Paraoxonase polymorphisms, haplotypes, and enzyme activity in Latino mothers and newborns

Recent studies have demonstrated widespread pesticide exposures in pregnant women and in children. Plasma paraoxonase 1 (PON1) plays an important role in detoxification of various organophosphates. The goals of this study were to examine in the Center for Health Assessment of Mothers and Children of Salinas (CHAMACOS) birth cohort of Latina mothers and their newborns living in the Salinas Valley, California, the frequencies of five PON1 polymorphisms in the coding region (192QR and 55LM) and the promoter region (-162AG, -909CG, and -108CT) and to determine their associations with PON1 plasma levels [phenylacetate arylesterase (AREase) ] and enzyme activities of paraoxonase (POase) and chlorpyrifos oxonase (CPOase) . Additionally, we report results of PON1 linkage analysis and estimate the predictive value of haplotypes for PON1 plasma levels. We found that PON1-909, PON1-108, and PON1(192) had an equal frequency (0.5) of both alleles, whereas PON1-162 and PON1(55) had lower variant allele frequencies (0.2) . Nearly complete linkage disequilibrium was observed among coding and promoter polymorphisms (p < 0.001) , except PON1(192) and PON1-162 (p > 0.4) . Children's PON1 plasma levels (AREase ranged from 4.3 to 110.7 U/mL) were 4-fold lower than their mothers' (19.8 to 281.4 U/mL) . POase and CPOase activities were approximately 3-fold lower in newborns than in mothers. The genetic contribution to PON1 enzyme variability was higher in newborns (R2 = 25.1% by genotype and 26.3% by haplotype) than in mothers (R2 = 8.1 and 8.8%, respectively) . However, haplotypes and genotypes were comparable in predicting PON1 plasma levels in mothers and newborns. Most of the newborn children and some pregnant women in this Latino cohort may have elevated susceptibility to organophosphate toxicity because of their PON1192 genotype and low PON1 plasma levels.     

Racial Differences in Paraoxonase-1 (PON1): A Factor in the Health of Southerners?

Background

The southern United States (excluding Florida) has the highest age-adjusted rate of cardiovascular disease (CVD) in the country, with African Americans having a higher prevalence of CVD than Caucasians. Paraoxonase-1 (PON1), an enzyme associated with high-density lipoprotein particles, participates both in the hydrolysis of oxidized lipids (thus protecting against atherosclerosis) and in the hydrolysis of organophosphates. Higher paraoxonase activity has been associated with lower risk of atherosclerosis.

Objectives

In this study we characterized the distribution of the functional PON1_Q192R polymorphisms (PON status as assessed by diazoxonase to paraoxonase ratios) and the PON1 activity levels in 200 adult males and females of both races (50 in each race/sex class) from the southern United States from commercially obtained blood bank serum samples.

Methods

We used spectrophotometric methods with serum to determine PON1 status, arylesterase activities (phenyl acetate hydrolysis), and levels of cotinine and C-reactive protein (CRP).

Results

African Americans had higher paraoxonase activities but lower diazoxonase activities than did Caucasians, consistent with African Americans having a lower proportion of the functional genotype QQ (QQ 15%, QR 34%, RR 44%, 7% indeterminate), than did Caucasians (QQ 60%, QR 31%, RR 7%, 2% indeterminate). Cotinine levels indicated that all samples came from non-smokers and that CRP levels were higher in African Americans than in Caucasians and higher in females than in males. CRP levels showed no association with paraoxonase activities.

Conclusions

These data present initial observations for use in characterizing the poorer cardiovascular health status of the population in the southern United States and more specifically southern African Americans.     

