Promoter polymorphism T(-107)C of the paraoxonase PON1 gene is a risk factor for coronary heart disease in type 2 diabetic patients.

James, Richard; Leviev, Ilia; Ruiz, Juan Carlos; Passa, P; Froguel, Philippe; Garin, Marie-Claude Blatter

doi:10.2337/diabetes.49.8.1390

Cited by 131 publications

(85 citation statements)

References 20 publications

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“…This has been confirmed independently (8 -11), although not consistently (12,13). In subsequent studies we have shown that PON1 promoter polymorphisms, which affect promoter activity and serum PON1 concentrations (14), are also independent risk factors for coronary disease (15). This is consistent with gene expression being a determinant of the influence of PON1 on vascular disease.…”

Section: Paraoxonase-1 (Pon1)supporting

confidence: 70%

Enzymatically Active Paraoxonase-1 Is Located at the External Membrane of Producing Cells and Released by a High Affinity, Saturable, Desorption Mechanism

Deakin

Leviev

Gomaraschi

et al. 2002

Journal of Biological Chemistry

220

186

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Paraoxonase-1 (PON1) is a high density lipoprotein (HDL)-associated serum enzyme that protects low density lipoproteins from oxidative modifications. There is a relative lack of information on mechanisms implicated in PON1 release from cells. The present study focused on a model derived from stable transfection of CHO cells, to avoid co-secretion of apolipoprotein (apo) A-I and lipids, which could lead to formation of HDL-like complexes. Our results indicate that, in the absence of an appropriate acceptor, little PON1 is released. The results designate HDL as the predominant, physiological acceptor, whose efficiency is influenced by size and composition. Neither lipid-poor apoA-I or apoA-II nor low density lipoproteins could substitute for HDL. Protein-free phospholipid complexes promoted PON1 release. However, the presence of both apolipoprotein and phospholipid were necessary to promote release and stabilize the enzyme. Immunofluorescence studies demonstrated that PON1 was inserted into the external membrane of CHO cells, where it was enzymatically active. Accumulation of PON1 in the cell membrane was not influenced by the ability of the cell to co-secrete of apoA-I. Release appeared to involve desorption by HDL; human and reconstituted HDL promoted PON1 release in a saturable, high affinity manner (apparent affinity 1.59 ؎ 0.3 g of HDL protein/ml). Studies with PON1-transfected hepatocytes (HuH-7) revealed comparable structural features with the peptide located in a punctate pattern at the external membrane and enzymatically active. We hypothesize that release of PON1 involves a docking process whereby HDL transiently associate with the cell membrane and remove the peptide from the external membrane. The secretory process may be of importance for assuring the correct lipoprotein destination of PON1 and thus its functional efficiency. Paraoxonase-1 (PON1)1 is a high density lipoprotein (HDL)-associated serum enzyme that protects low density lipoproteins (LDL) from oxidative modifications. In vitro studies have demonstrated the capacity of PON1 to prevent LDL (and HDL) oxidation by a variety of pro-oxidant factors, including cellinduced LDL oxidation (1, 2). Complementary studies have shown that the anti-oxidant activity of PON1 prevents LDL from acquiring a number of pathological characteristics associated with the atherosclerotic process, notably monocyte mobilization and gene activation (3). The PON1 knockout mouse model confirmed that absence of serum PON1 activity increases the level of lipoprotein oxidation, renders LDL more susceptible to oxidation, decreases the anti-oxidant capacity of HDL and leads to more extensive atheroma formation (4, 5). In man, we first demonstrated that PON1 was an independent, genetic risk factor for coronary disease (6, 7). This has been confirmed independently (8 -11), although not consistently (12,13). In subsequent studies we have shown that PON1 promoter polymorphisms, which affect promoter activity and serum PON1 concentrations (14), are also independent risk factors for...

