L55M Genotypes Research Articles

Role of PON1 L55M Gene Polymorphism in Parkinson's Disease among North Indian Population.

The role of various genetic markers including alpha synuclein, Parkin, etc., is known in the pathogenesis of Parkinson's disease (PD). Novel genetic markers including paraoxonase 1 (PON1) have also been linked to PD pathogenesis in recent studies. The PON1 L55M allele carriers may have defective clearance of environmental toxins and may result in increased susceptibility to PD. Hence, we studied the role of PON1 L55M polymorphism in PD among a North Indian population. Seventy-four PD patients and 74 age- and sex-matched controls were recruited in this hospital-based case-control study. Baseline characteristics were recorded using structured questionnaire. DNA was extracted from 3-4 ml of venous blood, followed by PCR and restriction digestion. PON1 L55M genotypes were visualized as bands: LL (177 bp), LM (177, 140 bp) and MM (140,44 bp) on 3% agarose gel. Mann-Whitney U test and Chi-squared test were used for comparing two groups of skewed and categorical variables, respectively. Measures of strength of association were calculated by binary regression analysis. P value < 0.05 was considered as significant. Parkinson's disease patients had significantly higher exposure to pesticides (12.2%; P (organophosphate exposure) < 0.001) and well water drinking (28.4%; P = 0.006) compared to controls. Frequency distribution of LL, LM, MM genotypes was 67.5% (50/74), 28.4% (21/74), and 4.1% (3/74), respectively, for cases and 72.6% (54/74), 26% (19/74) and 1.4% (1/74), respectively, for controls. PON1 L55M genotype distribution between Parkinson's disease cases and controls was not significant (P = 0.53). PON1 L55M polymorphism was not associated with PD after adjusting for confounders by binary regression analysis. There was no significant association between PON1 L55M polymorphism and PD. Larger population-based studies would be required from India before drawing any definite conclusions.

Organophosphate pesticides and PON1 L55M in Parkinson's disease progression

BackgroundParkinson's disease (PD) has motor and non-motor features that contribute to its phenotype and functional decline. Organophosphate (OP) pesticides and PON1 L55M, which influences OP metabolism, have been implicated in multiple mechanisms related to neuronal cell death and may influence PD symptom progression. ObjectiveTo investigate whether ambient agricultural OP exposure and PON1 L55M influence the rate of motor, cognitive, and mood-related symptom progression in PD. MethodsWe followed a longitudinal cohort of 246 incident PD patients on average over 5years (7.5years after diagnosis), repeatedly measuring symptom progression with the Mini-Mental State Exam (MMSE), Unified Parkinson's Disease Rating Scale (UPDRS), and Geriatric Depressive Scale (GDS). OP exposures were generated with a geographic information system (GIS) based exposure assessment tool. We employed repeated-measures regression to assess associations between OP exposure and/or PON1 L55M genotype and progression. ResultsHigh OP exposures were associated with faster progression of motor (UPDRS β=0.24, 95% CI=−0.01, 0.49) and cognitive scores (MMSE β=−0.06, 95% CI=−0.11, −0.01). PON1 55MM was associated with faster progression of motor (UPDRS β=0.28, 95% CI=0.08, 0.48) and depressive symptoms (GDS β=0.07; 95% CI=0.01, 0.13). We also found the PON1 L55M variant to interact with OP exposures in influencing MMSE cognitive scores (β=−1.26, 95% CI=−2.43, −0.09). ConclusionOur study provides preliminary support for the involvement of OP pesticides and PON1 in PD-related motor, cognitive, or depressive symptom progression. Future studies are needed to replicate findings and examine whether elderly populations generally are similarly impacted by pesticides or PON1 55M genotypes.

Association of paraoxonase 1 (PON1) L55M and PON1 Q192R gene polymorphisms and risk of psoriasis.