Risk of brain tumors in children and susceptibility to organophosphorus insecticides: the potential role of paraoxonase (PON1)

Prior research suggests that childhood brain tumors (CBTs) may be associated with exposure to pesticides. Organophosphorus insecticides (OPs) target the developing nervous system, and until recently, the most common residential insecticides were chlorpyrifos and diazinon, two OPs metabolized in the body through the cytochrome P450/paraoxonase 1 (PON1) pathway. To investigate whether two common PON1 polymorphisms, C-108T and Q192R, are associated with CBT occurrence, we conducted a population-based study of 66 cases and 236 controls using DNA from neonatal screening archive specimens in Washington State, linked to interview data. The risk of CBT was nonsignificantly increased in relation to the inefficient PON1 promoter allele [per PON1(-108T) allele, relative to PON1(-108CC): odds ratio (OR) = 1.4; 95% confidence interval (CI), 1.0-2.2; p-value for trend = 0.07]. Notably, this association was strongest and statistically significant among children whose mothers reported chemical treatment of the home for pests during pregnancy or childhood (per PON1(-108T) allele: among exposed, OR = 2.6; 95% CI, 1.2-5.5; among unexposed, OR = 0.9; 95% CI, 0.5-1.6) and for primitive neuroectodermal tumors (per PON1(-108T) allele: OR = 2.4; 95% CI, 1.1-5.4). The Q192R polymorphism, which alters the structure of PON1 and influences enzyme activity in a substrate-dependent manner, was not associated with CBT risk, nor was the PON1(C-108T/Q192R) haplotype. These results are consistent with an inverse association between PON1 levels and CBT occurrence, perhaps because of PON1's ability to detoxify OPs common in children's environments. Larger studies that measure plasma PON1 levels and incorporate more accurate estimates of pesticide exposure will be required to confirm these observations.     

Prenatal exposure to organophosphates, paraoxonase 1, and cognitive development in childhood

Background: Prenatal exposure to organophosphate pesticides has been shown to negatively affect child neurobehavioral development. Paraoxonase 1 (PON1) is a key enzyme in the metabolism of organophosphates.Objective: We examined the relationship between biomarkers of organophosphate exposure, PON1, and cognitive development at ages 12 and 24 months and 6–9 years.Methods: The Mount Sinai Children’s Environmental Health Study enrolled a multiethnic prenatal population in New York City between 1998 and 2002 (n = 404). Third-trimester maternal urine samples were collected and analyzed for organophosphate metabolites (n = 360). Prenatal maternal blood was analyzed for PON1 activity and genotype. Children returned for neurodevelopment assessments ages 12 months (n = 200), 24 months (n = 276), and 6–9 (n = 169) years of age.Results: Prenatal total dialkylphosphate metabolite level was associated with a decrement in mental development at 12 months among blacks and Hispanics. These associations appeared to be enhanced among children of mothers who carried the PON1 Q192R QR/RR genotype. In later childhood, increasing prenatal total dialkyl- and dimethylphosphate metabolites were associated with decrements in perceptual reasoning in the maternal PON1 Q192R QQ genotype, which imparts slow catalytic activity for chlorpyrifos oxon, with a monotonic trend consistent with greater decrements with increasing prenatal exposure.Conclusion: Our findings suggest that prenatal exposure to organophosphates is negatively associated with cognitive development, particularly perceptual reasoning, with evidence of effects beginning at 12 months and continuing through early childhood. PON1 may be an important susceptibility factor for these deleterious effects.     

Effect of cigarette smoking on paraoxonase?1 activity according to PON1 L55M and PON1 Q192R gene polymorphisms

Objective

This study aims to investigate the effect of cigarette smoking on paraoxonase 1 (PON1) activity according to PON1 L55M and PON1 Q192R gene polymorphisms.

Materials and methods

Our sample included 300 voluntary subjects: 138 nonsmokers and 162 current smokers aged 38.47 ± 21.91 and 35.55 ± 16.03 years, respectively. PON1 activity was determined by kinetic methods. L55M and Q192R gene polymorphisms of PON1 were determined by multiplex polymerase chain reaction (PCR) restriction fragment length polymorphism (RFLP).

