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.
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.
Authors: S Kruse; X Q Mao; A Heinzmann; S Blattmann; M H Roberts; S Braun; P S Gao; J Forster; J Kuehr; J M Hopkin; T Shirakawa; K A Deichmann Journal: Am J Hum Genet Date: 2000-03-24 Impact factor: 11.025
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Authors: Hok-Hay S Oei; Irene M van der Meer; Albert Hofman; Peter J Koudstaal; Theo Stijnen; Monique M B Breteler; Jacqueline C M Witteman Journal: Circulation Date: 2005-02-08 Impact factor: 29.690
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