Although there have been significant advances for clarifying the pathogenesis of psoriasis, exact pathogenic mechanism of the disease is still unknown. Oxidative stress is considered to be a new etiopathogenetic key factor in the pathogenesis of psoriasis, as a result of the studies performing the association between psoriasis and paraoxonase 1 (PON1) activity. In this study, we aimed to examine the possible associations between the both PON1 L55M and PON1 Q192R polymorphisms and psoriasis susceptibility and disease progression in Turkish population. The study group consisted of 100 unrelated patients with psoriasis and 153 unrelated healthy controls with no psoriatic lesions in their personal history or on clinical examination. Genomic DNA was extracted from peripheral leukocytes from EDTA-anticoagulated blood using the High Pure Polymerase Chain Reaction Template Preparation Kit. To identify PON1 L55M and Q192R single-nucleotide polymorphisms, genotyping was performed using commercially synthesized primers and fluorescently labeled probes and the LightCycler 480 II Real-Time Polymerase Chain Reaction System. The genotyping method was based on methods developed previously for genotyping both PON1 55 and 192 polymorphisms using LightCycler real-time polymerase chain reaction technology, which relies on fluorescence resonance energy transfer. There was no significant difference between the PON1 L55M genotype distributions and allele frequencies of the psoriasis patients and the control group. There was a statistically significant difference between distributions of the genotype or allele frequencies of the PON1 Q192R of the patient groups and control subjects (P=0.0018 and P=0.0001, respectively). PON192Q/R polymorphisms have been found to be associated with susceptibility to psoriasis. This is the first report simultaneously investigating the possible associations between the PON1 L55M and PON1 Q192R polymorphisms and psoriasis susceptibility and disease progression in Turkish population. We provide evidence that PON1 Q192R polymorphisms may have an effect on the risk of psoriasis in the Turkish population.

Distribution of Paraoxonase 1 polymorphisms and activities in obese patients

Study objective. The objective of this study was to investigate PON1 phenotype and genotype in Romanian patients with abdominal obesity. Materials and methods. The study groups consisted of 88 patients with abdominal obesity and 46 subjects with normal waist circumference, matched for age and gender. For each patient, we determined the clinical parameters that may influence PON1 activities. Q192R and L55M polymorphisms analysis in the PON1 gene were performed by PCR-RFLP using specific primers and restriction enzymes. PON1 lactonase, paraoxonase and arylesterase activities were assayed by spectrophotometric methods. Analysis of PON1 genotypes and activities distribution in the obese and non-obese individuals was performed with MedCalc Software (Version 12.4.0.0). Results. There was no statistically significant difference between obese and controls in regards to age and gender. The study revealed that PON1 activities were not influenced by gender. Of all PON1 activities, only the paraoxonase activity was inversely correlated with age, being significantly reduced in patients with abdominal obesity compared to non-obesity (p=0.009). Abdominal circumference independently influenced only the variation of arylesterase activity (R=6.5%, p=0.003). Distribution of PON1 genotypes in the study groups was significantly different (p=0.007) only for the Q192R but not for the L55M genotypes. The QR Corresponding author: Stefan Cristian Vesa, Department of Pharmacology, Toxicology and Clinical Pharmacology, ”Iuliu Haţieganu” University of Medicine and Pharmacy Cluj-Napoca, 6 Pasteur Street, 400349, Cluj-Napoca, Cluj, Romania Telephone: +40740125980, Fax: +40264595629, Email: stefanvesa@gmail.com 381 DOI: 10.2478/rrlm-2013-0037 Research article Unauthenticated Download Date | 7/15/16 6:10 AM Revista Româna de Medicina de Laborator Vol. 21, Nr. 4/4, Decembrie 2013 genotype had the highest influence on paraoxonase activity (R=40.6; p<0.001). The MM genotype had the greatest influence on arylesterase (R=11.3%, p<0.001) and lactonase activities (R=7.4%, p<0.001). Conclusions. Q192R genotypes distribution was significantly different in obese patients and the QR genotype influenced greatly the paraoxonase activity. The MM genotype had the most important independent influence on the lactonase and arylesterase activities.

