Cholesteryl ester transfer protein TaqIB polymorphism and its relation to parameters of the insulin resistance syndrome in an Austrian cohort.

The cholesteryl ester transfer protein (CETP) is responsible for the exchange of triglycerides and cholesteryl esters between lipoprotein particles leading to an increased hepatic clearance of HDL-cholesteryl esters. A high CETP activity reduces serum HDL levels, whereas persons without CETP activity have high HDL levels. We investigated the association of the TaqIB CETP polymorphism and various parameters of the insulin resistance syndrome in a cross sectional population based study. We included 1029 persons without known cardiovascular disease or diabetes mellitus consecutively enrolled in our SAPHIR program (Salzburg Atherosclerosis Prevention program in persons with a High Infarction Risk). Numerous clinical and laboratory data were accomplished. Insulin sensitivity was measured by a short insulin tolerance test. The TaqIB CETP polymorphism was determined by PCR, TaqI restriction and electrophoresis. 35.2% were homozygous for the prevalence (B1B1), 46.7% were heterozygous (B1B2), and 18.1% homozygous for the absence (B2B2) of the restriction site. HDL cholesterol and apolipoprotein A1 were lower and small dense low-density lipoproteins (sdLDL) higher in B1B1 compared to B2B1 and B2B2 persons. In women, we found a significant interaction effect between CETP genotype and adiposity for HDL cholesterol. B1B1 women with a BMI and a waist circumference above the median had 9.7 mg/dl lower HDL than B1B2 and 9.1 mg/dl lower HDL than B2B2 women (P < 0.001). In men, no interaction effect but a marked genotype to HDL correlation was found. There was a high CETP effect on sdLDL detected in men (P = 0.001). B1B1 men had sdLDL in 36%, B1B2 in 24.6%, and B2B2 in only 14.5%. Men with adiposity and insulin resistance had twice as many sdLDL as insulin sensitive men. We found a significant sex specific effect of the TaqIB CETP polymorphism on the insulin resistance parameters HDL-cholesterol and sdLDL in an Austrian population based study.

Lack of association of the Glu298Asp polymorphism of endothelial nitric oxide synthase with manifest coronary artery disease, carotid atherosclerosis and forearm vascular reactivity in two Austrian populations.

OBJECTIVE: Conflicting data exists about the possible contribution of the homozygous Asp/Asp genotype of the Glu298Asp polymorphism of endothelial nitric oxide synthase to human atherosclerotic vascular disease. We investigated the polymorphism in two independent study populations: a case-control study including patients with angiographically verified coronary artery disease (CAD) on the one hand and a cross-sectional epidemiological study on the other hand. METHODS: The Glu298Asp polymorphism was determined by PCR-RFLP as established. In the case-control study (240 patients and 248 controls) a possible association between the polymorphism and CAD, and age of onset of CAD and myocardial infarction was investigated. In the cross-sectional epidemiological study (932 subjects) intima-media thickness (IMT) of the carotid artery as well as morphological plaque burden and forearm vascular reactivity (peak postischemic reactive hyperaemia, determined by venous occlusion plethysmography) were measured. RESULTS: In the case-control study genotype distribution (Glu/Glu; Glu/Asp; Asp/Asp) was not different between the CAD patients (43/46/11%) and the controls (49/41/10%, P = NS). No association of the polymorphism with age of onset of CAD or myocardial infarction was found. In the epidemiological study no influence of the genetic variant on IMT was observed after correction for classical determinants of IMT (average IMT: Asp/ Asp: 0.077 +/- 0.011 mm; Glu/Glu and Glu/Asp: 0.080 +/- 0.012 mm, P = NS). Forearm vascular reactivity was also not different between homozygous Asp/Asp subjects and Glu/Glu and Glu/Asp subjects (peak-reactive hyperaemia 20.1 +/- 7.3 mL min-1 100 mL-1 vs. 20.0 +/- 6.5 mL min-1 100 mL-1, P = NS). CONCLUSIONS: Our results suggest that there is no association of the Glu298Asp polymorphism with coronary or carotid atherosclerosis or forearm vascular reactivity in these populations recruited in a country with a rather high risk for atherosclerosis. We suggest additional investigations to be performed in populations at different risk for coronary events to further elucidate the possible contribution of this polymorphism to vascular disease.

The angiotensin-converting-enzyme insertion/deletion polymorphism is not a risk factor for peripheral arterial disease.

