Rare coding variation in paraoxonase-1 is associated with ischemic stroke in the NHLBI Exome Sequencing Project

Kim, Daniel S.; Crosslin, David R.; Auer, Paul L.; Suzuki, Stephanie M.; Marsillach, Judit; Burt, Amber; Gordon, Adam S.; Meschia, James F.; Nalls, Mike A.; Worrall, Bradford B.; Longstreth, W. T.; Gottesman, Rebecca F.; Furlong, Clement E.; Peters, Ulrike; Rich, Stephen S.; Nickerson, Deborah A.; Jarvik, Gail P.

doi:10.1194/jlr.p049247

Cited by 25 publications

(14 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Sequencing of the PON1 genes from individuals discrepant for the functional analyses and SNV analysis of the Q192R polymorphism revealed a P90L SNV, an Asp124missplice mutation and a partial deletion of the PON1 allele bearing the Q192 genotype [27]. Recently, a PON1 V109I SNV has been associated with ischemic stroke in African-Americans [28]. …”

Section: Pon1mentioning

confidence: 99%

Paraoxonases-1, -2 and -3: What are their functions?

Furlong

Marsillach

Jarvik

et al. 2016

Chemico-Biological Interactions

Self Cite

164

122

View full text Add to dashboard Cite

Paraoxonase-1 (PON1), an esterase/lactonase primarily associated with plasma high-density lipoprotein (HDL), was the first member of this family of enzymes to be characterized. Its name was derived from its ability to hydrolyze paraoxon, the toxic metabolite of the insecticide parathion. Related enzymes PON2 and PON3 were named from their evolutionary relationship with PON1. Mice with each PON gene knocked out were generated at UCLA and have been key for elucidating their roles in organophosphorus (OP) metabolism, cardiovascular disease, innate immunity, obesity, and cancer. PON1 status, determined with two-substrate analyses, reveals an individual’s functional Q192R genotype and activity levels. The three-dimensional structure for a chimeric PON1 has been useful for understanding the structural properties of PON1 and for engineering PON1 as a catalytic scavenger of OP compounds. All three PONs hydrolyze microbial N-acyl homoserine lactone quorum sensing factors, quenching Pseudomonas aeruginosa’s pathogenesis. All three PONs modulate oxidative stress and inflammation. PON2 is localized in the mitochondria and endoplasmic reticulum. PON2 has potent antioxidant properties and is found at 3- to 4-fold higher levels in females than males, providing increased protection against oxidative stress, as observed in primary cultures of neurons and astrocytes from female mice compared with male mice. The higher levels of PON2 in females may explain the lower frequency of neurological and cardiovascular diseases in females and the ability to identify males but not females with Parkinson’s disease using a special PON1 status assay. Less is known about PON3; however, recent experiments with PON3 knockout mice show them to be susceptible to obesity, gallstone formation and atherosclerosis. Like PONs 1 and 2, PON3 also appears to modulate oxidative stress. It is localized in the endoplasmic reticulum, mitochondria and on HDL. Both PON2 and PON3 are upregulated in cancer, favoring tumor progression through mitochondrial protection against oxidative stress and apoptosis.

show abstract

Section: Pon1mentioning

confidence: 99%

Paraoxonases-1, -2 and -3: What are their functions?

Furlong

Marsillach

Jarvik

et al. 2016

Chemico-Biological Interactions

Self Cite

164

122

View full text Add to dashboard Cite

show abstract

“…PLTP activity was associated with PON arylesterase activity and the paraoxonase polymorphism PCPIF1 rs181914932, and both were inversely correlated with carotid arterial disease. 32 Although the association with HDL subclasses and PLTP activity was not reported in this study, another report from this same cohort showed that HDL-3 (small HDL) levels were more predictive of carotid artery status than HDL-2 (large HDL) or HDL cholesterol. In men, paraoxonase 1 activity improved the overall model prediction for carotid arterial disease that was additive to HDL-3 levels.…”

