Association between paraoxonase-1 gene polymorphisms

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Introduction

         Metabolic syndrome (MES) is a collective of cardiovascular risk factors, including hypertension, dyslipidemia, hyperglycemia, and abdominal obesity. Resulting from the term 'syndrome X' suggested as early as 1988 by Reaven, MES is found to predict development of type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD) in the future. In addition, MES has also been reported to be linked with elevated serum high-sensitive C-reactive protein (hsCRP), endothelial dysfunction increased carotid intimamedia thickness (IMT), and cardiovascular disorder and mortality. MES has been defined by International Diabetes Federation (IDF), American Heart Association and the National Heart, Lung, and Blood Institute (AHA/NHLBI), National Cholesterol Education Program Adult Treatment Panal III (NCEP-ATP III), and World Health Organization. Reports from different populations estimate the incidence of metabolic syndrome by each of the three definitions. 40% of US adults have MES by the IDF criteria, which is higher than the prevalence defined by the ATPIII criteria. IDF-defined MES is present in nearly half of the Greek population. Regarding ,Iran population epidemiological data on the prevalence of the metabolic syndrome are rare , most frequently used definitions for metabolic syndrome engage with different criteria for diagnosis of obesity ,therefore variation in the occurrence of metabolic syndrome seem to effect the prevalence of adiposity, the incidence of obesity has increased in the developing Countries such as Iran.

It is commonly accepted that efforts to develop the understanding of the genetic role to complex diseases of infancy will lead to enhancement in the diagnosis and prevention of such diseases. Many genes, including the human paraoxonase (PON) genes, have been implicated in development of complex disease such as Coronary heart disease. The paraoxonase gene family contains at least 3 members, including PON1, PON2 and PON3, which are located on chromosome 7q21.3-22.1. These genes share substantial structural homology and may have derived from the tandem replication of a common evolutionary precursor.

Human serum paraoxonase (PON1. EC 3.1.8.1.), a 43-kDa protein, catalyses the hydrolysis of organophosphate esters, aromatic carboxylic acid esters, and carbonates. PON1 is synthesized in the liver and is mainly related with high-density lipoprotein (HDL). The enzyme decreases gathering of the lipid peroxides in low density lipoprotein (LDL) due to its ability to reduce hydro peroxides.

PON1 activity in human sera shows enormous inter individual variation (40 fold) as a result of genetic and environmental factors, including environmental chemicals, pharmaceutical compounds, smoking, diet, alcohol, and certain pathological and physiological conditions Genetic factors include polymorphisms in the coding and promoter regions of the pon1 gene that might be influenced the PON1 expression and its catalytic activity. Three common polymorphisms have been identified within PON1 gene such as , Q192R glutamine to arginine substitution at position 192, L55M leucine to methionine substitution at position 55 and -108 C/T at promoter region which affect PON1 activity towards paraoxon, diazoxon, soman and sarin ,it is linked with coronary artery disease, stroke, familial hypercholesterolemia, type 2 diabetes and Parkinson's disease.Therfore, L55M and-108C>T polymorphisms can affect its protein activity and mRNA level , which might be concerned in stroke, coronary artery disease, Parkinson's disease, alteration in plasma total cholesterol and LDL cholesterol levels. The aims of this study were to seek the important role of Pon1 gene polymorphism in the genetic susceptibility to MES and assay the distribution of pon1 SNPs (Q192R, L55M and -108 C>T) in healthy individuals and patients with MES which diagnosed according to laboratory tests in a Southeast Iranian population.

Materials and methods

Subjects

The study included 140 and 180 healthy unrelated individuals and patients respectively. This study was performed from September 2008 to March 2009 in Zahedan, southeast, Iran. The study was approved by the local ethical committee of Zahedan University of Medical Sciences and consented form was obtained from all subjects. The following were collected by the investigators and a staff of medically trained volunteers, demographic data (date of birth, contact information, medical history, current medications, family history, length of residence in the Zahedan); height (by a stadiometer using a centimeter scale), weight (by a clinical scale); waist circumference (by a tape measure just upper the superior iliac crest with the subject standing, at the end of normal expiration); blood pressure (by a mercury sphygmomanometer with the subject sitting); and 5 ml of venous blood drained after 8-12 h fasting for laboratory tests. Blood samples were collected by venopuncture after overnight fasting. Blood collected in EDTA-coated tubes was used for determination of pon1 genotypes while sera were analyzed for Biochemical analysis (fasting blood glucose, triglyceride, HDL-cholestrol) was assayed using a commercially available kit. Collected samples were stored at -20 °C until analysis. Genomic DNA was isolated from EDTA-anticoagulated blood by a standard proteinase K digestion and phenol chloroform extraction method. The prevalence of metabolic syndrome among individuals was determined according to IDF criteria

Polymerase Chain Reaction (PCR)

Polymorphisms were determined by the polymerase chain reaction followed by the amplification refractory mutation system (ARMS) is a simple and rapid detection method of point mutation and small nucleotide insertion or deletion.

The current study, we used two tetra primer ARMS for the detection of Q192R and L55M polymorphism as previously described and designed two outer primers (forward and reverse primer) and two inner primers( forward and reverse) for detection variations in -108 C>T gene.

Statistical Analysis

The association between polymorphism in the Q 192R, L55M and -108C/T genes with the risk of Metabolic syndrome was estimated by computing odds ratio (OR) and 95% confidence intervals (95%CI), Categorical data were tested using Pearson's x2. Multivariate logistic regression models were used to estimate adjusted odds ratio (OR) and 95% confidence intervals (95% CI).. Statistical analysis was performed using SPSS version 10.0 (SPSS, Chicago, IL) and Epical version 3.2

Results:

One hundred forty MES individuals (age 44.9+15.1 years) and 183 controls (age 34.7+13.5 years) were successfully genotyped for the three PON1 polymorphisms. The corresponding genotype and allele frequencies differed widely according to cognitive status. They were in Hardy-Weinberg equilibrium.

