Associação do Genótipo e Fenótipo da Paraoxonase-1 com Angiografia Positiva para Doença Arterial Coronariana / Association of Paraoxonase-1 Genotype and Phenotype with Angiogram Positive Coronary Artery Disease

Resumo Fundamento Tem sido demonstrado que um aumento dos níveis séricos de PON1 é protetor contra vários distúrbios. Foi relatado que vários polimorfismos de nucleotídeo único (SNPs, single nucleotide polymorphisms ) do gene PON1 estão associados a níveis e atividade de proteínas enzimáticas séricas. Objetivos Investigar a associação de SNPs do PON1 e atividade da paraoxonase sérica com a doença arterial coronariana (DAC). Métodos Foram estudados 601 pacientes não relacionados submetidos à angiografia coronária, incluindo aqueles com estenose >50% (N=266) e aqueles com estenose <30% (N=335). Os SNPs rs662 e rs840560 do gene da paraoxonase foram determinados utilizando o método ARMS-PCR e o SNP rs705379 foi genotipado utilizando análise de PCR-RFLP. A atividade da paraoxonase sérica foi medida utilizando paraoxon como substrato. O valor de p<0,05 foi considerado significante. Resultados A atividade da paraoxonase sérica não foi significativamente diferente entre os grupos de estudo. Após ajuste para idade, sexo, hipertensão, diabetes mellitus e dislipidemia, o genótipo GG e o modelo codominante de rs662 foram positivamente associados a uma angiografia positiva (respectivamente, OR = 2,424, IC 95% [1,123-5,233], p <0,05, OR = 1,663, IC 95% [1,086-2,547]). A atividade da paraoxonase sérica foi significativamente maior no alelo G e variante GG do polimorfismo rs662, alelo A e variante AA de rs854560 e alelo C e variante CC de rs705379. A análise de haplótipos mostrou que o haplótipo ATC foi significativamente mais prevalente no grupo com angiografia negativa. A análise entre os grupos indicou que o alelo A de rs662 foi significativamente associado à menor atividade da paraoxonase no grupo com angiografia positiva (p=0,019). Conclusões A presença do alelo G do polimorfismo de nucleotídeo único rs662 está independentemente associada ao aumento do risco de DAC.

Abstract Background It has been shown that increased serum PON1 levels are protective against several disorders. Several single nucleotide polymorphisms (SNPs) of the PON1 gene have been reported to be associated with serum enzyme protein levels and activity. Objective To investigate the association of SNPs of PON1 and serum paraoxonase activity with coronary artery disease (CAD). Methods A total of 601 unrelated patients who underwent coronary angiography including those who had >50% stenosis (N=266) and those with <30% stenosis (N=335) were studied. The Paraoxonase gene rs662 and rs840560 SNPs were determined using the ARMS-PCR method and the rs705379 SNP was genotyped using PCR-RFLP analysis. Serum paraoxonase activity was measured using paraoxon as a substrate. A p value of p<0.05 was considered as significant. Results Serum paraoxonase activity was not significantly different between the study groups. After adjustment for age, sex, hypertension, diabetes mellitus and dyslipidemia, the GG genotype and co-dominant model of rs662 was positively associated with a positive angiogram (respectively, OR=2.424, 95%CI [1.123-5.233], p<0.05, OR=1.663, 95%CI [1.086-2.547]). Serum paraoxonase activity was significantly higher in the G allele and GG variant of rs662, A allele and AA variant of rs854560 and C allele and CC variant of rs705379. The haplotype analysis has shown that the ATC haplotype was significantly more prevalent among the angiogram negative group. The analysis between groups indicated that the A allele of rs662 was significantly associated with lower paraoxonase activity in the positive angiogram group (p=0.019). Conclusions The presence of the G allele of the rs662 single nucleotide polymorphism is independently associated to increased risk of CAD.

