Sex‐specific QTL effects on variation in paraoxonase 1 (PON1) activity in Mexican Americans

Winnier, Deidre; Rainwater, David L.; Cole, Shelley A.; Williams, Jeff T.; Dyer, Thomas D.; Blangero, John; MacCluer, Jean W.; Mahaney, Michael C.

doi:10.1002/gepi.20191

Cited by 12 publications

(11 citation statements)

References 44 publications

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“…The topic of gender differences in antioxidant status is complex, not sufficiently studied, and sometimes controversial. There are studies that found no gender differences (e.g., TEAC) (Rahman et al 2000 ), while others reported such sex dependence of various parameters (e.g., TEAC, PON) (Valabhji et al 2001 ; Winnier et al 2007 ).…”

Section: Discussionmentioning

confidence: 99%

A study of antioxidant activity in patients with schizophrenia taking atypical antipsychotics

et al. 2014

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IntroductionAtypical antipsychotics have significantly improved the quality of life for schizophrenic patients. Despite their beneficial effects, these antipsychotics induce weight gain, diabetes, and dyslipidemia. The aims of this study were to investigate the antioxidative activity of paraoxonase and assess lipid profile as a cardiovascular risk factor in patients with schizophrenia under long-term clozapine or risperidone treatment.MethodsThe study included 66 patients with schizophrenia under clozapine or risperidone treatment and 19 healthy control subjects. Serum paraoxonase activities against paraoxon (PON(PO)), phenylacetate (PON(PA)), dihydrocoumarin (PON(DHC)), serum Trolox equivalent antioxidant activity (TEAC), antioxidant gap (GAP), and lipid profile were determined.ResultsPON(DHC) activity was reduced in both antipsychotic drug-treated groups (clozapine 43.46 ± 1.06 U/ml, p < 0.001; risperidone 50.57 ± 1.54 U/ml, p < 0.01; control 52.27 ± 1.34 U/ml). A similar pattern was observed for the PON(DHC)/HDL-cholesterol (HDLC) ratio. On the contrary, PON(PO) and PON(PA) were increased in the treated group, but the corresponding paraoxonase/HDLC ratios were not significantly different from controls, except for PON/HDLC in the clozapine group. TEAC and GAP were only decreased in the clozapine-treated group.ConclusionsIn patients with schizophrenia, clozapine or risperidone treatment had different effects on various paraoxonase activities. The results of the present study suggest that patients with schizophrenia might be at increased risk for metabolic and cardiovascular disease related to reduced PON(DHC), TEAC, and GAP.

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Section: Discussionmentioning

confidence: 99%

A study of antioxidant activity in patients with schizophrenia taking atypical antipsychotics

et al. 2014

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“…Male mice are more likely than female mice to become obese and to develop atherosclerosis when put on atherogenic diet 21 and thus the modest effect of human PON3 overexpression may be diluted and not obvious in the females. Sex differences in PON1 activity and expression (higher in females than in males) have been reported in both human and nonhuman animals, 22 and warrant further investigations of the interactions between gender, sex hormones and PON proteins. …”

