Genome-wide association study of Lp-PLA(2) activity and mass in the Framingham Heart Study.
Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) 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-PLA(2) 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-PLA(2) 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-PLA(2) activity, polymorphisms at four independent loci reached genome-wide significance, including the APOE/APOC1 region on chromosome 19 (p = 6 x 10(-24)); CELSR2/PSRC1 on chromosome 1 (p = 3 x 10(-15)); SCARB1 on chromosome 12 (p = 1x10(-8)) and ZNF259/BUD13 in the APOA5/APOA1 gene region on chromosome 11 (p = 4 x 10(-8)). All of these remained significant after accounting for associations with LDL cholesterol, HDL cholesterol, or triglycerides. For Lp-PLA(2) 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-PLA(2) activity and mass.
Suchindran
Sunil
S
Institute for Genome Sciences and Policy, Duke University Medical Center, Durham, North Carolina, United States of America.
Rivedal
David
D
Guyton
John R
JR
Milledge
Tom
T
Gao
Xiaoyi
X
Benjamin
Ashlee
A
Rowell
Jennifer
J
Ginsburg
Geoffrey S
GS
McCarthy
Jeanette J
JJ
D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000235:genetics* / Q000378:metabolism*; D002318:Cardiovascular Diseases / Q000201:enzymology / Q000235:genetics; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors
D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase