 women, mean age 39 years) of a first MI before the age of 45 years were enrolled in this study. Two control groups were included. One group consisted of age-matched, randomly selected, population-based healthy individuals, 79 men and 11 women, without features of coronary heart disease. An additional control group was used only for the determination of serum antibodies against some of the alimentary proteins and consisted of 139 healthy blood donors, 95 men and 44 women, with a mean age of 42 years. Sucrose density gradient centrifugation, gel filtration and precipitation by polyethylene glycol were used for the isolation of CIC, and enzyme-linked immunosorbent assay (ELISA) was used to measure the immunoglobulin levels and specific antibodies against alimentary proteins in both sera and isolated CIC. Sodium dodecylsulfate (SDS) polyacrylamide gel electrophoresis and Western blotting were used to determine alimentary proteins in the CIC. RESULTS: Alimentary antigens/antibodies were present in immune complex form in seven out of 14 (50%) postinfarction patients who had persistent high concentrations of CIC, the latter constituting 18% of the entire group. Antibodies of the IgG isotype predominated. A rise in CIC, signs of activation of the classical complement pathway, and a rise in plasma concentrations of von Willebrand factor antigen (vWFAg) were evident within 1 week in four patients subjected to a 2-week elimination diet followed by a single challenge with cow's milk. CONCLUSION: This study suggests that dietary proteins occasionally give rise to persistent CIC, which may predispose to MI at a young age.

Adult↗

PubMed2001

Remnant lipoproteins are related to intima-media thickness of the carotid artery independently of LDL cholesterol and plasma triglycerides.

Remnants of triglyceride-rich lipoproteins (TRL) have been implicated in the early development of atherosclerosis. We tested this hypothesis by quantifying the plasma concentration of remnant-like particle cholesterol (RLP-C) in a cohort of healthy 50-year-old men in whom the common carotid artery intima-media thickness (CCA-IMT) was assessed by B-mode ultrasound as a surrogate marker for atherosclerosis. The subjects were given a fat-rich meal to study the generation of RLP-C during postprandial lipemia. Fasting plasma RLP-C and other major fasting plasma lipids and lipoproteins were determined twice, and the mean RLP-C concentration was strongly correlated with CCA-IMT (r = 0.32, P = 0.002). In addition, low density lipoprotein (LDL) cholesterol (r = 0.25, P = 0.01) and plasma triglycerides (r = 0.20, P = 0.05) were significantly related to CCA-IMT. Multivariate analyses showed a triglyceride-independent contribution of RLP-C to CCA-IMT. After fat intake, the median plasma RLP-C concentration was doubled after 3 h. The increase was strongly related to the postprandial generation of TRL apolipoprotein (apo)B-48, and large (S(f) 60;-400) TRL apoB-100. The association with CCA-IMT was somewhat stronger for the 3-h RLP-C level than for the fasting RLP-C concentration [r = 0.27, P < 0.01 (3 h) compared with r = 0.22, P < 0.05 (0 h)]. We conclude that the plasma concentration of RLP-C is related to CCA-IMT, independent of plasma triglycerides and LDL cholesterol, in a healthy middle-aged male population. - Karpe, F., S. Boquist, R. Tang, G. M. Bond, U. de Faire, and A. Hamsten. Remnant lipoproteins are related to intima-media thickness of the carotid artery independently of LDL cholesterol and plasma triglycerides. J. Lipid Res. 2001. 42: 17;-21.

Apolipoproteins↗

PubMed2001

Effects of oral and transdermal estrogen replacement therapy on markers of coagulation, fibrinolysis, inflammation and serum lipids and lipoproteins in postmenopausal women.

We compared the effects of oral estradiol (2 mg), transdermal estradiol (50 microg), and placebo on measures of coagulation, fibrinolysis, inflammation and serum lipids and lipoproteins in 27 postmenopausal women at baseline and after 2 and 12 weeks of treatment. Oral and transdermal estradiol induced similar increases in serum free estradiol concentrations. Oral therapy increased the plasma concentrations of factor VII antigen (FVIIag) and activated factor VII (FVIIa), and the plasma concentration of the prothrombin activation marker prothrombin fragment 1+2 (F1+2). Oral but not transdermal estradiol therapy significantly lowered plasma plasminogen activator inhibitor-1 (PAI-1) antigen and tissue-type plasminogen activator (tPA) antigen concentrations and PAI-1 activity, and increased D-dimer concentrations, suggesting increased fibrinolysis. The concentration of soluble E-selectin decreased and serum C-reactive protein (CRP) increased significantly in the oral but not in the transdermal or placebo groups. In the oral but not in the transdermal or placebo estradiol groups low-density-lipoprotein (LDL) cholesterol, apolipoprotein B and lipoprotein (a) concentrations decreased while high-density-lipoprotein (HDL) cholesterol, apolipoprotein AI and apolipoprotein All concentrations increased significantly. LDL particle size remained unchanged. In summary, oral estradiol increased markers of fibrinolytic activity, decreased serum soluble E-selectin levels and induced potentially antiatherogenic changes in lipids and lipoproteins. In contrast to these beneficial effects, oral estradiol changed markers of coagulation towards hypercoagulability, and increased serum CRP concentrations. Transdermal estradiol or placebo had no effects on any of these parameters. These data demonstrate that oral estradiol does not have uniformly beneficial effects on cardiovascular risk markers and that the oral route of estradiol administration rather than the circulating free estradiol concentration is critical for any changes to be observed.

Administration, Cutaneous↗

PubMed2001

Coagulation factor VII in middle-aged women with and without coronary heart disease.

Epidemiological studies of coagulation factor VII as a risk factor for coronary heart disease (CHD), mainly conducted in men, have shown discrepant results. We examined the associations of coagulation factor VII antigen (VIIag) and activated factor VII (VIIa) with manifest CHD in a community-based case-control study of women aged < or =65 years. Mean plasma concentrations of VIIag and VIIa in patients and controls were 443 +/- 10(8) and 418 +/- 89 ng/L (p <0.01) and 5.26 +/- 2.21 and 4.90 +/- 1.65 ng/L (NS), respectively. The odds ratio (OR) for CHD for the highest versus the lowest quartile of VIIag was 1.75 (95% CI, 1.05 to 2.92). The adjusted OR was 0.76 (95% CI, 0.28-1.98) after controlling for other cardiovascular risk factors. The corresponding ORs for VIIa were non-significant. In conclusion, the plasma concentration of VIIa was not significantly increased in a large group of women with precocious CHD, and VIIag levels, although elevated, were not independently associated with manifest disease.

Case-Control Studies↗

PubMed2000

Allele-specific regulation of matrix metalloproteinase-12 gene activity is associated with coronary artery luminal dimensions in diabetic patients with manifest coronary artery disease.

Both the processes of atherosclerosis and plaque rupture are indicated to be influenced by matrix metalloproteinase (MMP) activity. We therefore searched for common functional variation in the matrix metalloelastase (MMP-12) gene locus that may be implicated in coronary artery disease. Single-strand conformation polymorphism analysis of DNA from healthy individuals detected a common polymorphism within the MMP-12 gene promoter (an A-to-G substitution at position -82). The frequency of the G allele was 0. 19. The polymorphism influences the binding of the transcription factor activator protein-1 (AP-1) in electromobility shift assay. A higher binding affinity of AP-1 to the A allele was associated with higher MMP-12 promoter activity in vitro in transient transfection studies in U937 and murine lung macrophage (MALU) cells. Phorbol 12-myristate 13-acetate (PMA) and insulin, 2 known activators of AP-1, increased the binding of AP-1 to the MMP-12 promoter, with higher affinity for the A allele. In transfection experiments, both the A and the G alleles responded to insulin and PMA, the A allele showing higher promoter activity than the G allele. Furthermore, Western blot analysis demonstrated that insulin increased MMP-12 protein production. To analyze whether the -82 A/G polymorphism is associated with coronary artery disease, 367 consecutive patients who underwent percutaneous transluminal coronary angiography with stent implantation were genotyped. In patients (n=71) with diabetes, the A allele was associated with a smaller luminal diameter. In conclusion, a common functional polymorphism within the MMP-12 promoter influences coronary artery luminal dimensions in diabetic patients with manifest coronary artery disease.

Adult↗

PubMed2000

Haemostatic function in patients undergoing coronary artery bypass grafting: peroperative perturbations and relations to saphenous vein graft closure.

Vein graft failure remains a major problem after coronary artery bypass grafting. Occlusion in the first weeks usually is caused by thrombosis, whereas intimal hyperplasia and eventually atherosclerotic changes with superimposed thrombus formation underlie subsequent closure. The present investigation was conducted as a pilot study to examine whether perturbations of haemostatic function predispose to early saphenous vein graft occlusion after coronary artery bypass grafting. Pre- and postoperative determinations (performed on the first, third, and sixth postoperative days) of haemostatic factors and inhibitors were related to the presence of graft occlusion assessed by angiography at 3 months after surgery in 100 men undergoing elective coronary artery bypass grafting for stable angina pectoris. Occlusion of one or more vein grafts within three months of surgery occurred in 23 of the 100 patients examined. The percentage increase in plasma plasminogen activator inhibitor-1 activity on the first postoperative day was significantly higher in patients who subsequently were found to have vein graft occlusion (p<0.05). Otherwise no postoperative haemostatic measurements were found to predict early vein graft closure. A perturbed plasma plasminogen activator inhibitor-1 response to coronary artery bypass grafting tentatively could be added to the vessel-specific factors that remain the main determinants of early vein graft closure.

Adult↗

PubMed2000

Serum insulin-like growth factor-I level is independently associated with coronary artery disease progression in young male survivors of myocardial infarction: beneficial effects of bezafibrate treatment.

OBJECTIVES: We investigated whether the effect of bezafibrate on progression of coronary atherosclerosis in the BEzafibrate Coronary Atherosclerosis Intervention Trial (BECAIT) was related to insulin-like growth factor (IGF)-I and glucose-insulin homeostasis. BACKGROUND: BECAIT, the first double-blind, placebo-controlled, randomized, serial angiographic trial of a fibrate compound, demonstrated that progression of focal coronary atherosclerosis in young patients after infarction could be retarded by bezafibrate treatment. METHODS: The treatment effects on serum concentrations of IGF-I and insulin-like growth factor binding protein (IGFBP)-1, as well as on basal and postload glucose and insulin levels, were examined, and on-trial determinations were related to the angiographic outcome measurements. RESULTS: Bezafibrate treatment resulted in a significant reduction of serum IGF-I levels, both at two and five years, and on-trial serum IGF-I levels were directly related to changes in both minimal lumen diameter (r = 0.25, p < 0.05) and mean segment diameter (r = 0.29, p < 0.05). In contrast, none of the available indexes of insulin resistance (homeostasis model assessment estimate, basal and postload plasma insulin concentrations and serum IGFBP-1 levels) were related to the angiographic changes, nor were they significantly affected by bezafibrate treatment. Multiple stepwise regression analysis showed that the relation between on-trial serum IGF-I level and coronary artery disease (CAD) progression was independent of baseline angiographic score, age, body mass index, serum lipoprotein and plasma fibrinogen concentrations and measures of glucose-insulin homeostasis. CONCLUSIONS: IGF-I could be implicated in the progression of premature CAD, and a reduction of serum IGF-I concentration could account partly for the effect of bezafibrate on progression of focal coronary atherosclerosis.

Adult↗

PubMed2000

Accumulation of apolipoprotein C-I-rich and cholesterol-rich VLDL remnants during exaggerated postprandial triglyceridemia in normolipidemic patients with coronary artery disease.

BACKGROUND: Exaggerated postprandial triglyceridemia is common in normolipidemic patients with coronary artery disease (CAD). Alterations in the composition of triglyceride-rich lipoproteins (TRLs) are likely to underlie this metabolic disturbance. However, the composition of very-low-density lipoproteins (VLDLs), which are the most abundant postprandial TRLs, has never been defined in CAD patients. METHODS AND RESULTS: We examined postprandial changes in the number and composition of VLDLs in middle-aged, normolipidemic CAD patients and control subjects. TRLs from 14 patients and 14 control subjects aged 45 to 55 years were subfractionated by density gradient ultracentrifugation into Svedberg flotation rate (Sf) fractions >400, 60 to 400, and 20 to 60. The VLDLs were separated from chylomicron remnants by immunoaffinity chromatography. In CAD patients, the postprandial concentrations of triglycerides and large (Sf 60 to 400) VLDL particles were elevated. In addition, their postprandial large VLDLs were enriched in apolipoprotein (apo) C-I and their postprandial small (Sf 20 to 60) VLDL remnants were enriched with apo C-I and cholesterol. CONCLUSIONS: Perturbed handling of postprandial triglycerides in normolipidemic CAD patients involves the accumulation of apo C-I-rich large VLDL particles and the generation of small, apo C-I- and cholesterol-rich VLDL remnants.

Apolipoprotein B-100↗

PubMed2000

Insulin and non-esterified fatty acid relations to alimentary lipaemia and plasma concentrations of postprandial triglyceride-rich lipoproteins in healthy middle-aged men.

AIMS/HYPOTHESIS: Enhanced and prolonged postprandial lipaemia is related to cardiovascular disease but how postprandial lipaemia is regulated is poorly known. We therefore determined the relations of fasting insulin concentrations to fasting and postprandial lipids, lipoproteins and non-esterified fatty acids in middle-aged men. METHODS: The subjects, 99 healthy 50-year-old men with an apolipoprotein E3/3 genotype, ate a mixed meal. The apolipoprotein B-48 and B-100 contents were determined in triglyceride-rich lipoproteins as a measure of chylomicron remnant and very low density lipoprotein particle concentrations. RESULTS: Fasting plasma insulin was associated with the triglyceride response to the test meal, independently of body mass index, waist-to-hip circumference ratio, blood glucose and the insulin effect on fasting plasma triglycerides. Exaggerated and prolonged postprandial lipaemia in subjects in the upper quartile of the plasma insulin distribution was largely accounted for by large (Svedberg flotation rate > 60) very low density lipoproteins and chylomicron remnants. Insulin relations to large postprandial triglyceride-rich lipoproteins exclusively reflected the association between plasma insulin and the fasting plasma concentrations of these lipoprotein species, whereas plasma insulin and late postprandial plasma concentrations of small (Svedberg flotation rate 20-60) chylomicron remnants were related, independently of insulin influences on fasting concentrations. Strong positive relations were found between the late increases in large triglyceride-rich lipoproteins and plasma non-esterified fatty acid concentrations after 6 h. CONCLUSION/INTERPRETATION: The degree of insulin sensitivity is a major determinant of postprandial lipaemia in healthy middle-aged men and could add to the regulation of the basal production of large triglyceride-rich lipoproteins.

