CETP is one of only two loci genome-wide-significantly associated with Lp-PLA2 mass in a five-study CHARGE Consortium meta-analysis (Eur Heart J 2011)

Original title: Eight genetic loci associated with variation in lipoprotein-associated phospholipase A2 mass and activity and coronary heart disease: meta-analysis of genome-wide association studies from five community-based studies

Eur Heart J · 14 October 2011 · 5

Grallert H, Dupuis J, Bis JC, Dehghan A, Barbalic M, Baumert J, Lu C, Smith NL, Uitterlinden AG, Roberts R, Khuseyinova N, Schnabel RB et al.

Meta-analyzing genome-wide association data from five population-based studies totaling 13 664 subjects within the CHARGE Consortium, researchers searched for genetic loci affecting lipoprotein-associated phospholipase A2 (Lp-PLA2), a proinflammatory, proatherogenic enzyme and coronary heart disease drug target. Variants at only two loci, PLA2G7 and CETP, were associated with Lp-PLA2 mass, with the strongest signal at PLA2G7 (P=2.4x10-23). Variants at six loci, including PLA2G7, APOC1, CELSR2, LDLR, ZNF259, and SCARB1, were associated with Lp-PLA2 activity, with no significant gene-environment interactions detected with age, sex, BMI, or smoking. Among the six activity-associated loci, four (APOC1, CELSR2, SCARB1, ZNF259), but not PLA2G7, were subsequently associated with coronary heart disease in a second study, establishing CETP as a genetic determinant specifically of Lp-PLA2 mass rather than activity, a distinct role from the other loci examined.

Original abstract

Aims: Lipoprotein-associated phospholipase A2 (Lp-PLA2) generates proinflammatory and proatherogenic compounds in the arterial vascular wall and is a potential therapeutic target in coronary heart disease (CHD). We searched for genetic loci related to Lp-PLA2 mass or activity by a genome-wide association study as part of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium.

Methods And Results: In meta-analyses of findings from five population-based studies, comprising 13 664 subjects, variants at two loci (PLA2G7, CETP) were associated with Lp-PLA2 mass. The strongest signal was at rs1805017 in PLA2G7 [P = 2.4 × 10(-23), log Lp-PLA2 difference per allele (beta): 0.043]. Variants at six loci were associated with Lp-PLA2 activity (PLA2G7, APOC1, CELSR2, LDL, ZNF259, SCARB1), among which the strongest signals were at rs4420638, near the APOE-APOC1-APOC4-APOC2 cluster [P = 4.9 × 10(-30); log Lp-PLA2 difference per allele (beta): -0.054]. There were no significant gene-environment interactions between these eight polymorphisms associated with Lp-PLA2 mass or activity and age, sex, body mass index, or smoking status. Four of the polymorphisms (in APOC1, CELSR2, SCARB1, ZNF259), but not PLA2G7, were significantly associated with CHD in a second study.

Conclusion: Levels of Lp-PLA2 mass and activity were associated with PLA2G7, the gene coding for this protein. Lipoprotein-associated phospholipase A2 activity was also strongly associated with genetic variants related to low-density lipoprotein cholesterol levels.

Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 19 August 2026. Methods.