THE PARAOXONASE L55M POLYMORPHISM IN PATIENTS WITH CORONARY HEART DISEASE IN CHINESE POPULATION

ObjectivesTo investigate the distribution of the L/M polymorphism of PON-1 gene in Chinese Han nationality and to analyse the association of PON-1 gene, serum PON-1 activity with coronary hear t...

Paraoxonase-1 Is Not Associated with Coronary Artery Calcification in Type 2 Diabetes: Results from the PREDICT Study

Objectives: To determine any association between serum paraoxonase-1 (PON1) activity, protein and coding region genetic polymorphisms and coronary artery calcification (CACS) and to determine factors which modulate serum PON1 in type 2 diabetes (T2DM).Methods and results: 589 patients (419 Caucasian, 120 South Asian, 50 other) from the PREDICT Study were investigated. All patients were asymptomatic for coronary disease and had established T2DM. CACS, lipids, lipoproteins, inflammatory markers, insulin resistance and PON1 activity, concentration and Q192R and L55M genotypes were measured. Independent associations were: 1) PON1 activity negatively with insulin resistance, triglycerides and PON1-55 genotype and positively with PON1-192 genotype; 2) PON1 concentration negatively with Caucasian ethnicity, duration of diabetes and statin use and positively with plasma creatinine and PON1-192 genotype. There was no association between CACS and any of the PON1 activity, concentration or genotype and this finding was not different in the various ethnic groups within the PREDICT study.Conclusion: PON1 is modulated by a number of factors, some of which are reported here for the first time, including ethnicity and insulin resistance in subjects with T2DM. No association between CACS and PON1 was found.

Paraoxonase-1 is not associated with coronary artery calcification in type 2 diabetes: results from the PREDICT study.

Objectives: To determine any association between serum paraoxonase-1 (PON1) activity, protein and coding region genetic polymorphisms and coronary artery calcification (CACS) and to determine factors which modulate serum PON1 in type 2 diabetes (T2DM). Methods and results: 589 patients (419 Caucasian, 120 South Asian, 50 other) from the PREDICT Study were investigated. All patients were asymptomatic for coronary disease and had established T2DM. CACS, lipids, lipoproteins, inflammatory markers, insulin resistance and PON1 activity, concentration and Q192R and L55M genotypes were measured. Independent associations were: 1) PON1 activity negatively with insulin resistance, triglycerides and PON1-55 genotype and positively with PON1-192 genotype; 2) PON1 concentration negatively with Caucasian ethnicity, duration of diabetes and statin use and positively with plasma creatinine and PON1-192 genotype. There was no association between CACS and any of the PON1 activity, concentration or genotype and this finding was not different in the various ethnic groups within the PREDICT study. Conclusion: PON1 is modulated by a number of factors, some of which are reported here for the first time, including ethnicity and insulin resistance in subjects with T2DM. No association between CACS and PON1 was found.

Association of L55M and Q192R Polymorphisms of Paraoxonase-1 Gene with Preeclampsia

Although preeclampsia is one of the most common complications of pregnancy, the exact etiology of preeclampsia is unknown. Paraoxonase-1 (PON1) is a high-density lipoprotein-associated enzyme, which exhibits antioxidative and antiatherogenic activities. This study was aimed to determine the possible association between L55M and Q192R polymorphisms of paraoxonase-1 gene as well as serum PON1 and arylesterase (ARE) activities in preeclampsia. This case-control study was performed on 105 preeclampsia patients and 84 normal healthy pregnant women. The polymorphisms of PON1 were determined using tetra ARMS-PCR method and serum paroxonase (PON1) and arylesterase (ARE) activities were measured spectrophotometrically. Results showed that 192 QR genotype of PON1 was higher among preeclampsia patients (43.8%) than control subjects (31.0%) (crude OR = 1.92, 95% CI, 1.03-3.57; adjusted OR = 2.07, 95% CI, 1.04-4.16,). The R allele is a risk factor for preeclampsia (OR = 1.64, 95% CI, 1.03-2.60, p = 0.038). There were no significant differences regarding L55M genotypes or alleles frequencies of PON1 among groups (p >0.05). We found that serum paraoxonase and aryesterase activities were significantly higher in preeclampsia than controls (p <0.05). PON1 allele 192R is a risk factor for preeclampsia. The clinical significance of an increase of serum PON1 and ARE activities in preeclampsia remains to be elucidated. More studies in larger samples with different ethnic groups are required to validate our findings.