Results

We found in smokers a significant decrease of PON1 activity before and after adjustment. We noted a significant association between smoking status and lower PON1 activity [odds ratio (OR) = 3.03, confidence interval 95% = 1.5–5.9, p = 0.001]. In smokers, there was significant association between PON1 activity and PON1 L55M polymorphisms (p = 0.01). Also, the 55MM genotype presented the lowest paraoxonase activity, while the 55LL genotype showed the highest one. After adjustment for confounding variables, smokers with PON1 L55M polymorphism had the highest risk for lower PON1 activity; however, PON1 Q192R genotype might protect smokers from decrease in PON1 activity. We found significant interaction between the effect of cigarette smoking and both PON1 L55M and PON1 Q192R polymorphisms on lower PON1 activity.

Conclusions

Cigarette smoking was significantly associated with decrease in PON1 activity. Moreover, PON1 L55M polymorphism predisposes smokers to decreased PON1 activity in contrast to PON1 Q192R genotype.     

Lead exposure is associated with decreased serum paraoxonase 1 (PON1) activity and genotypes

Lead exposure causes cardiac and vascular damage in experimental animals. However, there is considerable debate regarding the causal relationship between lead exposure and cardiovascular dysfunction in humans. Paraoxonase 1 (PON1), a high-density lipoprotein-associated antioxidant enzyme, is capable of hydrolyzing oxidized lipids and thus protects against atherosclerosis. Previous studies have shown that lead and several other metal ions are able to inhibit PON1 activity in vitro. To investigate whether lead exposure has influence on serum PON1 activity, we conducted a cross-sectional study of workers from a lead battery manufactory and lead recycling plant. Blood samples were analyzed for whole-blood lead levels, serum PON1 activity, and three common PON1 polymorphisms (Q192R, L55M, -108C/T). The mean blood lead level (+/-SD) of this cohort was 27.1+/-15 microg/dL. Multiple linear regression analysis showed that blood lead levels were significantly associated with decreased serum PON1 activity (p<0.001) in lead workers. This negative correlation was more evident for workers who carry the R192 allele, which has been suggested to be a risk factor for coronary heart disease. Taken together, our results suggest that the decrease in serum PON1 activity due to lead exposure may render individuals more susceptible to atherosclerosis, particularly subjects who are homozygous for the R192 allele.     

Arylesterase activity and antioxidant status depend on PON1-Q192R and PON1-L55M polymorphisms in subjects with increased risk of cardiovascular disease consuming walnut-enriched meat

Human paraoxonase (PON1) exists in 2 major polymorphic forms and has been shown to protect LDL and HDL against oxidation. The aim of this study was to assess the differences between subjects at increased risk of cardiovascular disease (CVD), taking into account the effects of PON1-Q192R and PON1-L55M polymorphisms on 1) basal serum arylesterase activity, lipid peroxidation (LPO), and LDL-cholesterol (LDL-C), HDL-C, total cholesterol (TC), and oxidized-LDL (ox-LDL) concentrations; 2) the relations between arylesterase activity and lipid variables; and 3) the effect of walnut-enriched meat (WM) consumption on arylesterase activity and lipid variables. Twenty-three Caucasians at increased risk of CVD were randomly assigned to diet order groups in a crossover, nonblinded, placebo-controlled trial, consisting of two 5-wk experimental periods [WM and control meat (CM)]. Significant PON1-L55M x PON1-Q192R interactions affected basal serum HDL-C (P = 0.019), LDL-C (P = 0.028) and TC (P = 0.022) and tended to affect arylesterase activity (P = 0.083). Basal arylesterase activity was positively correlated with basal HDL-C (r = 0.53; P < 0.05) and TC (r = 0.43; P < 0.05) and negatively correlated with LPO (r = -0.70; P < 0.01) and the ox-LDL:LDL ratio (r = -0.63; P < 0.01). WM decreased arylesterase activity in PON1-55M carriers (P = 0.012) but not in PON1-L55 individuals, and decreased LPO concentrations in PON1-192R carriers (P = 0.031) but not in PON1-Q192 subjects. To conclude, serum TC, HDL-C, and LDL-C concentrations and arylesterase activity depend on the interaction of PON1-L55M and PON1-Q192R polymorphisms. However, the PON1-Q192R polymorphism is more closely related to antioxidant status. Both polymorphisms modulate the effect of WM consumption on CVD biomarkers.     

