Abstract P221: Genome-wide Association Study Evaluating Genetic Determinants of Rosuvastatin Effects on Lp-PLA2 Mass and Activity
Aims: Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a pro-inflammatory enzyme bound to LDL-C and other lipoproteins in circulation that is associated with increased cardiovascular risk. There is little data regarding genetic determinants of Lp-PLA2 mass and activity, and no prior data are available addressing genetic determinants of statin-induced changes for this inflammatory biomarker. Methods and Results: We performed a genome-wide association study of Lp-PLA2 mass and activity at baseline and after 12 months of rosuvastatin therapy (20 mg/day) among 6,851 participants of European ancestry from the JUPITER trial. Genome-wide associations (p<5x10-8) were identified in GCKR and CETP for baseline Lp-PLA2 mass, and at MS4A4E and the APOC1-APOE locus for baseline Lp-PLA2 activity. A variant in PLA2G7, the gene encoding the Lp-PLA2 enzyme was associated with Lp-PLA2 activity (p=3.1x10-7) at a sub-genome-wide significance (p<5x10-6); this association attained genome-wide significance after adjusting for either baseline apoB (p=2.9x10-8) or HDL-C levels (p=2.5x10-9). Two other sub-genome-wide associations with Lp-PLA2 activity attained genome-wide significance after adjusting for baseline lipoproteins: at the PSRC1-SORT1 locus (before adjustment, p=8.3x10-7; adjusting for triglycerides, p=3.4x10-8) and the TMEM49 locus (before adjustment p=3.8x10-6, adjusting for HDL-C p=1.4x10-8). Among 2,673 statin-allocated participants, median reductions were approximately 30% for Lp-PLA2 mass and activity (versus ~50% for LDL-C) after 12 months of statin therapy (all p-values <0.001). Variants in ABCG2 and LPA were associated with statin-induced change in Lp-PLA2 activity at genome-wide significance, and associations at sub-genome-wide significance (p<5x10-6) were observed for EDG7, C14orf177, NOX5, AP3B2 and RNF213. All associations, with the exception of AP3B2, were substantially attenuated after adjustment for statin induced changes in LDL-C or apoB.
Conclusion: Genome-wide associations at the MS4A4E and TMEM49 loci may reflect novel influences on circulating levels of Lp-PLA2 activity. In addition, genome-wide determinants of rosuvastatin-induced change in Lp-PLA2 activity were observed in ABCG2 and LPA, likely due to their impact on statin-induced LDL-C reduction.
- © 2012 by American Heart Association, Inc.