Paraoxonase 1 polymorphisms and haplotypes and the risk for having offspring affected with spina bifida in Southeast Mexico

Spina bifida (SB) is a common congenital malformation in Southeast Mexico. Parents of children with SB reside in areas with frequent pesticide spraying or have agriculture activities, suggesting potential exposure to pesticides. Paraoxonase 1 (PON1) is the responsible enzyme for deactivation of organophosphates (OP) in the central nervous system. Polymorphisms of PON1 genes influence the catalytic activity and plasma protein level of the enzyme, therefore, genotypic characterization of PON1 gene represents a potential predictor for susceptibility to OP-related effects. The frequency of PON1 haplotypes and polymorphisms (-108CT, L55M, and Q192R) were determined in this study. A case-control study was performed to evaluate the risk for having offspring affected by SB in 152 cases and 160 control parents. Polymorphisms were determined by PCR amplification and restriction fragment length polymorphism and Real Time-PCR. Odds ratios and confidence interval 95% were estimated. Genotype frequencies for the three PON1 polymorphisms were distributed according to Hardy-Weinberg expectations (p > 0.05) and were significantly different between cases and controls (p < 0.05). The heterozygous CT genotype of -108CT polymorphism, the RR genotype of Q192R polymorphism, both LM and MM genotypes of L55M polymorphism, and the haplotypes 221 and 222 (for -108CT, L55M, and Q192R) were associated with the risk for having a child affected by SB (p < 0.02). The heterozygous -108CT genotype was associated only maternally, whereas the heterozygous L55M genotype was relevant only in the fathers. The RR homozygous genotype was relevant both in mothers and fathers, suggesting the importance of this substrate-specific polymorphism. Results suggest that PON1 polymorphisms are relevant risk factors for having offspring affected with SB in this population from Southeast Mexico.

Paraoxonase 1 Polymorphisms and Risk of Myocardial Infarction in Women and Men

Previous studies of genetic variants of paraoxonase 1 (PON1) and coronary heart disease (CHD) have been conflicting and the modifying effects of lifestyle factors that affect PON1 activity are uncertain. In parallel nested case-control studies, the prospective associations between PON1 polymorphisms Q192R and L55M and incident CHD were examined among participants in the Nurses' Health and Health Professionals Follow-up Studies. Women were followed for 8 years and men for 6 years, and 249 women and 266 men were documented with incident CHD. Neither polymorphism was associated with risk of CHD in either sex, and neither monounsaturated fat intake nor smoking interacted with genotype. Among women, there was a possible interaction of Q192R with alcohol intake (P interaction 0.06) and a suggestion of a similar interaction with the L55M genotype (P interaction 0.11). In analyses of both polymorphisms, alcohol intake > or =2.5 g/day was associated with lower risk among all women (odds ratio 0.45), except those with the Q192Q/L55M genotype (OR 1.33; P 3-way interaction 0.07). PON1 polymorphisms are not associated with the risk of CHD nor do they interact with smoking or monounsaturated fat intake. A possible gene-alcohol interaction should be considered in future studies of PON1 and CHD.

Genetic and environmental determinants of the PON‐1 phenotype

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. 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. 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. 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.

Human paraoxonase gene cluster polymorphisms as predictors of coronary heart disease risk in the prospective Northwick Park Heart Study II.