Polymorphisms of the paraoxonase gene and risk of preterm delivery

BACKGROUND: Human paraoxonase (PON) is an enzyme involved in vasodilation and thrombosis. Disruption of blood blow through the placenta could be part of the pathophysiological mechanism leading to preterm delivery. The purpose of this study was to examine the association between polymorphisms in 2 paraoxonase genes (PON1 and PON2) and preterm delivery. METHODS: We conducted a case-control study using infant-parents triads in Anqing, China. Between July 1999 and June 2001, we enrolled the families of 105 infants born at term and 80 infants born preterm. Genotyping was performed for the polymorphisms of PON1 Q192R, PON2 A148G, and PON2 S311C using standard techniques. We used log-linear modeling to analyze the association of PON1 and PON2 gene polymorphisms with the risk of preterm delivery. RESULTS: In the analysis of children's genotypes, the relative risk was 3.6 (95% confidence interval [CI] = 1.3-11) for PON1 RR compared with PON1 QQ. An association was also seen for PON2 CC compared with PON2 SS (relative risk = 4.6; CI = 1.5-14). There was no association between the mother's PON1 and PON2 genotypes and preterm delivery, and we did not observe an interaction between mothers' and children's genotypes. Analysis of control triads suggests Mendelian transmissions of the variant alleles of PON1 192R, PON2 148G, and PON2 311C. CONCLUSION: Infant PON1 RR and PON2 CC genotypes were associated with preterm delivery in our study population, which suggests a possible role for human paraoxonase variability in the etiology of preterm delivery.     

Interethnic variability of plasma paraoxonase (PON1) activity towards organophosphates and PON1 polymorphisms among Asian populations--a short review

Organophosphate (OP) poisoning is a progressively worrying phenomenon as worldwide pesticide production and consumption has doubled. On average, WHO estimates that 3% of agricultural workers in developing Asian countries suffer an episode of pesticide poisoning every year. Furthermore, the threat of OP usage in terrorism is existent, as seen by the subway tragedy in Tokyo in 1995 where sarin was used. Despite these alarming facts, there is currently no global system to track poisonings related to pesticide use. Human serum paraoxonase (PON1) is the enzyme that hydrolyses OP compounds. Serum PON1 levels and activity vary widely among different ethnic populations. Two commonly studied polymorphisms of PON1 are PON1Q192R and PON1L55M. PON1R192 hydrolyses paraoxon faster than PON1Q192 but hydrolyses diazoxon, sarin and soman eight times slower, and vice versa. PON1M55 has lower plasma levels of PON1 than PON1L55. As the prevalence of the different alleles and genotypic distribution vary between the Asian populations we studied, we propose the necessity to study PON1 polymorphisms and its role in OP toxicity in Asian populations. This would help safeguard the proper care of agricultural workers who might be affected by OP poisoning, and alert relevant anti biological terrorism agencies on possible risks involved in the event of an OP attack and provide effective counter measures.     

Developmental Changes in PON1 Enzyme Activity in Young Children and Effects of PON1 Polymorphisms

Background

Paraoxonase 1 (PON1) is an enzyme that detoxifies activated organophosphorus pesticides (OPs) and is also involved in oxidative stress pathways.

Objectives

PON1 activity in newborns is lower than in adults, but the ontogeny of PON1 activity is poorly characterized in young children. We examined the effects of age and PON1 genotype on enzyme activity in a birth cohort of Mexican-American children.

