Dataset Information

Clinical and genetic factors associated with lipoprotein-associated phospholipase A2 in the Framingham Heart Study.

ABSTRACT: OBJECTIVE:To conduct an investigation of clinical and genetic correlates of lipoprotein-associated phospholipase (Lp-PLA(2)) activity and mass in a large community-based cohort. Higher circulating Lp-PLA(2) predicts cardiovascular disease risk, but sources of inter-individual variability are incompletely understood. METHODS:We conducted stepwise regression of clinical correlates of Lp-PLA(2) in four Framingham Heart Study cohorts (n=8185; mean age 50+/-14 years, 53.8% women, 9.8% ethnic/racial minority cohort). We also conducted heritability and linkage analyses in Offspring and Generation 3 cohorts (n=6945). In Offspring cohort participants we performed association analyses (n=1535 unrelated) with 1943 common tagging SNPs in 233 inflammatory candidate genes. RESULTS:Sixteen clinical variables explained 57% of the variability in Lp-PLA(2) activity; covariates associated with Lp-PLA(2) mass were similar but only explained 27% of the variability. Multivariable-adjusted heritability estimates for Lp-PLA(2) activity and mass were 41% and 25%, respectively. A linkage peak was observed for Lp-PLA(2) activity (chromosome 6, LOD score 2.4). None of the SNPs achieved experiment-wide statistical significance, though 12 had q values <0.50, and hence we expect at least 50% of these associations to be true positives. The strongest multivariable-association with Lp-PLA(2) activity was found for MEF2A (rs2033547; nominal p=3.20 x 10(-4)); SNP rs1051931 in PLA2G7 was nominally associated (p=1.26 x 10(-3)). The most significant association to Lp-PLA(2) mass was in VEGFC (rs10520358, p=9.14 x 10(-4)). CONCLUSIONS:Cardiovascular risk factors and genetic variation contribute to variability in Lp-PLA(2) activity and mass. Our genetic association analyses need replication, which will be facilitated by web posting of our genetic association results.

SUBMITTER: Schnabel R

PROVIDER: S-EPMC2893025 | biostudies-literature | 2009 Jun

REPOSITORIES: biostudies-literature

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Clinical and genetic factors associated with lipoprotein-associated phospholipase A2 in the Framingham Heart Study.

Schnabel Renate R Dupuis Josée J Larson Martin G MG Lunetta Kathryn L KL Robins Sander J SJ Zhu Yanyan Y Rong Jian J Yin Xiaoyan X Stirnadel Heide A HA Nelson Jeanne J JJ Wilson Peter W F PW Keaney John F JF Vasan Ramachandran S RS Benjamin Emelia J EJ

Atherosclerosis 20081105 2

<h4>Objective</h4>To conduct an investigation of clinical and genetic correlates of lipoprotein-associated phospholipase (Lp-PLA(2)) activity and mass in a large community-based cohort. Higher circulating Lp-PLA(2) predicts cardiovascular disease risk, but sources of inter-individual variability are incompletely understood.<h4>Methods</h4>We conducted stepwise regression of clinical correlates of Lp-PLA(2) in four Framingham Heart Study cohorts (n=8185; mean age 50+/-14 years, 53.8% women, 9.8% ...[more]