Pon1 genotypes and alleles frequency were found to vary between different ethnic groups. When comparing Iranian population with other population such as European and Asian, it has higher frequency of M allele for L55M and C allele for-108C>T polymorphisms. In Asia Japanese population shows predominance of R192 over Q192 allele and a very low frequency of M55 allele.

Statistically, Significant association was found between patients with MES and RR genotype of PON1Q192R (OR=2; 95%CI, 1.17-3.40, P=0.001). Therefore, the combined QR+RR genotype of Q192R gene increased the risk of metabolic syndrome significantly [1.62; 95%CI, 1.0-2.63,p=0.05].

The risk in patients(MES) with MM and LM+MM genotypes of L54M gene was in marginal border (OR;1.33;95%CI,068-1.85;p=0.73 and OR;1.12;95%CI,0.68-1.85, P=0.73 respectively), In contrast, the CC genotype of 108C/T gene was linked with a not significantly increased risk of MES (OR;1.61;95%CI,0.67-3.87). In analysis of gene-gene interaction between Q192R and L55M genes, the magnitude of the association was greater with combined MM/RR genotypes [OR=3.3(1, 34-8.24),p=0.007]. Even though in some combined genotypes OR was elevated up to risk level, but, none of them had statistically significant association with MES incidence.

Discussion:

Paraoxonases (PONs) i.e. PON1, PON2, PON3 are basically lactonases. Of these, PON1 in addition has an efficient esterase activity and can hydrolyze organophosphates. The PONs prevent low density lipoprotein cholesterol (LDL-C) from peroxidation, PON1 is exclusively associated with high density lipoprotein cholesterol (HDL-C) and its antioxidant activity. Variations within PON1 gene independently influence PON1 activity and have been defined as the molecular basis for interindividual variability. These sites are designated as PON1 Q192R, L55M and -108 C>T which, the PON1 Q192R polymorphism appears to be the major determinant of the well known biochemical polymorphism in serum PON activity towards various organophosphates.

The frequencies of the PON1 alleles vary greatly across human populations. The distributions of two polymorphisms were significantly different between white and black women. The frequency of the PON1Met55 allele was higher in white than blacks, whereas the frequency of the PON1 Arg192 allele was reverse. The lowest frequency of the PON1 Met55 allele had ever been reported in Chinese, the relatively high frequency of the PON1 Arg192 allele in blacks is similar to that reported in Chinese and Japanese, varying from 58% to 65%. The frequency of Q192R allele in our study was 54.7% in cases and 68.40% in controls which close to previous report in Chinas and Japanese population. However, Ferre et al. have not found any significant differences in genotype and allele frequencies for PON1 polymorphisms at position 55 and 192 between healthy subjects and patients with myocardial infarction in Spanish population . The frequencies were similar to those described for other Caucasian populations. These discrepancies may be related to the effects caused by other genes as PON2 or to posttranslational modifications of the enzymes.

The results presented here for a case-control study indicate that carriers of the Arg allele at position 192 of PON1 or subjects with QR heterozygote for the promoter polymorphism are at risk of MES,this result is only suggestive of an impact of paraoxonase polymorphisms on the risk of MES. Investigation of gene-gene interaction between Q192R and L55M showed that the magnitude of the association was greater statistically with combined genotypes of MM/RR [OR=3.3(1,34-8.24),p=0.007],suggesting that they functioned in combined manner.

Certain reports suggesting a lack of association between paraoxonase polymorphism and AD or a protective effect of the ArgArg genotype in Alzheimer's disease (AD). Helbecque et al concluded that subjects with TT heterozygote (PON1 -108 C>T) simultaneously carrying an Arg allele are at higher risk of developing Eosinophilia-Myalgia Syndrome (EMS). McGeachie et al., (2009) reported a weak association of PON1 L55M with an increased risk of wet Age-Related Macular Degeneration (AMD), their findings indicated a protective role for Gln192Arg, mainly for patients with the wet form.

Sinha et al ., (2009) suggested that there is a strong significant correlation between RR genotype of PON1Q192R and patients with Cardiovascular disease in north of India.The PON1-HDL complex may play a role in the homeostasis of atherosclerosis and HIV infection. Paragh and his colleagues hypothesized that arylesterase activity of PON1 would help the formation of free-radical type arylamine derivates on the bladder epithelial surface, so that secondary metabolites of paraoxon or related chemicals and biotransformed intermediates of arylamines might be involved in formation of bladder carcinoma. Regarding kidney disease, there was no significant difference between patients and healthy groups in the frequency of PON1 polymorphisms (L55M and Q 192 R). From this viewpoint, paraoxonase is a good candidate gene for studying involved risk factors in MES development.

Conclusion, in the southeast Iranian population, PON1 (Q192R) genotypes is significantly associated with increased risk of MES. Therefore, it is possible that the relative importance of PON1 as a risk factor for MES here and other diseases might vary in other populations because other gene-gene and gene-environment combinations are present. Therefore, it seems that the PON1 genotypes studied here do not fully account for the variability in PON1 metabolic capacity. Further analyses with larger sample size in different populations are needed to be clarifying the role of PON1 in the risk of MES.

Acknowledgements: The authors thank the University of Sistan and Baluchistan-Zahedan, Iran, for financially supporting this project under grand 88G02. We are also thankful to Zahedan University of medical science, Zahedan Iran, for providing us the Clinical samples.

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