Section: In This Issue Of Circulationmentioning

confidence: 82%

Human PON3, Effects Beyond the HDL

Draganov

2007

Circulation Research

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T he article by Shih et al 1 in this issue of CirculationResearch is the first report of transgenic expression of human Paraoxonase 3 (PON3) in mice and its ability to decrease significantly atherosclerotic lesion formation and adiposity. These effects were, interestingly, observed only in male but not in female mice on either C57BL/6J or LDLR KO backgrounds. Noteworthy, no human or mouse PON3 were detected in mouse HDL and plasma and therefore the effects of human PON3 were derived from PON3 in the tissues, not in the blood.PON3 is a member of the PON gene family that includes PON1, PON2, and PON3. 2 PON enzymes are well conserved in mammals: at the amino acid level, the orthologs share 79% to 95% and the paralogs Ϸ65% identity. 2,3 PON1, PON2 and PON3, have different cell and tissue distribution as well as different regulation of expression, suggesting distinct physiological roles for each of them. These roles, however, remain largely unknown. Phylogenetic, structural and biochemical data demonstrate that all three PONs are primarily lactone hydrolyzing enzymes, albeit with different substrate specificity. [3][4][5] PON1 is by far the most studied member of the family, and much of our understanding of the PON enzymes is derived primarily from studies involving PON1 protein. PON1 is synthesized in the liver and secreted in the blood where it associates almost exclusively with the HDL fraction. There is ample evidence from in vitro, animal and epidemiological studies that PON1 protects against atherosclerosis 6,7 ; however, the exact mechanisms are still elusive.When PON3 proteins were detected in rabbit and human serum associated with the HDL fraction, 8,9 they were first tested in systems in which PON1 had demonstrated an effect: purified rabbit PON3 protected LDL against copper induced oxidation in vitro 8 ; stably transfected cells overexpressing human PON3 oxidized LDL to a less extent than control cells and were able to retard biological effects of preformed mildly oxidized LDL. 9 Thus, PON3 became well thought-out like another HDL protein with antioxidant/antiatherogenic properties 10 despite the fact that in rabbit and human sera PON3 is at least 2 orders of magnitude less abundant than PON1. 8,9 So, is the HDL indeed the place where PON3 acts physiologically, at least for all mammalian species?Here is a brief review of the interspecies differences in PON3 expression and tissue distribution. PON3 protein has been isolated from and/or detected in the livers or liverderived cell lines from rabbit, rat, mouse and human. 1,9,11,12 Human PON3 is expressed throughout the entire gastrointestinal tract, with highest message and protein levels in the esophagus and stomach. 13 In mouse gastro-intestinal tract, PON3 has highest expression in jejunum and ileum and was not detected in colon. 13 PON3 cDNA was detected in cultured airway epithelial from wild type and at even higher levels from PON1-knockout mice. 14 PON3 is expressed in murine, but not in human macrophages. 15 Shih and colleagues 1 report the presence ...

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“…Details about analyses on HapMap samples are available upon request) Second, gene-regulation for many quantitative traits differs significantly between males and females. In particular, evidences suggested a differential genotype by sex interaction on variation on Paraoxonase-1 ( PON1 , a calcium dependent esterase known to have antioxidant properties) activity in Mexican American populations [35]. We tested for interaction between available functional variants on both OLR1 and PON1 from the HapMap dataset and found suggestive evidences for differences in gene-by-gender interactions in populations with different ancestry (details about analyses on HapMap samples are available upon request).…”

Section: Discussionmentioning

confidence: 98%

Association between OLR1 K167N SNP and Intima Media Thickness of the Common Carotid Artery in the General Population

et al. 2012

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Background and PurposeThe lectin-like oxidised LDL receptor-1 (OLR1) gene encodes a scavenger receptor implicated in the pathogenesis of atherosclerosis. Although functional roles have been suggested for two variants, epidemiological studies on OLR1 have been inconsistent. Methods - We tested the association between the non-synonymous substitution K167N (rs11053646) and intima media thickness of the common carotid artery (CCA-IMT) in 2,141 samples from the Progression of Lesions in the Intima of the Carotid (PLIC) study (a prospective population-based study).ResultsSignificantly increased IMT was observed in male carriers of the minor C (N) allele compared to GC and GG (KN and KK) genotype. Functional analysis on macrophages suggested a decreased association to Ox-LDL in NN carriers compared to KN and KK carriers which is also associated with a reduced OLR1 mRNA expression. Macrophages from NN carriers present also a specific inflammatory gene expression pattern compared to cells from KN and KK carriers.ConclusionsThese data suggest that the 167N variant of LOX-1 receptor affects the atherogenic process in the carotid artery prior to evidence of disease through an inflammatory process.

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Sex‐specific QTL effects on variation in paraoxonase 1 (PON1) activity in Mexican Americans

Cited by 12 publications

References 44 publications

A study of antioxidant activity in patients with schizophrenia taking atypical antipsychotics

A study of antioxidant activity in patients with schizophrenia taking atypical antipsychotics

Human PON3, Effects Beyond the HDL

Association between OLR1 K167N SNP and Intima Media Thickness of the Common Carotid Artery in the General Population

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