van Himbergen TM


Full name : van Himbergen Thomas M

First name : Thomas M

Mail : Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht

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Country : The Netherlands

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References (8)

Title : Paraoxonase (PON1) and the risk for coronary heart disease and myocardial infarction in a general population of Dutch women - van Himbergen_2008_Atherosclerosis_199_408
Author(s) : van Himbergen TM , van der Schouw YT , Voorbij HA , van Tits LJ , Stalenhoef AF , Peeters PH , Roest M
Ref : Atherosclerosis , 199 :408 , 2008
Abstract : There is strong evidence from both animal- and in vitro-models that paraoxonase (PON1) is involved in the onset of cardiovascular disease. In humans there is no consensus on this issue and therefore we investigated the effect of PON1 genotype and activity on the incidence of coronary heart disease (CHD) and acute myocardial infarction (AMI) in a large prospective cohort of 17,357 middle-aged women. We applied a case-cohort design using the CHD (n=211) and AMI cases (n=71) and a random sample from the baseline cohort (n=1527). A weighted Cox proportional hazards model was used to estimate age- and multivariate-adjusted hazard ratios (HR) for the PON1 genetic variants (192Q > R and -107C > T) and tertiles of the PON1 arylesterase- and paraoxonase activities. Neither the PON1 genetic variants, nor the PON1 activities affected the incidence of CHD in general, but, an increased paraoxonase activity was associated with a higher risk of AMI: the second and third tertile HR were 1.31 and 2.07, respectively (P-trend=0.029, multivariate model). In the subgroup of never-smokers, paraoxonase activity was associated with an increased risk for AMI: the second and third tertile HR were 4.1 and 4.7, respectively (P-trend=0.009, multivariate model). Additionally, when compared to the lowest paraoxonase tertile in never-smokers, the highest paraoxonase tertile in current-smokers showed a 19.2-fold higher risk for AMI (95%CI: 5.3-69.5, P < 0.0001, multivariate model). In conclusion, this study shows that in middle-aged women paraoxonase activity was associated with an increased risk for AMI and that the risk was modified by the effects of smoking.
ESTHER : van Himbergen_2008_Atherosclerosis_199_408
PubMedSearch : van Himbergen_2008_Atherosclerosis_199_408
PubMedID: 18164014

Title : Paraoxonase (PON1) is associated with familial combined hyperlipidemia - van Himbergen_2008_Atherosclerosis_199_87
Author(s) : van Himbergen TM , van Tits LJ , Ter Avest E , Roest M , Voorbij HA , de Graaf J , Stalenhoef AF
Ref : Atherosclerosis , 199 :87 , 2008
Abstract : Familial combined hyperlipidemia (FCH) is a common genetic lipid disorder of which the molecular basis still remains to be elucidated. Since the HDL-associated enzyme serum paraoxonase (PON1) is associated with variation in serum lipids and lipoproteins, we determined whether variation in PON1 also contributes to the FCH phenotype. The study population consisted of 32 well-defined families with FCH, including 103 FCH patients and 240 normolipidemic relatives (NLR). In addition to plasma lipids and lipoproteins we determined PON1 activity (arylesterase- and paraoxonase activity) as well as the common genetic variants -107C>T, 55L>M and 192Q>R in the PON1 gene. The arylesterase activity was significantly higher in FCH patients when compared to NLR (P<0.001). In the total population, the PON1 genetic variants associated with the highest arylesterase activity (-107CC and 55LL) also associated with higher levels of total cholesterol, apolipoprotein B, triglycerides and VLDL-cholesterol and decreased levels of HDL-cholesterol. In support, the combination of the -107CC with the 55LL genotype associated with a significant increased risk for FCH when compared to the -107TT/55MM genotype (odds ratio 5.0 (95% CI, 1.3-19.1, P=0.02)). In conclusion, in this population of subjects from well-defined families with FCH, PON1 is biochemically and genetically associated with FCH.
ESTHER : van Himbergen_2008_Atherosclerosis_199_87
PubMedSearch : van Himbergen_2008_Atherosclerosis_199_87
PubMedID: 18096166