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Section: Paraoxonase-1 (Pon1)supporting

confidence: 70%

Enzymatically Active Paraoxonase-1 Is Located at the External Membrane of Producing Cells and Released by a High Affinity, Saturable, Desorption Mechanism

Deakin

Leviev

Gomaraschi

et al. 2002

Journal of Biological Chemistry

220

186

View full text Add to dashboard Cite

show abstract

“…Another possibility is that relatively reduced enzyme activity rather than increased absolute PON1 activity promotes vascular complications. Some have reported that a higher LDL cholesterol-to-PON concentration ratio may indicate a reduced capacity of the enzyme to limit LDL oxidation (22). The low-activity allele at the PON1 gene has also been associated with a less harmful lipoprotein profile (23).…”

Section: Discussionmentioning

confidence: 99%

Association Between p.Leu54Met Polymorphism at the Paraoxonase-1 Gene and Plantar Fascia Thickness in Young Subjects With Type 1 Diabetes

et al. 2008

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OBJECTIVE -In type 1 diabetes, plantar fascia, a collagen-rich tissue, is susceptible to glycation and oxidation. Paraoxonase-1 (PON1) is an HDL-bound antioxidant enzyme. PON1 polymorphisms have been associated with susceptibility to macro-and microvascular complications. We investigated the relationship between plantar fascia thickness (PFT) and PON1 gene variants, p.Leu54Met, p.Gln192Arg, and c.-107CϾT, in type 1 diabetes. RESEARCH DESIGN AND METHODS-This was a cross-sectional study of 331 adolescents with type 1 diabetes (162 male and 169 female). PFT was assessed by ultrasound, PON1 was assessed by genotyping with PCR and restriction fragment-length polymorphism, and serum PON1 activity was assessed by rates of hydrolysis of paraoxon and phenylacetate.RESULTS -Median (interquartile range) age was 15.4 (13.5-17.3) years, and diabetes duration was 7.6 (4.9 -10.6) years. The distribution of p.Leu54Met genotypes was LL 135 (40.8%), ML 149 (45%), and MM 47 (14.2%). PFT was abnormal (Ͼ1.7 mm) in 159 adolescents (48%). In multivariate analysis, predictors of abnormal PFT were ML/LL versus MM p. CONCLUSIONS -Thickening of the plantar aponeurosis occurs predominantly in overweight and male adolescents with type 1 diabetes. The MM genotype at PON1 p.Leu54Met is associated with a reduced risk of abnormal PFT.

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“…There may be linkage [32,34] or at least a complex interaction [36] between the 192 site and the 107 promoter polymorphism, which could confound the association between the R192 allele and paraoxonase activity in earlier studies.…”

Section: Activity Hdl and Apoa-1 According To Pon55 Genotypementioning

confidence: 97%

Paraoxonase activity and coronary heart disease risk in healthy middle-aged males: The PRIME study

et al. 2008

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Objective: Classic coronary heart disease (CHD) risk factors fail to explain the large gradient in CHD incidence between Northern Ireland and France. The Prospective Epidemiological Study of Myocardial Infarction (PRIME) study, a multicentre prospective study of 10,593 middle-aged males, investigated novel risk factors in these populations. We tested the hypotheses that (1) higher paraoxonase activity is associated with decreased CHD risk and (2) PON55 LL genotype is associated with increased CHD risk. Methods: Paraoxonase activity was measured in 299 men who had developed CHD at 5-year follow-up and in 576 matched controls. DNA was available from 247 cases and 433 controls for genotyping for the PON55 polymorphism. Results: There was no significant difference in paraoxonase activity between cases and controls (geometric means 73.8 and 74.2 U/l; p = 0.81). There was no significant difference in CHD risk between fifths of paraoxonase activity either before (p = 0.55) or after adjustment for classical risk factors (p = 0.58).There was no significant association between genotype and CHD risk; relative to the LL genotype, the OR (95% CI) for the LM and MM genotypes were 0.92 (0.66-1.29) and 0.83 (0.50-1.36), respectively. The frequency of the L allele in cases (66.6%) and controls (64.5%) did not differ significantly, p = 0.45. Conclusions: These findings suggest that neither paraoxonase activity nor PON55 genotype is associated with CHD risk in males in the PRIME study.

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Promoter polymorphism T(-107)C of the paraoxonase PON1 gene is a risk factor for coronary heart disease in type 2 diabetic patients.

Cited by 131 publications

References 20 publications

Enzymatically Active Paraoxonase-1 Is Located at the External Membrane of Producing Cells and Released by a High Affinity, Saturable, Desorption Mechanism

Enzymatically Active Paraoxonase-1 Is Located at the External Membrane of Producing Cells and Released by a High Affinity, Saturable, Desorption Mechanism

Association Between p.Leu54Met Polymorphism at the Paraoxonase-1 Gene and Plantar Fascia Thickness in Young Subjects With Type 1 Diabetes

Paraoxonase activity and coronary heart disease risk in healthy middle-aged males: The PRIME study

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