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-PLA₂) activity and mass in a large community-based cohort. Higher circulating Lp-PLA₂ predicts cardiovascular disease risk, but sources of inter-individual variability are incompletely understood.

Methods

We conducted stepwise regression of clinical correlates of Lp-PLA₂ 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-PLA₂ activity; covariates associated with Lp-PLA₂ mass were similar but only explained 27% of the variability. Multivariable-adjusted heritability estimates for Lp-PLA₂ activity and mass were 41% and 25%, respectively. A linkage peak was observed for Lp-PLA₂ 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-PLA₂ activity was found for MEF2A (rs2033547; nominal p=3.20×10⁻⁴); SNP rs1051931 in PLA2G7 was nominally associated (p=1.26×10⁻³). The most significant association to Lp-PLA₂ mass was in VEGFC (rs10520358, p=9.14×10⁻⁴).

Conclusions

Cardiovascular risk factors and genetic variation contribute to variability in Lp-PLA₂ activity and mass. Our genetic association analyses need replication, which will be facilitated by web posting of our genetic association results.

Abbreviations: CVD, cardiovascular disease, HDL, high-density lipoprotein, LD, linkage disequilibrium, LDL, low-density lipoprotein, Lp-PLA₂, lipoprotein-associated phospholipase A₂, LOD, logarithm of the odds, SE, standard error, SNP, single nucleotide polymorphism

Keywords: Lipoprotein-associated phospholipase A2, Inflammation, Heritability, Single nucleotide polymorphism