Analysis of Variance↗

PubMed2000

The Q/E27 polymorphism in the beta2-adrenoceptor gene is associated with increased body weight and dyslipoproteinaemia involving triglyceride-rich lipoproteins.

OBJECTIVES: To investigate whether a substitution of glutamine by glutamic acid at amino acid position 27 (Q/E27) and an arginine to glycine transition at amino acid 16 (R/G16) in the beta2-adrenoceptor gene are associated with lipid and lipoprotein disturbances and/or increased body weight in men. DESIGN: Population-based study. SETTING: Department of medicine at a university hospital. SUBJECTS: A total of 180 healthy men, aged 30-45 years, were recruited at random from a register containing all permanent residents in Stockholm County (response rate of 70%). MAIN OUTCOME MEASURES: Frequency of beta2-adrenoceptor genotypes and alleles in relation to plasma lipid and lipoprotein levels and body mass index. RESULTS: Individuals carrying the E27 allele and/or the G16 allele had significantly higher body mass index (BMI). Furthermore, carriers of the E27 allele had significantly higher plasma concentrations of cholesterol, triglycerides, VLDL cholesterol and VLDL triglycerides than did subjects homozygous for the Q allele. CONCLUSION: The E27 allele of the beta2-adrenoceptor gene is associated with slightly to moderately elevated BMI and dyslipoproteinaemia involving triglyceride-rich lipoproteins in healthy younger and middle-aged men.

Adult↗

PubMed2000

Genetic diversity in the matrix metalloproteinase family. Effects on function and disease progression.

Atherosclerosis is an example of a complex trait, where the course of the disease is influenced by a combination of common variation in a constellation of genes and the effect of a wide range of environmental variables. Thus, the underlying disease mechanisms will be modulated by genetic diversity and the effect this diversity has on an individual's response to environmental challenges such as smoking, diet, and exercise. Unlike the consequences of mutations in severe single-gene disorders on protein function, the impact of individual common, functionally important sequence changes in genes contributing to multifactorial diseases is likely to be very small. The challenge is to dissect the contribution that each of these genes makes to the disease process. We have tackled this by identifying common genetic variants, studying their effects on function, and applying them to the analysis of association in appropriately structured and suitably powered studies. Even with our incomplete understanding of the disease, the list of potential candidate genes we could study is vast; but, we do know from pathological studies that a wide spectrum of structural architecture exists in atherosclerotic plaques, suggesting that remodeling of vascular connective tissue is fundamentally important. Matrix remodeling is controlled by a complex network of cell and matrix interactions, the net outcome of which is the product of a balance between synthetic and degradative processes. Our work has focused on the family of enzymes and inhibitors most directly associated with matrix turnover--the matrix metalloproteinases (MMPs) and their natural inhibitors (TIMPs, tissue inhibitors of MPs). We specifically searched for functionally relevant genetic variants that might modulate the delicate control of matrix turnover. Using these molecular genetic strategies to investigate the impact of natural genetic variation on vascular matrix remodeling has begun to shed new light on the importance of these genes in atherogenesis.

Arteriosclerosis↗

PubMed2000

Functional characterization of 4 polymorphisms in promoter region of hepatic lipase gene.

Hepatic lipase (HL) is a lipolytic enzyme involved in the metabolism of plasma lipoproteins, especially high density lipoproteins. Association studies have provided strong evidence for relations of common mutations in the promoter region of the HL gene to postheparin plasma HL activity and the plasma high density lipoprotein cholesterol concentration, but the functional relevance of these polymorphisms has not been evaluated to date. We analyzed the physiological significance of 4 common polymorphisms (-250G/A, -514C/T, -710T/C, and -763A/G, all in strong linkage disequilibrium) in the promoter of the HL gene by use of electrophoretic mobility shift assays and transient transfection studies in HepG2 cells. No consistent evidence was found for a significant contribution of any of these polymorphisms to the basal rate of transcription of the HL gene. These data suggest that the 4 polymorphisms in the promoter region of the HL gene are in linkage disequilibrium with >/=1 as-yet-unknown functional polymorphisms in the HL gene locus with a significant effect on HL metabolism and/or enzymatic activity.

Adult↗