Title : Genetic and environmental determinants of the PON-1 phenotype - Roest_2007_Eur.J.Clin.Invest_37_187
Author(s) : Roest M , van Himbergen TM , Barendrecht AB , Peeters PH , van der Schouw YT , Voorbij HA
Ref : European Journal of Clinical Investigation , 37 :187 , 2007
Abstract : BACKGROUND: Paraoxonase (PON-1) is a high-density lipoprotein (HDL)-associated enzyme that may protect against cardiovascular disease (CVD), because it hydrolyses oxidized phospholipids of low-density lipoprotein (LDL) and therefore prevents the detrimental effects on the arterial wall. The current report describes the determinants of PON-1 bioavailability and activity. MATERIALS AND
METHODS: This is the largest (n = 1527) cross-sectional evaluation performed on PON-1 genotypes (Q192R, T-107C and L55M) and environmental determinants to PON-1 catalytic activity and bioavailability in serum of postmenopausal women. PON-1 catalytic activity and PON-1 bioavailability were measured, in vitro, with a paraoxon hydrolysis assay and a phenylacetate hydrolysis assay, respectively.
RESULTS: The major determinant of paraoxon hydrolytic activity is the Q192R genotype, but there was also a relation with the C-107T and L55M genotype, HDL levels and alcohol consumption. Phenylacetate hydrolytic activity was most strongly affected by the C-107T genotype followed by the L55M genotype, HDL levels, alcohol consumption and smoking.
CONCLUSIONS: PON-1 Q192R, C-107T and L55M genotype, alcohol consumption, smoking and HDL levels are determinants of serum PON-1 phenotype. The contributions of the genetic markers to the PON-1 phenotype are stronger than the contributions of the lifestyle determinants.
ESTHER : Roest_2007_Eur.J.Clin.Invest_37_187
PubMedSearch : Roest_2007_Eur.J.Clin.Invest_37_187
PubMedID: 17359486

Title : The story of PON1: how an organophosphate-hydrolysing enzyme is becoming a player in cardiovascular medicine - van Himbergen_2006_Neth.J.Med_64_34
Author(s) : van Himbergen TM , van Tits LJ , Roest M , Stalenhoef AF
Ref : Neth J Med , 64 :34 , 2006
Abstract : Since the discovery of human serum paraoxonase (PON1), the enzyme has been the subject of various fields of research. Initially, PON1 was identified as an enzyme capable of hydrolysing organophosphate compounds, but there is a growing body of evidence that PON1 plays a role in lipid metabolism and the onset of cardiovascular disease. Still, the precise mechanism by which PON1 functions in vivo remains to be clarified. Here we will briefly review developments in the field of PON1 research which merit further attention.
ESTHER : van Himbergen_2006_Neth.J.Med_64_34
PubMedSearch : van Himbergen_2006_Neth.J.Med_64_34
PubMedID: 16517986

Title : High-throughput genotyping with infrared fluorescence allele specific hybridization (iFLASH): a simple, reliable and low-cost alternative - van Himbergen_2006_Clin.Biochem_39_739
Author(s) : van Himbergen TM , Voorbij HA , Barendrecht AD , van Rijn BB , Brambilla R , van Tits LJ , Roest M
Ref : Clinical Biochemistry , 39 :739 , 2006
Abstract : OBJECTIVES: To develop and validate a novel genotyping approach, named infrared Fluorescence Allele Specific Hybridization (iFLASH), which combines the principles of allele specific oligonucleotide (ASO) hybridization with the advanced possibilities of infrared imaging. DESIGN AND
METHODS: As an example, we genotyped the 55L > M and the 192Q > R common genetic variants of the paraoxonase-1 gene in 92 DNA samples using the iFLASH technique, and validated the outcomes with the restriction fragment length polymorphism (RFLP) and TAQman genotyping assays.
RESULTS: There was a 100 percent agreement in genotype outcome among the three methods.
CONCLUSIONS: Although we found complete unity in genotype outcome, the iFLASH assay has essential advantages over the RFLP and TAQman genotyping assays. First, the iFLASH technique is capable of handling up to 1536 samples per assay, which makes it a suitable technique for high-throughput genotyping. Secondly, because the costs per assay are lower, high-throughput genotyping with iFLASH is affordable.
ESTHER : van Himbergen_2006_Clin.Biochem_39_739
PubMedSearch : van Himbergen_2006_Clin.Biochem_39_739
PubMedID: 16624270