The anti-atherogenic effect of HDL has been suggested to be partly due to the action of HDL-associated paraoxonase (PON). Three distinct enzymes have been identified, encoded by PON1, PON2 and PON3, clustered on chromosome 7q21-q22. Two cSNPs in PON1 (L55M and Q192R) and one in PON2 (S311C) have been implicated as independent risk factors for coronary heart disease (CHD) in some, but not all, studies. A PON3 SNP (A99A) was identified and the effect of these four PON SNPs on HDL levels and CHD risk was examined in the prospective Northwick Park Heart Study II (NPHSII). Genotype frequencies did not differ between cases and controls but the CHD risk associated with smoking was significantly modified by PON1 L55M genotype. Compared to LL non-smokers, LL smokers had a hazard ratio (HR) of 1.30 (95% CI 0.81-2.06) while M-allele carriers had a HR of 1.76 (1.17-2.67). When genotypes were analysed in combination, men with the genotype PON1 55 LM/MM+PON2 311 CC, had HR of 3.54 (1.81-6.93) compared to PON1 LL+PON2 SS/SC men (interaction P=0.004). These effects were independent of classical risk factors. These data demonstrate the importance of stratifying by environmental factors and the use of multiple SNPs for genetic analysis.

Paraoxonase-1 L55M polymorphism is associated with an abnormal oral glucose tolerance test and differentiates high risk coronary disease families.

Polymorphisms of the gene for the antioxidant enzyme, paraoxonase-1 (PON1), have been identified as risk factors for coronary disease (CHD), notably in diabetic patients. The polymorphisms have also been linked with other diabetic complications. The present study analyzed glucose metabolism as a function of PON1 polymorphisms in young healthy nondiabetic men from families with premature CHD and matched controls. The L55M PON1 polymorphism was independently associated with the glucose response to an oral glucose tolerance test. LL homozygotes had significantly impaired glucose disposal (P = 0.0007) compared with (LM+MM) genotypes. It was particularly marked for subjects from high CHD risk families and differentiated them from matched controls (P = 0.049). The area under the glucose curve (P = 0.0036) and the time to peak glucose value (P = 0.026) were significantly higher in the LL carriers, whereas the insulin response was slower (P = 0.013). Insulin resistance did not differ between L55M genotypes. There was a trend for reduced pancreatic beta-cell function as measured by glucose-induced insulin secretion (LL vs. LM vs. MM, 20.26 vs. 23.74 vs. 25.60; P = 0.077). The frequency of the L55 allele decreased significantly (P = 0.028) across regions defining a north-south European axis. No significant differences for the glucose response or case-control populations were observed as a function of the PON1 Q192R polymorphism. The study demonstrates an association between PON1 gene polymorphisms and glucose metabolism. The L55M-glucose interaction differentiated offspring of high CHD risk families, suggesting that it may be of particular relevance for vascular disease and possibly other diabetic complications.

Paraoxonase-1 L55M Polymorphism Is Associated with an Abnormal Oral Glucose Tolerance Test and Differentiates High Risk Coronary Disease Families

Polymorphisms of the gene for the antioxidant enzyme, paraoxonase-1 (PON1), have been identified as risk factors for coronary disease (CHD), notably in diabetic patients. The polymorphisms have also been linked with other diabetic complications. The present study analyzed glucose metabolism as a function of PON1 polymorphisms in young healthy nondiabetic men from families with premature CHD and matched controls. The L55M PON1 polymorphism was independently associated with the glucose response to an oral glucose tolerance test. LL homozygotes had significantly impaired glucose disposal (P = 0.0007) compared with (LM+MM) genotypes. It was particularly marked for subjects from high CHD risk families and differentiated them from matched controls (P = 0.049). The area under the glucose curve (P = 0.0036) and the time to peak glucose value (P = 0.026) were significantly higher in the LL carriers, whereas the insulin response was slower (P = 0.013). Insulin resistance did not differ between L55M genotypes. There was a trend for reduced pancreatic β-cell function as measured by glucose-induced insulin secretion (LL vs. LM vs. MM, 20.26 vs. 23.74 vs. 25.60; P = 0.077). The frequency of the L55 allele decreased significantly (P = 0.028) across regions defining a north-south European axis. No significant differences for the glucose response or case-control populations were observed as a function of the PON1 Q192R polymorphism. The study demonstrates an association between PON1 gene polymorphisms and glucose metabolism. The L55M-glucose interaction differentiated offspring of high CHD risk families, suggesting that it may be of particular relevance for vascular disease and possibly other diabetic complications.