Methods

We determined three substrate-specific measures of PON1 activity in 1,143 plasma samples collected longitudinally from 458 children at five time points from birth through 7 years of age, and genotyped PON1 polymorphisms at positions 192 and –108 in these children.

Results

Contrary to previous reports that PON1 activities plateau by 2 years of age, we observed an age-dependent increase in all three PON1 measures from birth through 7 years of age (p < 0.0001). The PON1₁₉₂ genotype significantly modified the effect of age on paraoxonase (POase) activity (p < 0.0001) such that increases in enzyme activity with age were influenced by the number of R alleles in a dose-dependent manner. Children with the PON1_-108CC192RR diplotype had significantly higher mean PON1 activities and also experienced steeper increases of POase activity over time compared with children with the PON1_-108TT192QQ diplotype.

Conclusions

Lower levels of the PON1 enzyme, which is involved in protection against OPs and oxidative stress, persist in young children past 2 years of age through at least 7 years of age. Future policies addressing pesticide exposure in children should take into account that the window of vulnerability to OPs in young children may last beyond infancy.     

The association of the paraoxonase (PON1) Q192R polymorphism with depression in older women: findings from the British Women's Heart and Health Study

BACKGROUND: The association between the R allele of PON1 Q192R and symptoms reported by sheep dippers and Gulf War veterans has been used to suggest a biological basis for these symptoms. In the absence of such studies in non-occupational populations, these conclusions may not be valid. OBJECTIVE: To examine the association of paraoxonase (PON1) Q192R with a report of ever being diagnosed with depression among a random sample of 3266 British women, aged 60-79 years. RESULTS: The R allele of PON1 Q192R was associated with depression: per-allele odds ratio 1.22 (95% confidence interval: 1.05 to 1.41) in this population. CONCLUSIONS: These findings suggest that the association of PON1 Q192R with symptoms of depression in occupationally exposed groups may be driven by exposure to toxins that everyone in the general population is exposed to rather than exposure to toxins specifically used by sheep dippers or Gulf War veterans, or that other mechanisms underlie the association. This is because the study population in which we have found an association consisted of British women aged 60-79 years, few of whom were sheep dippers or Gulf War veterans. When using genotype-outcome associations to infer causality with respect to an environmental exposure modified by the genotype, it is important to examine these associations in general populations and in those specifically exposed to the putative agent. The possible role of PON1 Q192R in psychiatric morbidity requires further examination.     

Paraoxonase polymorphisms and self-reported chronic ill-health in farmers dipping sheep

BACKGROUND: Serum paraoxonase (PON1) provides protection against organophosphate induced toxicity. Recently we reported that the frequency of paraoxonase polymorphisms in sheep dippers with self-reported chronic ill-health differed from that in dippers with a similar dipping history but no ill-health. As these analyses may have included subjects with conditions unrelated to organophosphate exposure, the aim of this study was to examine whether the risk associated with PON1 polymorphisms varied using a more homogenous case and referent population. METHODS: Each subject completed a detailed symptom questionnaire and their general practitioner was asked whether there was any history of neurological disease that could be confused with the effects of organophosphate poisoning. Subjects were then excluded both on clinical grounds and where identified as atypical on discriminant analysis. RESULTS: Risk associated with the PON1 192 and 55 genotypes altered little with these changes in the population. CONCLUSIONS: These findings are consistent with the hypothesis that organophosphates contribute to the self-reported ill-health of sheep dippers.     