Section: Genetic Epidemiology: Hdl Particlesmentioning

confidence: 58%

The High-Density Lipoprotein Puzzle

Rosenson

2016

ATVB

View full text Add to dashboard Cite

High-density lipoprotein (HDL) cholesterol is a robust biomarker of atherosclerotic cardiovascular disease (CVD) events. In observational studies and many clinical trials of statin therapy, HDL cholesterol levels are inversely associated with CVD events. In the Emerging Risk Factors Collaboration that included 302,430 participants enrolled in 68 long-term prospective studies, for every 15 mg/dL increase in HDL cholesterol, the hazard ratio for coronary heart disease (CHD) events was 0.71 (95% confidence interval: 0.68-0.75) in models that were stratified by sex and trial group and further adjusted for age, systolic blood pressure, smoking status, history of diabetes mellitus, and body mass index.1 These associations remained significant in models that included triglycerides and non-HDL cholesterol.Low levels of HDL cholesterol are inversely associated with apolipoprotein B-containing lipoproteins; thus, HDL cholesterol has been considered no more than a biomarker for atherogenic lipoproteins. Several studies have investigated the association between HDL cholesterol, atherogenic lipoproteins, and CVD. [2][3][4] In multivariate models that include apolipoprotein B or low-density lipoprotein (LDL) particle concentration, HDL cholesterol was not associated with increased cardiovascular risk. In the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) that included study participants with low levels of HDL cholesterol (men <45 mg/dL and women <47 mg/dL) and nonelevated triglycerides (<400 mg/dL), the risk of future CHD events was linearly associated with baseline and 6-month levels of apolipoprotein B but not with HDL cholesterol. 4 These analyses indicate that low levels of HDL cholesterol are not associated with CVD events after adjustment for atherogenic lipoprotein concentrations.

show abstract

“…Finally, the percentage of CSI and stenosis in our population was higher compared to other cohorts both in the United States and Europe. The majority of our patients were from West Africa and it could be that ethnic differences could play a role in the variability of cerebral vasculopathy in children with SCD as it happens in stroke for adults [ 49 ].…”

Section: Discussionmentioning

confidence: 99%

Cognition and the Default Mode Network in Children with Sickle Cell Disease: A Resting State Functional MRI Study

et al. 2016

View full text Add to dashboard Cite

Cerebrovascular complications are frequent events in children with sickle cell disease, yet routinely used techniques such as Transcranial Doppler (TCD), Magnetic Resonance (MRI) and Angiography (MRA), insufficiently explain the cause of poor cognitive performances. Forty children with SS-Sβ° (mean age 8 years) underwent neurocognitive evaluation and comprehensive brain imaging assessment with TCD, MRI, MRA, Resting State (RS) Functional MRI with evaluation of the Default Mode Network (DMN). Sixteen healthy age-matched controls underwent MRI, MRA and RS functional MRI.Children with SCD display increased brain connectivity in the DMN even in the absence of alterations in standard imaging techniques. Patients with low neurocognitive scores presented higher brain connectivity compared to children without cognitive impairment or controls, suggesting an initial compensatory mechanism to maintain performances. In our cohort steady state haemoglobin level was not related to increased brain connectivity, but SatO2<97% was. Our findings provide novel evidence that SCD is characterized by a selective disruption of connectivity among relevant regions of the brain, potentially leading to reduced cognition and altered functional brain dynamics. RS functional MRI could be used as a useful tool to evaluate cognition and cerebral damage in SCD in longitudinal trials.

show abstract

Rare coding variation in paraoxonase-1 is associated with ischemic stroke in the NHLBI Exome Sequencing Project

Cited by 25 publications

References 19 publications

Paraoxonases-1, -2 and -3: What are their functions?

Paraoxonases-1, -2 and -3: What are their functions?

The High-Density Lipoprotein Puzzle

Cognition and the Default Mode Network in Children with Sickle Cell Disease: A Resting State Functional MRI Study

Contact Info

Product

Resources

About