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Background: Advances in lipidomics allow profiling of hundreds of lipid compounds, but prior studies have been limited by relatively small case numbers and scant data in women. Methods: Four hundred confirmed, incident cases of MI and fatal CHD in the Women’s Health Initiative (WHI-OS) were frequency matched to 400 controls by age, race, hysterectomy, and time-period (mean age 62.7 years; no hormone use). Lipidomic analysis of 196 lipid species from 13 different lipid classes including cholesterol esters (CE), diacylglycerols (DAG),and triacylglycerols [TAG) was performed by liquid chromatography mass spectroscopy. Two independent modeling approaches were used: 1) Individual lipids were studied in logistic regression models and a false-discovery rate (FDR) correction was used to adjust for multiple comparisons (FDR corrected p-value of < 0.05); 2) Lipids were simultaneously considered using a least absolute shrinkage and selection operator (LASSO) algorithm. Metabolites selected by both approaches were included in combined multivariable logistic regression models. Results: In multivariable-adjusted logistic models, 17 lipid metabolites were individually and significantly associated with CHD controlling for multiple comparisons, while in mutually adjusted LASSO regression, 8 lipids were significantly associated with CHD. Five lipids were associated with CHD by both methods (Table). When modeled together, only C18.1 CE and C34.3 DAG were associated with risk in fully adjusted models. Results will be validated in separate replication dataset of women from the WHI (396 cases/ 396 controls; to be presented). Conclusions: Three long chain highly unsaturated triacylglycerols and one diacylglycerol were associated with decreased risk, while a short chain monounsaturated lipid CE (18.1) was associated with increased risk of CHD in women. Lipidomics may offer insights into biological mechanisms of CHD as well as identify potential markers of risk.

Aims: Lipoprotein-associated phospholipase A2 (Lp-PLA 2 ) 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-PLA 2 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-PLA 2 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-8 ) were identified in GCKR and CETP for baseline Lp-PLA 2 mass, and at MS4A4E and the APOC1 - APOE locus for baseline Lp-PLA 2 activity. A variant in PLA2G7 , the gene encoding the Lp-PLA 2 enzyme was associated with Lp-PLA2 activity (p=3.1x10 -7 ) at a sub-genome-wide significance (p-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-PLA 2 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-PLA 2 mass and activity (versus ~50% for LDL-C) after 12 months of statin therapy (all p-values ABCG2 and LPA were associated with statin-induced change in Lp-PLA 2 activity at genome-wide significance, and associations at sub-genome-wide significance (p-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-PLA 2 activity. In addition, genome-wide determinants of rosuvastatin-induced change in Lp-PLA 2 activity were observed in ABCG2 and LPA , likely due to their impact on statin-induced LDL-C reduction.

Background— In randomized trials, statins reduce plasma levels of C-reactive protein (CRP) and low-density lipoprotein cholesterol (LDL-C), and the magnitude of event reduction relates to on-treatment levels of both. However, whether different mechanisms underlie statin-induced CRP and LDL-C reduction is unknown. Methods and Results— We performed a study to evaluate potential genetic determinants of CRP response using genome-wide genetic data from a total of 6766 participants of European ancestry randomly allocated to 20 mg/d of rosuvastatin or placebo in the JUPITER trial. Among 3386 rosuvastatin-allocated individuals, both CRP and LDL-C levels were reduced by 50% after 12 months of therapy ( P r 2 ABCG2 , LPA , and APOE ) that previously showed genome-wide association with LDL-C reduction in this cohort and none of the candidate single-nucleotide polymorphisms associated with LDL-C reduction were associated with rosuvastatin-induced CRP change after multiple testing correction. Among candidate single-nucleotide polymorphisms selected from prior genetic analyses of baseline CRP, CRP reduction was associated with rs2794520 in CRP (mean, −3.5% [SE, 2.0%] change in CRP per minor allele; P =6.4×10 −4 ) and with rs2847281 in PTPN2 (mean, 3.7% [SE, 1.9%] change in CRP per minor allele; P =7.4×10 −4 ). These associations remained significant after multiple testing correction but were not significant in a formal test of interaction. Neither variant was associated with rosuvastatin-induced LDL-C reduction or with CRP reduction among 3380 placebo-allocated JUPITER participants. Conclusions— The genetic determinants of rosuvastatin-induced CRP reduction differ from, and are largely independent of, the major pharmacogenetic determinants of rosuvastatin-induced LDL-C reduction. This supports the hypothesis that differing pathways may mediate the anti-inflammatory and lipid-lowering properties of statin therapy.

Background— Lipoprotein-associated phospholipase A 2 (Lp-PLA 2 ) is a proinflammatory enzyme bound to low-density lipoprotein cholesterol and other circulating lipoproteins. Two measures of Lp-PLA 2 , mass and activity, are associated with increased cardiovascular risk. Data are sparse regarding genetic determinants of Lp-PLA 2 mass and activity, and no prior data are available addressing genetic determinants of statin-induced changes for this proinflammatory biomarker. Methods and Results — We performed a genome-wide association study of Lp-PLA 2 mass and activity at baseline and after 12 months of rosuvastatin therapy (20 mg/d) among 6851 participants of European ancestry from the Justification for Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) and performed replication in a meta-analysis of 13 664 participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Novel associations were identified and replicated at MS4A4E and TMEM49 for baseline Lp-PLA 2 activity with genome-wide significant joint P values ( P =2.0×10 −11 and P =2.9×10 −9 , respectively). In addition, genome-wide associations ( P −8 ) were identified and replicated for baseline Lp-PLA 2 mass at CETP and for Lp-PLA 2 activity at the APOC1-APOE and PLA2G7 loci. Among 2673 statin-allocated participants, both Lp-PLA 2 mass and activity were reduced by >30% and low-density lipoprotein cholesterol by 50% after 12 months of statin therapy ( P ABCG2 and LPA were associated with change in statin-induced Lp-PLA 2 activity at genome-wide significance but were substantially attenuated after adjustment for statin-induced changes in lipid levels. Conclusions— Genome-wide significant associations at MS4A4E and TMEM49 may reflect novel influences on circulating levels of Lp-PLA 2 activity. In addition, genome-wide significant associations with rosuvastatin-induced change in Lp-PLA 2 activity were observed in ABCG2 and LPA , likely because of their impact on statin-induced low-density lipoprotein cholesterol lowering.