Paraoxonase in Persian Gulf War veterans

Serum paraoxonase (PON1) is responsible for the metabolism of organophosphates in serum, and PON1 activity is a major determinant of their toxicity in humans. There have been reports linking lowered PON1 activity to physical symptoms after deployment to the Persian Gulf War (PGW) of 1990 to 1991. Therefore, the object of this study was to determine (1) whether PON1 activity was decreased among symptomatic PGW veterans compared with asymptomatic PGW veterans and (2) to determine whether PGW veterans as a whole had lower PON1 activity compared with other military control groups. This was a case control study nested in occupational cohort study of military personnel. Four groups of military personnel were identified from a large epidemiological study of health effects of deployment to the PGW and Bosnia: (1) symptomatic PGW veterans, n = 115; (2) healthy PGW veterans, n = 95; (3) symptomatic Bosnia peacekeeping veterans, n = 52; and (4) symptomatic nondeployed military controls, n = 85. The main outcome measures were PON1 activity and genotype for PON1-55 and -192. We found significant differences in PON1 activity among these four groups, and although the two Gulf groups did not differ in PON1 activity, those deployed to the Gulf had significantly lower PON1 activity compared with the non-PGW groups (median difference = 70.9; 95% CI: 20.2, 121.5, P = 0.012). These differences were not explained by a range of potential confounders, or differences in PON1 coding region polymorphisms. PON1 activity is reduced in PGW veterans compared with military control groups. The effect is independent of ill health in PGW veterans.     

Genotype and phenotype frequencies of paraoxonase 1 in fertile and infertile men

Abstract

Paraoxonase1 (PON1) is a glycoprotein associated with high density lipoprotein and has antioxidant activity. The impact of PON1 in various stages of spermatogenesis has also been suggested. This study was aimed to investigate frequencies of phenotypes and Q192R genotypes of PON1 in fertile and infertile males. Q192R variants of PON1 were determined in 150 fertile and 150 infertile men using the polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP) technique. Plasma arylesterase and paraoxonase activities were detected by spectrophotometry and malondialdehyde (MDA) level was measured using thiobarbituric acid. Our results showed no significant difference in the distribution of PON1 genotypes and alleles between fertile and infertile groups. However morphology and motility of sperm were associated with various genotypes of PON1. The number of fertile males with the BB phenotype (high activity) was significantly higher than that of infertile males, whereas the number of individuals with the AB phenotype (moderate activity) was statistically higher in infertile men compared with the fertile group. Additionally, MDA and arylesterase activity levels were significantly higher in infertile subjects compared with fertile men. We speculate that the low activity of PON1 can be a risk factor for male infertility probably due to a decrease in antioxidant activity of PON1 and increase in lipid peroxidation.     

Genome-wide association study of antibody response to smallpox vaccine

We performed a genome-wide association study (GWAS) of antibody levels in a multi-ethnic group of 1071 healthy smallpox vaccine recipients. In Caucasians, the most prominent association was found with promoter SNP rs10489759 in the LOC647132 pseudogene on chromosome 1 (p=7.77×10(-8)). In African-Americans, we identified eight genetic loci at p<5×10(-7). The SNP association with the lowest p-value (rs10508727, p=1.05×10(-10)) was in the Mohawk homeobox (MKX) gene on chromosome 10. Other candidate genes included LOC388460, GPR158, ZHX2, SPIRE1, GREM2, CSMD1, and RUNX1. In Hispanics, the top six associations between genetic variants and antibody levels had p-values less than 5×10(-7), with p=1.78×10(-10) for the strongest statistical association (promoter SNP rs12256830 in the PCDH15 gene). In addition, SNP rs4748153 in the immune response gene PRKCQ (protein kinase C, theta) was significantly associated with neutralizing antibody levels (p=2.51×10(-8)). Additional SNP associations in Hispanics (p≤3.40×10(-7)) were mapped to the KIF6/LOC100131899, CYP2C9, and ANKLE2/GOLGA3 genes. This study has identified candidate SNPs that may be important in regulating humoral immunity to smallpox vaccination. Replication studies, as well as studies elucidating the functional consequences of contributing genes and polymorphisms, are underway.     

