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Genotype and phenotype of salt-stimulated paraoxonase 1 (PON1) is associated with atherogenic indices in type 2 diabetes.

ABSTRACT: Background:Paraoxonase 1 (PON1) and lipid abnormalities contribute to the development of cardiovascular disease, which is the principal cause of mortality in patients with type 2 diabetes (T2D). Data are not available on the potential association between salt-stimulated activity of PON1 (PON1-salt) and the atherogenic indices in T2D, therefore, we focused on these associations and evaluated whether the functional variants PON1-Q192R and PON1-L55M influence the associations. Methods:Paraoxonase activity (PON1-para), arylesterase activity (PON1-aryl) and salt-stimulated activity (PON1-salt) were measured by spectrophotometric assays. The atherogenic index of plasma (AIP) was calculated from the log (TG/HDL-C). The genetic analyses were made by the restricted fragment length polymorphism after PCR amplification. Results:We observed that PON1-salt was negatively correlated with total cholesterol (TC)/HDL-C (r?=?-0.441,p?=?0.006), LDL-C/HDL-C (r?=?-0.415, p?=?0.011), and AIP (r?=?-0.422, p?=?0.009). Correlations between PON1-salt and all three atherogenic indices were significantly affected by PON1-L55M and PON1-Q192R. Linear regression showed that AIP (p?=?0.002), LDL-C/HDL-C (p?=?0.005), and TC/HDL-C (p?=?0.002) were independently associated with PON1-salt. Based on Ridge regression, the standardized coefficients -0.358, -0.297, and?-?0.044 were obtained for AIP, LDL-C/HDL-C, and TC/HDL-C, respectively, and this shows that AIP could have more negative effect on PON1-salt than the others. Conclusions:The decreased PON1-salt may be considered as a risk factor for atherosclerosis in T2D, therefore, understanding the associations between PON1-salt as an important although neglected property and atherogenic indices may be valuable in T2D. Accordingly, detection of PON1-salt status (phenotype and genotype) together with the atherogenic indices particularly AIP could be beneficial in identifying the increased atherogenicity in T2D.

SUBMITTER: Qujeq D

PROVIDER: S-EPMC6154515 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Genotype and phenotype of salt-stimulated paraoxonase 1 (PON1) is associated with atherogenic indices in type 2 diabetes.

Qujeq Durdi D Mahrooz Abdolkarim A Mahrooz Abdolkarim A Alizadeh Ahad A Masoumi Parisa P Annemohammadzadeh Saleh S Boorank Ruzbeh R

Journal of diabetes and metabolic disorders 20180326 1

<h4>Background</h4>Paraoxonase 1 (PON1) and lipid abnormalities contribute to the development of cardiovascular disease, which is the principal cause of mortality in patients with type 2 diabetes (T2D). Data are not available on the potential association between salt-stimulated activity of PON1 (PON1-salt) and the atherogenic indices in T2D, therefore, we focused on these associations and evaluated whether the functional variants PON1-Q192R and PON1-L55M influence the associations.<h4>Methods</h ...[more]

PMID: 30288380

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Project description:Atorvastatin ?-lactone, a major, pharmacologically inactive metabolite, has been associated with toxicity. In a previous study we showed that polymorphisms of UGT1A3 influence atorvastatin ?-lactone formation. Here we investigated the reverse reaction, atorvastatin ?-lactone hydrolysis, in a human liver bank. Screening of microarray data revealed paraoxonases PON1 and PON3 among 17 candidate esterases. Microsomal ?-lactone hydrolysis was significantly correlated to PON1 and PON3 protein (r(s)?=?0.60; r(s)?=?0.62, respectively; P?<?0.0001). PON1 and PON3 were strongly correlated to each other (r(s)?=?0.60) but PON1 was shown to be more extensively glycosylated than PON3. In addition a novel splice-variant of PON3 was identified. Genotyping of 40 polymorphisms within the PON-locus identified PON1 promoter polymorphisms (-108T?>?C, -832G?>?A, -1741G?>?A) and a tightly linked group of PON3 polymorphisms (-4984A?>?G, -4105G?>?A, -1091A?>?G, -746C?>?T, and F21F) to be associated with changes in atorvastatin ?-lactone hydrolysis and expression of PON1 but not PON3. However, carriers of the common PON1 polymorphisms L55M or Q192R showed no difference in ?-lactone hydrolysis or PON expression. Haplotype analysis revealed decreased ?-lactone hydrolysis in carriers of the most common haplotype *1 compared to carriers of haplotypes *2, *3, *4, and *7. Analysis of non-genetic factors showed association of hepatocellular and cholangiocellular carcinoma with decreased PON1 and PON3 expression, respectively. Increased C-reactive protein and ?-glutamyl transferase levels were associated with decreased protein expression of both enzymes, and increased bilirubin levels, cholestasis, and presurgical exposure to omeprazole or pantoprazole were related to decreased PON3 protein. In conclusion, PON-locus polymorphisms affect PON1 expression whereas non-genetic factors have an effect on PON1 and PON3 expression. This may influence response to therapy or adverse events in statin treatment.

Dataset Information

Genotype and phenotype of salt-stimulated paraoxonase 1 (PON1) is associated with atherogenic indices in type 2 diabetes.

Publications

Genotype and phenotype of salt-stimulated paraoxonase 1 (PON1) is associated with atherogenic indices in type 2 diabetes.

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