PMID: 19135199

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Project description:Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)), also known as platelet-activating factor acetylhydrolase (PAF-AH), is a unique member of the phospholipase A(2) superfamily. This enzyme is characterized by its ability to specifically hydrolyze PAF as well as glycerophospholipids containing short, truncated, and/or oxidized fatty acyl groups at the sn-2 position of the glycerol backbone. In humans, Lp-PLA(2) circulates in active form as a complex with low- and high-density lipoproteins. Clinical studies have reported that plasma Lp-PLA(2) activity and mass are strongly associated with atherogenic lipids and vascular risk. These observations led to the hypothesis that Lp-PLA(2) activity and/or mass levels could be used as biomarkers of cardiovascular disease and that inhibition of the activity could offer an attractive therapeutic strategy. Darapladib, a compound that inhibits Lp-PLA(2) activity, is anti-atherogenic in mice and other animals, and it decreases atherosclerotic plaque expansion in humans. However, disagreement continues to exist regarding the validity of Lp-PLA(2) as an independent marker of atherosclerosis and a scientifically justified target for intervention. Circulating Lp-PLA(2) mass and activity are associated with vascular risk, but the strength of the association is reduced after adjustment for basal concentrations of the lipoprotein carriers with which the enzyme associates. Genetic studies in humans harboring an inactivating mutation at this locus indicate that loss of Lp-PLA(2) function is a risk factor for inflammatory and vascular conditions in Japanese cohorts. Consistently, overexpression of Lp-PLA(2) has anti-inflammatory and anti-atherogenic properties in animal models. This thematic review critically discusses results from laboratory and animal studies, analyzes genetic evidence, reviews clinical work demonstrating associations between Lp-PLA(2) and vascular disease, and summarizes results from animal and human clinical trials in which administration of darapladib was tested as a strategy for the management of atherosclerosis.

Project description:BackgroundB-cell non-Hodgkin's lymphoma (B-NHL) is one of the major complications of primary Sjögren's syndrome (SS). Chronic inflammation and macrophages in SS minor salivary glands have been previously suggested as significant predictors for lymphoma development among SS patients. Lipoprotein-associated phospholipase A2 (Lp-PLA2)-a product mainly of tissue macrophages-is found in the circulation associated with lipoproteins and has been previously involved in cardiovascular, autoimmune, and malignant diseases, including lymphoma.ObjectiveThe purpose of the current study was to investigate the contributory role of Lp-PLA2 in B-NHL development in the setting of primary SS.MethodsLp-PLA2 activity in serum samples collected from 50 primary SS patients with no lymphoma (SS-nL), 9 primary SS patients with lymphoma (SS-L), and 42 healthy controls (HC) was determined by detection of [3H]PAF degradation products by liquid scintillation counter. Moreover, additional sera from 50 SS-nL, 28 SS-L, and 32 HC were tested for Lp-PLA2 activity using a commercially available ELISA kit. Lp-PLA2 mRNA, and protein expression in minor salivary gland (MSG) tissue samples derived from SS-nL, SS-L patients, and sicca controls (SC) were analyzed by real-time PCR, Western blot, and immunohistochemistry.ResultsSerum Lp-PLA2 activity was significantly increased in SS-L compared to both SS-nL and HC by two independent methods implemented [mean ± SD (nmol/min/ml): 62.0 ± 13.4 vs 47.6 ± 14.4 vs 50.7 ± 16.6, p-values: 0.003 and 0.04, respectively, and 19.4 ± 4.5 vs 15.2 ± 3.3 vs 14.5 ± 3.0, p-values: <0.0001, in both comparisons]. ROC analysis revealed that the serum Lp-PLA2 activity measured either by radioimmunoassay or ELISA has the potential to distinguish between SS-L and SS-nL patients (area under the curve [AUC]: 0.8022, CI [95%]: 0.64-0.96, p-value: 0.004 for radioimmunoassay, and AUC: 0.7696, CI [95%]: 0.66-0.88, p-value: <0.0001, for ELISA). Lp-PLA2 expression in MSG tissues was also increased in SS-L compared to SS-nL and SC at both mRNA and protein level. ROC analysis revealed that both MSG mRNA and protein Lp-PLA2 have the potential to distinguish between SS-nL and SS-L patients (area under the curve [AUC] values of 0.8490, CI [95%]: 0.71-0.99, p-value: 0.0019 and 0.9444, CI [95%]: 0.79-1.00, p- value: 0.0389 respectively). No significant difference in either serum Lp-PLA2 activity or MSG tissue expression was observed between SS-nL and HC.ConclusionsLp-PLA2 serum activity and MSG tissue mRNA/protein expression could be a new biomarker and possibly a novel therapeutic target for B-cell lymphoproliferation in the setting of SS.

Dataset Information

Clinical and genetic factors associated with lipoprotein-associated phospholipase A2 in the Framingham Heart Study.

Publications

Clinical and genetic factors associated with lipoprotein-associated phospholipase A2 in the Framingham Heart Study.

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