A previously unreported impact of a PLA2G7 gene polymorphism on the plasma levels of lipoprotein-associated phospholipase A2 activity and mass

Abstract

Lipoprotein-associated phospholipase A2 (Lp-PLA2) levels are associated with the development of atherosclerosis. We aimed to assess the genetic determinants of Lp-PLA2 activity and mass by genotyping multiple polymorphisms in PLA2G7, the gene encoding Lp-PLA2, among 1258 participants from the Chinese Multi-provincial Cohort Study-Beijing Project. The Sequenom MassARRAY system, Taqman assay and direct sequencing were adopted. For the first time, the rs13218408 polymorphism was found to be significantly associated with reduced Lp-PLA2 levels. We also confirmed the significant association of previously validated polymorphisms (rs1421378, rs1805018, rs16874954 and rs2216465), even after adjusting for traditional cardiovascular risk factors and for Bonferroni correction. Percentages of variance attributable to rs13218408 were 7.2% for activity and 13.3% for mass, and were secondary to those of rs16874954 (8.1% for activity and 16.9% for mass). A significant joint effect of rs13218408 and rs16874954 was observed on Lp-PLA2 activity (P = 0.058) and mass (P = 0.003), with their minor alleles together linking to the largest reduction in Lp-PLA2 levels (37.8% reduction in activity and 41.6% reduction in mass). Taken together, our findings show a significant association of a PLA2G7 polymorphism with Lp-PLA2 levels, which was previously unreported in any population. The functionality of this genetic variation deserves further investigations.

Lipoprotein-associated phospholipase A2 and oxidized low-density lipoprotein in young patients with acute coronary syndrome in China

“…Lipoprotein-associated phospholipase A2 (Lp-PLA2), a unique member of the phospholipase A2 superfamily, is secreted in the active form by T lymphocytes, monocyte-derived macrophages and mast cells 12 . Lp-PLA2 has high specificity for vascular inflammation and been proposed to be a risk marker of CVD based on many epidemiological studies and meta-analyses 13 , 14 .…”

Lipoprotein‐associated phospholipase A2: The story continues

“…On the other hand, several studies reported that no significant impact of the V379 allele was observed on Lp‐PLA2 activity. Qi et al revealed no statistically significant effect of the V379A polymorphisms on Lp‐PLA2 activity in a Chinese Han population ( P > .05). A series of studies on PLA2G7 genetic polymorphisms reported similar conclusions in Chinese subjects with PCOS ( P > .05), AD ( P = .33), and CHD with ( P = .21) or without blood stasis syndrome (BSS) ( P = .98) .…”

“…Moreover, Casas et al were unsuccessful in detecting the clear involvement of this common variant with CHD risk, while Ferguson et al demonstrated a strong association of rs1421378 and CAC. A 5′‐UTR variant (rs9395208) might not be associated with Lp‐PLA2 activity and mass in the Chinese population, but in the same population, another study found the minor allele of rs9395208 to be a protective factor for CHD (OR = 0.78, 95% CI: 0.62‐0.98, P = .03) . However, Grallert et al established that this variant was significantly associated with Lp‐PLA2 mass but not with activity or prevalence of CHD or CAD in participants of European ancestry.…”

“…A functional study by Kruse et al demonstrated comparable kinetic characteristics between the recombinant mutant Lp‐PLA2 and wild type with respect to K M and V max . Similarly, Qi et al found that R92H was not associated with Lp‐PLA2 mass or activity in the Chinese Han population, even after Bonferroni correction. Nevertheless, a genome‐wide association study including data from five community‐based studies revealed a strong association of the R92H mutation with increased Lp‐PLA2 mass ( P = 2.4 × 10 −23 , significance threshold P < 5 × 10 −8 ), but a relatively weak association with Lp‐PLA2 activity ( P = 2.4 × 10 −6 ) .…”

“…The impact of the I198T variant on the plasma Lp-PLA2 level remained inconclusive. 88 Qi et al 92 found an evident reduction in both Lp-PLA2 mass and activity when carriers homozygous for the minor allele (TT) were compared with the major allele homozygotes (II) in a Chinese population. 92 protein by lowering the substrate affinities rather than its hydrolytic activity.…”