Clinical and genetic factors associated with lipoprotein-associated phospholipase A2 in the Framingham Heart Study.
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.
Schnabel
Renate
R
The NHLBI's Framingham Heart Study, Framingham, MA 01702-5827, USA.
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
D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; D000328:Adult; D015415:Biomarkers / Q000097:blood; D002318:Cardiovascular Diseases / Q000201:enzymology / Q000235:genetics*; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D005260:Female; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D006801:Humans; D007249:Inflammation / Q000235:genetics; D016014:Linear Models; D026161:MADS Domain Proteins / Q000235:genetics; D064326:MEF2 Transcription Factors; D008297:Male; D008875:Middle Aged; D018006:Myogenic Regulatory Factors / Q000235:genetics; D010375:Pedigree; D010641:Phenotype; D054467:Phospholipases A2 / Q000097:blood / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D018570:Risk Assessment; D012307:Risk Factors; D015854:Up-Regulation; D042582:Vascular Endothelial Growth Factor C / Q000235:genetics
D015415:Biomarkers; D026161:MADS Domain Proteins; D064326:MEF2 Transcription Factors; C578035:MEF2A protein, human; D018006:Myogenic Regulatory Factors; C467486:VEGFC protein, human; D042582:Vascular Endothelial Growth Factor C; D054467:Phospholipases A2; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; C526684:PLA2G7 protein, human