BACKGROUND: An insertion/deletion (I/D) polymorphism of the gene for angiotensin-converting-enzyme (ACE) is associated with ACE plasma levels and activity. Conflicting results have been reported about the relevance of this polymorphism for atherosclerotic vascular disease. The aim of the present study was to analyze the role of this polymorphism for peripheral arterial disease (PAD). METHODS: The study was designed as a case-control study including 522 patients with documented PAD and 522 sex- and age-matched controls. ACE genotype was determined by size-analysis of polymerase chain reaction products. RESULTS: ACE genotype frequencies were similar between patients (II: 23.4%; ID: 44.8%; DD: 31.8%) and controls (II: 23.8%; ID: 48.3%; DD: 27.9%, P=0.37). The adjusted odds ratio of carriers of the DD genotype for PAD was 1.29 (95% confidence interval 0.95-1.75). The polymorphism was furthermore not associated with age at onset of PAD (P=0.56), Fontaine stage of the disease (P=0.68) or ankle/brachial index of patients (P=0.86). CONCLUSION: The ACE I/D polymorphism is not a significant risk factor for PAD.

Insulin sensitivity is impaired in heterozygous carriers of lipoprotein lipase deficiency.

AIMS/HYPOTHESIS: Several studies have investigated the lipoprotein phenotype in heterozygous carriers of a defective lipoprotein lipase allele. We studied whether heterozygosity for lipoprotein lipase deficiency also affects glucose metabolism beyond its effect on plasma lipids. METHODS: To address this question 85 heterozygous carriers of either a missense mutation (Gly188Glu) or a splice site mutation (C-->A in position -3 at the acceptor splice site of intron 6) in the LPL gene which both result in a catalytically inactive product were compared with 108 unaffected subjects from the same families. RESULTS: Carriers for one of these mutations had higher fasting insulin levels but only a trend towards increased fasting blood glucose concentrations could be detected. HOMA index values were significantly higher in carriers than in non-carriers. Furthermore, in carriers, a significantly higher BMI and a trend towards higher systolic and diastolic blood pressure were observed. Carriers also had significantly higher fasting triglycerides, lower HDL cholesterol, and lipoprotein lipase particles of smaller size, confirming previous reports. Among carriers, subjects with one rare allele of the SstI polymorphism in the apo CIII gene had significantly higher plasma triglyceride levels than those with two common SstI alleles. This difference could not be observed in non-carriers of a mutant lipoprotein-lipase allele. The mean intima media thickness of the carotid arteries was slightly, but not significantly higher in carriers when compared with non-carriers. CONCLUSION/INTERPRETATION: This study shows that carrier status of one defective lipoprotein-lipase allele is associated with impaired insulin sensitivity, an atherogenic lipoprotein profile and other characteristics of the metabolic syndrome, which are risk factors for atherosclerotic vascular disease. A higher incidence of atherosclerotic vascular disease, however, could not be firmly established in carriers of this study population.

Influence of obesity and insulin sensitivity on phospholipid transfer protein activity.

AIMS/HYPOTHESIS: Phospholipid transfer protein plays a key role in lipoprotein metabolism by catalysing the transfer of phospholipids from triglyceride-rich lipoproteins to high-density lipoproteins and, also, within the high-density lipoprotein family, from particle to particle. This transfer results in a change of HDL particle size and the generation of pre-beta-high-density lipoproteins which function as initial lipid acceptors in the process of reverse cholesterol transport. Because adipose tissue is a source of phospholipid transfer protein we investigated the influence of obesity and insulin sensitivity on phospholipid transfer protein activity. METHODS: Using an exogenous substrate assay phospholipid transfer protein activity was measured in plasma specimens of 190 normolipidaemic, non-diabetic subjects with BMI ranging from 19 to 43 kg/m2. Insulin sensitivity was measured by the short insulin tolerance test. RESULTS: Phospholipid transfer protein activity was associated with BMI (r = 0.46, p < 0.01), body fat mass (r = 0.39, p < 0.01), subcutaneous fat area (r = 0.32, p < 0.01) and plasma leptin concentration (r = 0.24, p < 0.01) but not with insulin sensitivity expressed as the k(s) of the insulin tolerance test (kITT value) (r = -0.14, p = 0.40). Accordingly, phospholipid transfer protein activity was higher in obese than in nonobese subjects. As determined by linear regression analysis, BMI was the sole predictor of phospholipid transfer protein activity in plasma explaining 22.2% of the activity (p< 0.01). CONCLUSIONS/INTERPRETATIONS: This data suggests that increased phospholipid transfer protein activity in obese subjects is a consequence of obesity itself without the contribution of insulin resistance and can be explained by increased synthesis of phospholipid transfer protein from the enlarged mass of adipose tissue.