Association between the L55M and Q192R polymorphisms of the paraoxonase-1 gene and age-related macular degeneration: a meta-analysis / Associação entre os polimorfismos L55M e Q192R do gene da paraoxonase1 e a degeneração macular relacionada à idade: uma meta-análise

ABSTRACT Purpose: Paraoxonase-1 activity is associated with age-related macular degeneration. Two polymorphisms (L55M and Q192R) were shown to increase paraoxonase-1 activity and have been implicated in the development of age-related macular degeneration. The results of studies that have examined these polymorphisms are conflicting, showing no effect, as well as increased or decreased risk. Therefore, this meta-analysis was conducted to determine the effect of these polymorphisms on age-related macular degeneration. Methods: PubMed, EBSCO, LILACS, and Scopus databases, as well as and the retrieved bibliographies of publications were searched for case-control studies that examined for paraoxonase-1 polymorphisms and age-related macular degeneration. Data were analyzed using the Comprehensive Meta-Analysis Version 2.2 and the NCSS Statistical Version 2020 software. Genotype distributions were extracted and, depending on the level of heterogeneity, fixed effects or random effects models were used to calculate pooled odds ratios (ORs) with 95% confidence intervals (95% CIs) for the heterozygous, homozygous, dominant, recessive, and allelic genetic models. Results: Overall, for the L55M polymorphism, none of the genetic models demonstrated a significant association. However, for non-Asian populations, a significant association was determined for the heterozygous and dominant genetic models (ORrange=1.24-1.27, p<0.05). For the Asian population, the heterozygous, dominant, and allelic genetic models demonstrated a benefit/protective factor (ORrange=0.29-0.35, p<0.05). For the Q192R polymorphism, none of the genetic models demonstrated a significant association. However, when the cohort was grouped by ethnicity, a significant association was determined in the Asian population for the recessive and allelic genetic models (ORrange=1.63-2.08, p<0.05). However, for the non-Asian population, there was no association observed. Also, there was no identifiable risk when the cohort was stratified into exudative and non-exudative cases. Conclusions: The paraoxonase-1L55M polymorphism increases the risk of developing age-related macular degeneration in non-Asian populations, whereas in Asian populations, the polymorphism exerts a protective effect. However, for the paraoxonase-1 Q192R polymorphism, only the Asian population demonstrated a risk of developing age-related macular degeneration.(AU)

RESUMO Objetivo: A atividade da paraoxonase1 está associada à degeneração macular relacionada à idade. Dois polimorfismos (L55M e Q192R) mostraram aumentar a atividade da paraoxonase1 e foram implicados no desenvolvimento da degeneração macular relacionada à idade. Os estudos que examinaram esses polimorfismos apresentaram resultados conflitantes: nenhum efeito, risco aumentado ou diminuído. Assim, esta meta-análise foi realizada para determinar o efeito desses polimorfismos na degeneração macular relacionada à idade. Métodos: Foi feita uma busca nos bancos de dados PubMed, EBSCO, LILACS e SCOPUS, bem como nas bibliografias compiladas das publicações, buscando-se estudos caso-controle que tivessem analisado os polimorfismos da paraoxonase1 e a degeneração macular relacionada à idade. Os dados foram analisados com software Comprehensive Meta-Analysis, versão 2.2, e NCSS Statistical, versão 2020. As distribuições de genótipos foram extraídas e, dependendo do nível de heterogeneidade, modelos de efeitos fixos ou aleatórios foram utilizados para calcular razões de probabilidade (RPs) combinadas, com intervalos de confiança de 95% (IC 95%) para os modelos genéticos heterozigoto, homozigoto, dominante, recessivo e alélico. Resultados: Em geral, nenhum dos modelos genéticos demonstrou associação significativa para o polimorfismo L55M. Entretanto, em populações não asiáticas, foi determinada uma associação significativa para os modelos genéticos heterozigoto e dominante (RPfaixa=1,24-1,27, p<0,05). Para a população asiática, os modelos heterozigoto, dominante e alélico mostraram um fator benéfico ou protetor (RPfaixa=0,29-0,35, p<0,05). Para o polimorfismo Q192R, nenhum dos modelos genéticos demonstrou qualquer associação significativa. Porém, quando a coorte foi agrupada por etnia, determinou-se uma associação significativa na população asiática para os modelos genéticos recessivo e alélico (RPfaixa=1,63-2,08, p<0,05). Contudo, nenhuma associação foi observada para a população não asiática. Não houve risco identificável quando a coorte foi estratificada em exsudativa e não exsudativa. Conclusões: Determinamos que o polimorfismo L55M da paraoxonase1 de fato aumenta o risco de desenvolvimento de degeneração macular relacionada à idade em populações não asiáticas, enquanto que em populações asiáticas, esse polimorfismo tem um efeito protetor. Porém, para o polimorfismo Q192R da paraoxonase1, apenas a população asiática demonstrou risco de desenvolver degeneração macular relacionada à idade.(AU)