Title : Proportion of oxidized LDL relative to plasma apolipoprotein B does not change during statin therapy in patients with heterozygous familial hypercholesterolemia - van Tits_2006_Atherosclerosis_185_307
Author(s) : van Tits LJ , van Himbergen TM , Lemmers HL , de Graaf J , Stalenhoef AF
Ref : Atherosclerosis , 185 :307 , 2006
Abstract : OBJECTIVE: Circulating oxidized low-density lipoprotein (LDL) has been shown to be a useful marker for identifying patients with coronary heart disease (CHD) and persons at high cardiovascular risk. The effect of cholesterol-lowering therapy on plasma level of oxidized LDL is not clear. METHODS AND
RESULTS: We investigated effects of cholesterol lowering by therapeutic intervention (2 years) with atorvastatin (80 mg daily) and simvastatin (40 mg daily) on circulating oxidized LDL (absolute level and in proportion to plasma apolipoprotein B) in relation to atherosclerosis progression (carotid intima-media thickness, carotid IMT) and to inflammation (high-sensitivity C-reactive protein, hsCRP) in 115 stable patients with heterozygous familial hypercholesterolemia (FH). Atorvastatin and simvastatin reduced plasma-oxidized LDL (-43 and -35%, respectively) in proportion to the decrease in plasma apolipoprotein B. Neither absolute nor relative level of oxidized LDL correlated with carotid IMT or hsCRP at baseline. Also changes in levels of circulating oxidized LDL were not related to changes in carotid IMT and hsCRP.
CONCLUSIONS: In familial hypercholesterolemia-oxidized LDL carried in plasma is strongly associated with apolipoprotein B but not with inflammation nor with carotid IMT, and statin treatment does not reduce oxidized LDL relative to apolipoprotein B.
ESTHER : van Tits_2006_Atherosclerosis_185_307
PubMedSearch : van Tits_2006_Atherosclerosis_185_307
PubMedID: 16005883

Title : Indications that paraoxonase-1 contributes to plasma high density lipoprotein levels in familial hypercholesterolemia - van Himbergen_2005_J.Lipid.Res_46_445
Author(s) : van Himbergen TM , Roest M , de Graaf J , Jansen EH , Hattori H , Kastelein JJ , Voorbij HA , Stalenhoef AF , van Tits LJ
Ref : J Lipid Res , 46 :445 , 2005
Abstract : HDL-associated paraoxonase type 1 (PON1) can protect LDL and HDL against oxidative modification in vitro and therefore may protect against cardiovascular disease. We investigated the effects of PON1 levels, activity, and genetic variation on high density lipoprotein-cholesterol (HDL-C) levels, circulating oxidized LDL (OxLDL), subclinical inflammation [high-sensitive C-reactive protein (Hs-CRP)], and carotid atherosclerosis. PON1 genotypes (L55M, Q192R, -107C/T, -162A/G, -824G/A, and -907G/C) were determined in 302 patients with familial hypercholesterolemia. PON1 activity was monitored by the hydrolysis rate of paraoxon, diazoxon, and phenyl acetate. PON1 levels, OxLDL, and Hs-CRP were determined using an immunoassay. The genetic variants of PON1 that were associated with high levels and activity of the enzyme were associated with higher HDL-C levels (P values for trend: 0.008, 0.020, 0.042, and 0.037 for L55M, Q192R, -107C/T, and -907G/C, respectively). In addition to the PON1 genotype, there was also a positive correlation between PON1 levels and activity and HDL-C (PON1 levels: r = 0.37, P < 0.001; paraoxonase activity: r = 0.23, P = 0.01; diazoxonase activity: r = 0.29, P < 0.001; arylesterase activity: r = 0.19, P = 0.03). Our observations support the hypothesis that both PON1 levels and activity preserve HDL-C in plasma.
ESTHER : van Himbergen_2005_J.Lipid.Res_46_445
PubMedSearch : van Himbergen_2005_J.Lipid.Res_46_445
PubMedID: 15576850

Title : Paraoxonase-1 and linoleic acid oxidation in familial hypercholesterolemia - van Himbergen_2005_Biochem.Biophys.Res.Commun_333_787
Author(s) : van Himbergen TM , van Tits LJ , Hectors MP , de Graaf J , Roest M , Stalenhoef AF
Ref : Biochemical & Biophysical Research Communications , 333 :787 , 2005
Abstract : Serum paraoxonase-1 (PON1) is a high-density lipoprotein-associated enzyme that can inhibit low-density lipoprotein (LDL) oxidation in vitro. The role of PON1 in vivo still remains to be clarified. We investigated the effect of PON1 genotype (-107C > T and 192Q > R), concentration, paraoxonase activity, and arylesterase activity on the early phase of lipid peroxidation in plasma samples of 110 patients with heterozygous familial hypercholesterolemia. The degree of lipid oxidation was assessed by quantitation of oxidized-linoleic acid (the most abundant fatty acid present in LDL) using high performance liquid chromatography. We found a significant inverse correlation between paraoxonase activity and the oxidized-linoleic acid concentration (r = -0.22, P = 0.03), independent of baseline linoleic acid levels. These findings support an anti-oxidative role for PON1 in patients with FH, and thus may give insight into the functioning of PON1 in vivo.
ESTHER : van Himbergen_2005_Biochem.Biophys.Res.Commun_333_787
PubMedSearch : van Himbergen_2005_Biochem.Biophys.Res.Commun_333_787
PubMedID: 15963464