Additional Common Polymorphisms in the PON Gene Cluster Predict PON1 Activity but Not Vascular Disease

Crosslin

Auer

et al. 2014

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PON1Val109Ile (overall P = 7.88 × 10 ؊ 3 ; AA P = 6.52 × 10 ؊ 4 ), found at higher frequency in AA participants (1.16% vs. 0.02%) and whose protein is less stable than the common allele. In summary, rare genetic variation in PON1 was associated with ischemic stroke, with stronger associations identifi ed in those of AA. Increased focus on PON1 enzyme function and its role in cerebrovascular disease is warranted . ). Ethnic differences in the association between PON1 variants with stroke could be due to the effects of This work was supported in part by WA State

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Analysesmentioning

confidence: 99%

See 1 more Smart Citation

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

Crosslin

Auer

et al. 2014

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“…PON1 enzyme activity was measured by rate of enzymatic degradation of phenylacetate [arylesterase (AREase)] by a continuous spectrophotometric assay with lithium heparin plasma, as previously described (10)(11)(12). PON1 AREase activity had an approximate normal distribution.…”

Section: Pon1 Arylesterase Activity Measurementmentioning

confidence: 99%

PLTP activity inversely correlates with CAAD: effects of PON1 enzyme activity and genetic variants on PLTP activity

Burt

Ranchalis

et al. 2015

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Cholesterol carried on HDL (HDL-C) has long been believed to be cardioprotective, based on consistent epidemiologic fi ndings of an inverse relationship between incident CVD and HDL-C levels in subjects healthy at baseline ( 1, 2 ). Estimates from the Framingham Heart Study found that risk of myocardial infarction (MI) increased by 25% for each 5 mg/dl decrease in HDL-C below median values of HDL-C for both healthy men and women ( 2 ). Similar fi ndings of the cardioprotective effects of HDL-C have also been reported in subjects with CVD at baseline ( 3 ).In confl ict with these epidemiologic fi ndings, recent attempts to establish a causal relationship between HDL-C Abstract Recent studies have failed to demonstrate a causal cardioprotective effect of HDL cholesterol levels, shifting focus to the functional aspects of HDL. Phospholipid transfer protein (PLTP) is an HDL-associated protein involved in reverse cholesterol transport. This study sought to determine the genetic and nongenetic predictors of plasma PLTP activity (PLTPa), and separately, to determine whether PLTPa predicted carotid artery disease (CAAD). PLTPa was measured in 1,115 European ancestry participants from a casecontrol study of CAAD. A multivariate logistic regression model was used to elucidate the relationship between PLTPa and CAAD. Separately, a stepwise linear regression determined the nongenetic clinical and laboratory characteristics that best predicted PLTPa. A fi nal stepwise regression considering both nongenetic and genetic variables identifi ed the combination of covariates that explained maximal PLTPa variance. PLTPa was signifi cantly associated with CAAD (7.90 × 10 ؊ 9 ), with a 9% decrease in odds of CAAD per 1 unit increase in PLTPa (odds ratio = 0.91). Triglyceride levels ( P = 0.0042), diabetes ( P = 7.28 × 10 ؊ 5 ), paraoxonase 1 (PON1) activity ( P = 0.019), statin use ( P = 0.026), PLTP SNP rs4810479 ( P = 6.38 × 10 ؊ 7 ), and PCIF1 SNP rs181914932 ( P = 0.041) were all signifi cantly associated with PLTPa. PLTPa is signifi cantly inversely correlated with CAAD. Furthermore, we report a novel association between PLTPa and PON1 activity, a known predictor of

“…The study population for these analyses consisted of 1,128 subjects (772 subjects in the discovery subset and 356 subjects in the replication subset) from the previously described CLEAR study (8)(9)(10)(11)(12)(13), who had both diet and genetic data. The discovery set had Illumina HumanCVD BeadChip ( 14 ) genotypes, while the replication cohort was genotyped later for SNPs of interest, as outlined in the genotyping methods section.…”

Section: Samplementioning

confidence: 99%

Novel gene-by-environment interactions: APOB and NPC1L1 variants affect the relationship between dietary and total plasma cholesterol

Burt

Ranchalis

et al. 2013

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This article is available online at http://www.jlr.org Supplementary key words dietary cholesterol • total cholesterol • cardiovascular disease • Niemann-Pick C1-like 1 Cardiovascular disease (CVD), including coronary heart disease and carotid artery disease (CAAD), is the leading cause of death in developed countries, accounting for approximately one-third of all deaths in adults over age 35 ( 1 ). One of the key risk factors for CVD is hypercholesterolemia ( 2 ), with epidemiologic studies demonstrating a graded relationship between total plasma cholesterol and CVD risk ( 3 ). Levels of total cholesterol and other lipids and lipoproteins are both heritable and targets for pharmacologic and lifestyle interventions ( 4 ). One of the primary methods of lifestyle intervention to alter lipid levels is through dietary changes, such as decreasing total fat intake ( 5, 6 ).Genome-wide association studies (GWASs) have implicated numerous genetic loci for association with total cholesterol levels. A recent meta-analysis by Teslovich et al. ( 7 ) of over 100,000 individuals of European ancestry confi rmed numerous previous GWAS fi ndings and identifi ed novel variants and loci for prediction of total lipid phenotypes, including total cholesterol levels.While genetic evidence is accumulating for many of these loci, less is known about the specifi c mechanisms through which these genetic variants affect cholesterol levels. We hypothesized that one pathway through which these genetic variants could alter cholesterol homeostasis is through differential absorption or processing of dietary Abstract Cardiovascular disease (CVD) is the leading cause of death in developed countries. Plasma cholesterol level is a key risk factor in CVD pathogenesis. Genetic and dietary variation both infl uence plasma cholesterol; however, little is known about dietary interactions with genetic variants infl uencing the absorption and transport of dietary cholesterol . We sought to determine whether gut expressed variants predicting plasma cholesterol differentially affected the relationship between dietary and plasma cholesterol levels in 1,128 subjects (772/356 in the discovery/replication cohorts, respectively). Four single nucleotide polymorphisms (SNPs) within three genes ( APOB , CETP , and NPC1L1 ) were signifi cantly associated with plasma cholesterol in the discovery cohort. These were subsequently evaluated for geneby-environment (GxE) interactions with dietary cholesterol for the prediction of plasma cholesterol, with signifi cant fi ndings tested for replication. Novel GxE interactions were identifi ed and replicated for two variants: rs1042034, an APOB Ser4338Asn missense SNP and rs2072183 (in males only), a synonymous NPC1L1 SNP in linkage disequilibrium with SNPs 5 ′ of NPC1L1 . This study identifi es the presence of novel GxE and gender interactions implying that differential gut absorption is the basis for the variant associations with plasma cholesterol. These GxE interactions may account for part of the "missing heritability" no...