Paraoxonase-1 polymorphisms and cerebral ischemic stroke: a pilot study in mexican patients / Caracterización polimórfica de la paraoxonasa-1 en el infarto cerebral aterotrombótico de una poblacion mexicana: estudio piloto

Abstract Background: The serum paraoxonase-1 (PON1) associated to HDL presents two common polymorphisms in the positions 192 and 55. These polymorphisms are considered determinant of the capacity of HDL to protect LDL from their oxidative modification. In this context, the PON1 genotype has been associated with cardiovascular diseases, including stroke. Objective: To determine the allelic and genotypic frequencies of PON1 L55M and Q192R as well as the enzymatic activities of PON1 in subjects with and without atherothrombotic stroke. Methods: There were included 28 people with atherothrombotic stroke and 29 without stroke. The genotyping was carried out by PCR-RFLP and the phenotyping by measurement of the activities of paraoxonase and arylesterase in serum. Results: For the polymorphism Q192R, the allelic frequencies (Q/R) were 0.46/0.54 and 0.48/0.52 (p= 0.843) for the control group and the group with stroke, respectively. While for the polymorphism L55M, the allelic frequencies (L/M) were 0.81/0.19 for the control group, and 0.78/0.22 for the group with stroke (p= 0.610). The activity levels of paraoxonase were not significantly different between the control and stroke groups (450 vs. 348 UI/mL, p= 0.093) While the activity levels of arylesterase were significantly different between the studied groups (90 vs. 70 UI/mL, p= 0.001); however, upon adjustment by multiple linear regression, it was not longer significant. Conclusion: The polymorphisms Q192R and L55M, and the paraoxonase activity of PON1 are not risk factors for atherothrombotic stroke according to the results of this study.

Resumen Introducción: La paraoxonasa-1 (PON1) sérica asociada a las HDL presenta dos polimorfismos comunes en las posiciones 192 y 55. Estos polimorfismos se consideran determinantes para la capacidad de las HDL de proteger a las LDL de su modificación oxidativa. En este contexto, el genotipo de PON1 se ha asociado con enfermedades cerebrovasculares, que incluyen el infarto cerebral. Objetivo: Determinar las frecuencias alélicas y genotípicas de PON1-L55M y PON1- Q192R, así como las actividades enzimáticas de PON1 en sujetos con y sin infarto cerebral aterotrombótico. Métodos: Se incluyeron 28 personas con infarto cerebral aterotrombótico y 29 sin infarto. Las genotipificaciones se realizaron mediante PCR-RFLP y las fenotipificaciones mediante la medición de las actividades paraoxonasa y arilesterasa en suero. Resultados: Para el polimorfismo Q192R, las frecuencias alélicas (Q/R) fueron 0.46/0.54 y 0.48/0.52 (p= 0.843) para el grupo control y el grupo con infarto, respectivamente. Mientras que para el polimorfismo L55M, las frecuencias alélicas (L/M) fueron 0.81/0.19 para el grupo control y 0.78/0.22 para el grupo con infarto (p= 0.610). Los niveles de actividad paraoxonasa no fueron significativamente diferentes entre los grupos control y con infarto (450 vs. 348 Ul/mL, p= 0.093). Mientras que los niveles de actividad arilesterasa fueron significativamente diferentes entre los grupos estudiados (90 vs. 70 Ul/mL, p= 0.001), sin embargo, al ajustarla por regresión lineal múltiple, dejo de ser significativa. Conclusión: Los polimorfismos Q192R y L55M, y la actividad paraoxonasa de la PON1 no son factores de riesgo para el infarto cerebral aterotrombótico en este estudio.

