Lipoprotein-associated phospholipase A2 (Lp-PLA2) is an emerging risk factor and therapeutic target for cardiovascular disease. The activity and mass of this enzyme are heritable traits, but major genetic determinants have not been explored in a systematic, genome-wide fashion. We carried out a genome-wide association study of Lp-PLA2 activity and mass in 6,668 Caucasian subjects from the population-based Framingham Heart Study. Clinical data and genotypes from the Affymetrix 550K SNP array were obtained from the open-access Framingham SHARe project. Each polymorphism that passed quality control was tested for associations with Lp-PLA2 activity and mass using linear mixed models implemented in the R statistical package, accounting for familial correlations, and controlling for age, sex, smoking, lipid-lowering-medication use, and cohort. For Lp-PLA2 activity, polymorphisms at four independent loci reached genome-wide significance, including the APOE/APOC1 region on chromosome 19 (p = 6×10−24); CELSR2/PSRC1 on chromosome 1 (p = 3×10−15); SCARB1 on chromosome 12 (p = 1×10−8) and ZNF259/BUD13 in the APOA5/APOA1 gene region on chromosome 11 (p = 4×10−8). All of these remained significant after accounting for associations with LDL cholesterol, HDL cholesterol, or triglycerides. For Lp-PLA2 mass, 12 SNPs achieved genome-wide significance, all clustering in a region on chromosome 6p12.3 near the PLA2G7 gene. Our analyses demonstrate that genetic polymorphisms may contribute to inter-individual variation in Lp-PLA2 activity and mass.

Abstract

Abstract. Most of the biological studies have embraced statistical approaches to make inferences. It is common to have several independent experiments to test the same null hypothesis. The goal of research on pooling evidence is to combine the results of these tests to ask if there is evidence from the collection of studies to reject the null hypothesis. In this study, we evaluated four different pooling techniques (Fisher, Logit, Stouffer and Liptak) to combine the evidence from independent microarray experiments in order to identify cell cycle-regulated genes. We were able to identify a better set of cell cycle-regulated genes using the pooling techniques based on our benchmark study on budding yeast (Saccharomyces cerevisiae). Our gene ontology study on time series data of both the budding yeast and the fission yeast (Schizosaccharomyces pombe) showed that the GO terms that are related to cell cycle are significantly enriched in the cell cycleregulated genes identified using pooling techniques.

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