Genome-Wide Association Study Evaluating Lipoprotein-Associated Phospholipase A ₂ Mass and Activity at Baseline and After Rosuvastatin Therapy

Abstract

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 <5×10 −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 <0.001 for both). Variants in 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.

Genome‐wide linkage analyses of non‐Hispanic white families identify novel loci for familial late‐onset Alzheimer's disease

“…The 1-LOD limit identified a region 0.78 Mbp in length containing C14orf177 and Mir_320, both of which have some support for involvement in dementia-related disease and processes. C14orf177 for instance, has been associated with risk for amyotrophic lateral sclerosis [29] and lipoprotein cholesterol levels [30], while members of the mir-320 microRNA family are significantly altered in sporadic AD brains [31] and associated with both neurite outgrowth [32] and neurodegeneration [33]. Evidence for genomic features with regulatory potential such as several ESTs and lincRNAs also exists in the region (based on UCSC genome browser data)[26], including one lincRNA in particular, TCONS_12_00008237, which is highly expressed in brain [34,35].…”

SERUM LIPIDS AND Lp-PLA2 ACTIVITY IN MULTIPLE SCLEROSIS

“…These results might indicate that Lp-PLA2 activity was not involved in MS and disease progression. It was reported that there were differential associations of Lp-PLA2 mass and activity in vascular events [21]. In our study we did not measure Lp-PLA2 mass which was one of the limitations of this study.…”

Nonsynonymous polymorphisms in PLA2G7 gene are associated with the risk of coronary heart disease in a southern Chinese population

“…More samples were also needed to study the effect of A379V. Besides, we only studied three SNPs of PLA2G7, while more polymorphisms in the gene should be evaluated due to the possibility that other SNPs demonstrated subsequently as affecting Lp-PLA2 activity (Chu et al 2012;Grallert et al 2012;Suchindran et al 2010) could improve the precision of PLA2G7 genotyping in predicting CHD. These findings remain to be further validated in more studies.…”

“…It has been reported that genetic factors accounted for approximately 60 % of factors influencing activity of plasma Lp-PLA2 (Guerra et al 1997). Previous genome-wide association studies (GWAS) have revealed several single nucleotide polymorphisms (SNPs) that affect lipoprotein-associated phospholipase A2 (Lp-PLA2) activity or levels (Chu et al 2012;Grallert et al 2012;Suchindran et al 2010), which contributes much to our final selection of the PLA2G7 SNPs. Among polymorphism loci associated with CHD, there have been reports mostly about nonsynonymous polymorphisms with R92H, V279F, I198T, and A379V.…”