The association of genetic polymorphism with clopidogrel resistance among patients after ;percutaneous coronary intervention / 中华检验医学杂志

Objects To investigate the correlation of the single nucleotide polymorphism ( SNP) of clopidogrel related gene CYP2C19, ABCB1, PON1 to the occurrence of clopidogrel resistance ( CR) and TEG among patients after percutaneous coronary intervention.Methods A total of 299 patients after PCI were enrolled from April 2015 to December 2015.It genotyped the CYP2C19(rs4244285,rs4986893)ABCB1 ( rs1045642 ) and PON1 ( rs662 ) gene, measured clopidogrel response by TEG.Accordingly, all the enrolled 299 patients were then divided into CR group (n=17) +non-CR (NCR) group (n=282) or CLR group (n=54) +non-CR (NCR) group (n=245) by TEG(%).All the patients were divided into EM、IM and PM group by CYP2C19 genotype.The age of patient in CR (71.1 ±11.1) years old is higher than NCR (65.02 ±10.51) years old (t=2.559, P0.05).There was no significant difference between CR(χ2 =0.175,P=0.916) CLR(χ2 =1.589,P=0.452)and the level of TEG(ADP) (Z=-0.030,P=0.976) in PON1(rs662) polymorphism.There was no significant difference between CR(χ2 =1.722,P=0.423) CLR(χ2 =0.176,P=0.916) and the level of TEG(ADP) (Z=-0.331,P=0.741) in ABCB1(rs1045642) polymorphism.Conclusions CYP2C19 PM is associated with decreased of TEG(ADP).It is considered that no correlation exists between ABCB1(rs1045642) and PON1(rs662) polymorphism and clopidogrel resistance in patients with coronary heart diseases.The loss of function of ABCB1 ( rs1045642 ) and PON1 ( rs662 ) is not associated with decreased of TEG(ADP) in CYP2C19 PM patients.

The changes of serum paraoxonase-1 activity and blood Hpid in patients with obstructive sleep apnea-hypopnea syndrome and their correlation study / 中国医师进修杂志

ObjectiveTo study the correlation between serum paraoxanase-1 (PON-1) activity and blood lipid and their changes before and after nasal continuous positive airway pressure ventilation (nCPAP) in patients with obstructive sleep apnea-hypopnea syndrome (OSAHS) and to investigate the effect of PON-1 on the occurrence of candiovascular diseases in OSAHS patients.MethodsAccording to the apnea hypopnea index(AHI),86 OSAHS patients were divided into mild group(24 cases,5 ＜ AHI ≤20),moderate group (25 cases,20

Association of Paraoxonase 1 (PON1) polymorphisms with osteoporotic fracture risk in postmenopausal Korean women

There is increasing evidence of a biochemical link between lipid oxidation and bone metabolism. Paraoxonase 1 (PON1) prevents the oxidation of low-density lipoprotein (LDL) and metabolizes biologically active phospholipids in oxidized LDLs. Here, we performed association analyses of genetic variation in PON1 to ascertain its contribution to osteoporotic fractures (OFs) and bone mineral density (BMD). We directly sequenced the PON1 gene in 24 Korean individuals and identified 26 sequence variants. A large population of Korean postmenopausal women (n = 1,329) was then genotyped for eight selected PON1 polymorphisms. BMD at the lumbar spine and femoral neck was measured using dual-energy X-ray absorptiometry. Lateral thoracolumbar (T4-L4) radiographs were obtained for vertebral fracture assessment, and the occurrence of non-vertebral fractures (i.e., wrist, hip, forearm, humerus, rib, and pelvis) was examined using self-reported data. Multivariate analyses showed that none of the polymorphisms was associated with BMD at either site. However, +5989A>G and +26080T>C polymorphisms were significantly associated with non-vertebral and vertebral fractures, respectively, after adjustment for covariates. Specifically, the minor allele of +5989A>G exerted a highly protective effect against non-vertebral fractures (OR = 0.59, P = 0.036), whereas the minor allele of +26080T>C was associated with increased susceptibility to vertebral fractures (OR = 1.73, P = 0.020). When the risk for any OFs (i.e., vertebral or non-vertebral) was considered, the statistical significance of both polymorphisms persisted (P = 0.002-0.010). These results suggest that PON1 polymorphisms could be one of useful genetic markers for OF risk in postmenopausal women.