The association of the PON1 Q192R polymorphism with complications and outcomes of pregnancy: findings from the British Women's Heart and Health cohort study

It has been hypothesised that paraoxonase genes would be related to adverse pregnancy outcomes, via a maternal or fetal effect on placental hypoperfusion and thrombosis. To date only two studies have assessed this possibility. In this study we assessed the associations of the PON1 Q192R polymorphism with self-report of having pregnancy-induced hypertension, gestational hyperglycaemia and a preterm offspring birth. The associations were assessed in 3266 white women who were randomly selected from 23 British towns. There was no association between PON1 Q192R and either self-report of pregnancy-induced hypertension or gestational hyperglycaemia but the prevalence of reporting having a preterm birth increased with each R allele: per allele odds ratio 1.20 [95% confidence interval (CI) 1.03, 1.41]. When our results were pooled with the one previous study of the association of this polymorphism with preterm birth, the pooled per allele odds ratio was 1.19 [95% CI 1.02, 1.39]. Our findings provide some further evidence to suggest that PON1 Q192R is associated with preterm birth; they invite further investigation of both maternal and fetal genotype for PON1 Q192R in relation to preterm birth.     

Dietary modifications and gene polymorphisms alter serum paraoxonase activity in healthy women

Paraoxonase-1 (PON1), a HDL-associated enzyme, may protect against the development of atherosclerosis. Serum PON1 activity and PON1-mediated capacity of HDL to prevent lipoprotein oxidation are modulated by two common polymorphisms at positions 192 (Gln-->Arg) and 55 (Leu-->Met) of the PON1 gene. We studied the effect of dietary modifications on PON1 activity and the role of PON1 gene polymorphisms in the response. A controlled, crossover dietary intervention of two 5-wk periods was conducted in 37 healthy, nonsmoking women. The two study diets were either low or high in vegetables, and thus in natural antioxidants, with some differences in fatty acid contents. The mean plasma total (-8%, P < 0.001), LDL (-7%, P < 0.01) and HDL (-7%, P < 0.001%) cholesterol, and apolipoprotein A-I (-8%, P < 0.001) concentrations were lower after the high vegetable diet period than after the low vegetable diet period. Also, the serum PON1 activity was lower (P < 0.05) after the high vegetable compared with the low vegetable diet period. The reduction of PON1 activity correlated with the reduction in HDL cholesterol (r = 0.35, P < 0.05). High baseline PON1 activity was related to the presence of the PON1(192Arg) allele (P < 0.001) and PON1(55Leu/Leu) genotype (P < 0.001). The reduction of PON1 activity due to the high vegetable diet was greatest among the women with the PON1(192Arg) allele (P < 0.05) and PON1(55Leu/Leu) genotype (P < 0.05). In conclusion, a diet high in vegetables, berries and fruit reduces PON1 activity, and the response is modulated by the genetic variance of PON1.     

PON1 and neurodevelopment in children from the CHAMACOS study exposed to organophosphate pesticides in utero

Background

Paraoxonase 1 (PON1) detoxifies oxon derivatives of some organophosphate (OP) pesticides, and its genetic polymorphisms influence enzyme activity and quantity. We previously reported that maternal urinary concentrations of dialkyl phosphate (DAP) metabolites, a marker of OP pesticide exposure, were related to poorer mental development and maternally reported symptoms consistent with pervasive developmental disorder (PDD) in 2-year-olds participating in the Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS) study.

Objective

We determined whether PON1 genotypes and enzyme measurements were associated with child neurobehavioral development and whether PON1 modified the association of in utero exposure to OPs (as assessed by maternal DAPs) and neurobehavior.

Methods

We measured DAP concentrations in maternal urine during pregnancy, PON1₁₉₂ and PON1₋₁₀₈ genotypes in mothers and children, and arylesterase (ARYase) and paraoxonase (POase) in maternal, cord, and 2-year-olds’ blood. We assessed 353 2-year-olds on the Mental Development Index (MDI) and Psychomotor Development Index (PDI) of the Bayley Scales of Infant Development and queried their mothers on the Child Behavior Checklist to obtain a score for PDD.