Paraoxonase 1 gene polymorphisms contribute to coronary artery disease risk among north Indians.

Background: Polymorphisms in paraoxonase 1 (PON1) coding for PON1 enzyme have been studied as genetic markers of coronary artery disease (CAD). PON1 Q192R and PON1 L55M polymorphisms have been analyzed extensively, but data on association and role of these polymorphisms in the etiology of CAD are conflicting. In this study, we tested the genetic association between PON1 Q192R and PON1 L55M polymorphisms and CAD among north Indians. Materials and Methods: Two hundred eighty-five angiographically proven patients with coronary artery disease and 200 sex-matched and ethnically matched controls were genotyped for 2 PON1 polymorphisms by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. Genotype/ allele frequencies were compared in patients and controls using the chi-square test. Results: At PON1-192 locus, there were significant differences between patients and controls (P< 0.05), leading to significant odds ratios for RR genotype (OR= 1.92, CI: 1.19-3.10) and *R allele (OR= 1.30, CI: 1.00-1.70). These odds ratios were higher in the sub-sample of smokers (2.84 and 1.45, respectively). Binary logistic regression analysis also confirmed that *R allele carriers (QR and RR) have a higher risk of CAD (OR= 3.54, CI: 1.67-5.53). PON1-55 locus did not show significant differences between patients and controls, but LL genotype and *L allele were significant risk factors in the nonsmoker group. RL haplotype was also significantly associated with CAD risk (OR= 1.44, CI: 1.08-1.93). Conclusions: PON1-192R allele and RR genotype are significantly associated with CAD patients from the north Indian population (Uttar Pradesh). This association was stronger in smokers, supporting the conclusion that an interaction between PON1 activity and smoking augments CAD risk. Further studies with larger sample size are warranted to confirm these associations in different Indian populations.

Relationship of serum paraoxonase and oxidative stress with systemic inflammatory response in patients with chronic obstructive pulmonary disease / 中华老年医学杂志

Objective To analyze the activity of paraoxonase (PON1) and explore the relationship of PON1 and oxidative stress with systemic inflammation response in the acute exacerbation phase and stationary phase in patients with chronic obstructive pulmonary disease (COPD). Methods Serum PON1 activity was measured by phenylacetate in 38 patients with COPD and 30 healthy people. The activity of glutathione peroxidase (GSH-Px) was detected by improved Hafeman method. Total antioxidant capacity (TAC) was measured by eolorimetry and malondialdehyde (MDA) level was measured by thiobarbituric acid colouration method. The interleukin-6 (IL-6) and interleukin-8 (IL-8) levels were detected by radioimmunoassay. The level of C-reactive protein (CRP) was measured by immune turbidimetry. Results In the acute exacerbation phase, the activity of serum PON1 was significantly lower in COPD group than in control group [(98.03±42.40)×103U/L vs. (136.00±60. 50)×103U/L, t=4.962, P<0.01], and it was negatively related to the IL-8 level (r= - 0. 589, P<0.01) and positively related to FEV1% (r= 0. 434, P<0. 05). The activity of GSH-Px was negatively related to the IL-6 level (r=-0. 362, P< 0. 05). In the stationary phase of COPD group, the activity of serum PON1 had no statistical difference compared with control group[(131.50±53.65))×103U/L vs. (136. 00±60.50)×103U/ L, t=2. 457, P>0. 053, and it was negatively related to the IL-8 level (r=-0. 563, P<0.05). Conclusions Serum PON1 activity is significantly decreased in acute exacerbation phase of COPD group compared with control group and it is positively related to FEV1%. The oxidative stress is closely related to systemic inflammation response in patients with acute exacerbation of COPD.