Results

Children with the PON1_−108T allele had poorer MDI scores and somewhat poorer PDI scores. Children were less likely to display PDD when they or their mothers had higher ARYase activity and when their mothers had higher POase activity. The association between DAPs and MDI scores was strongest in children with PON1_−108T allele, but this and other interactions between DAPs and PON1 polymorphisms or enzymes were not significant.

Conclusion

PON1 was associated with child neurobehavioral development, but additional research is needed to confirm whether it modifies the relation with in utero OP exposure.     

HTR1B, ADIPOR1, PPARGC1A, and CYP19A1 and obesity in a cohort of Caucasians and African Americans: an evaluation of gene-environment interactions and candidate genes

The World Health Organization estimates that the number of obese and overweight adults has increased to 1.6 billion, with concomitant increases in comorbidity. While genetic factors for obesity have been extensively studied in Caucasians, fewer studies have investigated genetic determinants of body mass index (BMI; weight (kg)/height (m)(2)) in African Americans. A total of 38 genes and 1,086 single nucleotide polymorphisms (SNPs) in African Americans (n = 1,173) and 897 SNPs in Caucasians (n = 1,165) were examined in the Southern Community Cohort Study (2002-2009) for associations with BMI and gene × environment interactions. A statistically significant association with BMI survived correction for multiple testing at rs4140535 (β = -0.04, 95% confidence interval: -0.06, -0.02; P = 5.76 × 10(-5)) in African Americans but not in Caucasians. Gene-environment interactions were observed with cigarette smoking and a SNP in ADIPOR1 in African Americans, as well as between a different SNP in ADIPOR1 and physical activity in Caucasians. A SNP in PPARGC1A interacted with alcohol consumption in African Americans, and a different SNP in PPARGC1A was nominally associated in Caucasians. A SNP in CYP19A1 interacted with dietary energy intake in African Americans, and another SNP in CYP191A had an independent association with BMI in Caucasians.     

Paraoxonase 1 Q192R (PON1-192) polymorphism is associated with reduced lipid peroxidation in healthy young men on a low-carotenoid diet supplemented with tomato juice

The HDL-bound enzyme paraoxonase (PON) protects LDL from oxidation and may therefore attenuate the development of atherosclerosis. We examined the effect of tomato and carrot juice consumption on PON1 activity and lipid peroxidation in healthy young volunteers with different PON1-192 genotypes (Q/R substitution at position 192). In this randomized cross-over study twenty-two healthy, non-smoking men on a low-carotenoid diet received 330 ml/d tomato juice (37.0 mg lycopene, 1.6 mg beta-carotene) or carrot juice (27.1 mg beta-carotene, 13.1 mg alpha-carotene) for 2 weeks. Intervention periods were preceded by 2-week low-carotenoid intake. We determined the PON1-192 genotype by restriction fragment length polymorphism-polymerase chain reaction (RFLP-PCR) and measured ex vivo LDL oxidation (lag time), plasma malondialdehyde and PON1 activity at the beginning and end of each intervention period. At baseline, lag time was higher (P<0.05) in QQ (111 (sd 9) min) than in QR/RR subjects (101 (sd 8) min). Neither tomato nor carrot juice consumption had significant effects on PON1 activity. However, tomato juice consumption reduced (P<0.05) plasma malondialdehyde in QR/RR (Delta: -0.073 (sd 0.11) micromol/l) as compared to QQ subjects (Delta:+0.047 (sd 0.13) micromol/l). Carrot juice had no significant effect on malondialdehyde irrespective of the PON1-192 genotype. Male volunteers with the QR/RR genotype showed an increased lipid peroxidation at baseline. Although tomato and carrot juice fail to affect PON1 activity, tomato juice intake reduced lipid peroxidation in healthy volunteers carrying the R-allele of the PON1-192 genotype and could thus contribute to CVD risk reduction in these individuals.