title: Novel genetic approach to investigate the role of plasma secretory phospholipase A2 (sPLA2)-V isoenzyme in coronary heart disease: modified Mendelian randomization analysis using PLA2G5 expression levels.
abstract: BACKGROUND
  Secretory phospholipase A2 (sPLA2) enzymes are considered to play a role in atherosclerosis. sPLA2 activity encompasses several sPLA2 isoenzymes, including sPLA2-V. Although observational studies show a strong association between elevated sPLA2 activity and CHD, no assay to measure sPLA2-V levels exists, and the only evidence linking the sPLA2-V isoform to atherosclerosis progression comes from animal studies. In the absence of an assay that directly quantifies sPLA2-V levels, we used PLA2G5 mRNA levels in a novel, modified Mendelian randomization approach to investigate the hypothesized causal role of sPLA2-V in coronary heart disease (CHD) pathogenesis.
  
  
  RESULTS
  Using data from the Advanced Study of Aortic Pathology, we identified the single-nucleotide polymorphism in PLA2G5 showing the strongest association with PLA2G5 mRNA expression levels as a proxy for sPLA2-V levels. We tested the association of this SNP with sPLA2 activity and CHD events in 4 prospective and 14 case-control studies with 27 230 events and 70 500 controls. rs525380C>A showed the strongest association with PLA2G5 mRNA expression (P=5.1×10(-6)). There was no association of rs525380C>A with plasma sPLA2 activity (difference in geometric mean of sPLA2 activity per rs525380 A-allele 0.4% (95% confidence intervals [-0.9%, 1.6%]; P=0.56). In meta-analyses, the odds ratio for CHD per A-allele was 1.02 (95% confidence intervals [0.99, 1.04]; P=0.20).
  
  
  CONCLUSIONS
  This novel approach for single-nucleotide polymorphism selection for this modified Mendelian randomization analysis showed no association between rs525380 (the lead single-nucleotide polymorphism for PLA2G5 expression, a surrogate for sPLA2-V levels) and CHD events. The evidence does not support a causal role for sPLA2-V in CHD.
authors.forename: Michael V
authors.initials: MV
authors.lastname: Holmes
authors.forename: Holly J
authors.initials: HJ
authors.lastname: Exeter
authors.forename: Lasse
authors.initials: L
authors.lastname: Folkersen
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Nelson
authors.forename: Montse
authors.initials: M
authors.lastname: Guardiola
authors.forename: Jackie A
authors.initials: JA
authors.lastname: Cooper
authors.forename: Reecha
authors.initials: R
authors.lastname: Sofat
authors.forename: S Matthijs
authors.initials: SM
authors.lastname: Boekholdt
authors.forename: Kay-Tee
authors.initials: KT
authors.lastname: Khaw
authors.forename: Ka-Wah
authors.initials: KW
authors.lastname: Li
authors.forename: Andrew J P
authors.initials: AJ
authors.lastname: Smith
authors.forename: Ferdinand
authors.initials: F
authors.lastname: Van't Hooft
authors.forename: Per
authors.initials: P
authors.lastname: Eriksson
authors.forename: Anders
authors.initials: A
authors.lastname: Franco-Cereceda
authors.forename: Folkert W
authors.initials: FW
authors.lastname: Asselbergs
authors.forename: Jolanda M A
authors.initials: JM
authors.lastname: Boer
authors.forename: N Charlotte
authors.initials: NC
authors.lastname: Onland-Moret
authors.forename: Marten
authors.initials: M
authors.lastname: Hofker
authors.forename: Jeanette
authors.initials: J
authors.lastname: Erdmann
authors.forename: Mika
authors.initials: M
authors.lastname: Kivimaki
authors.forename: Meena
authors.initials: M
authors.lastname: Kumari
authors.forename: Alex P
authors.initials: AP
authors.lastname: Reiner
authors.forename: Brendan J
authors.initials: BJ
authors.lastname: Keating
authors.forename: Steve E
authors.initials: SE
authors.lastname: Humphries
authors.forename: Aroon D
authors.initials: AD
authors.lastname: Hingorani
authors.forename: Ziad
authors.initials: Z
authors.lastname: Mallat
authors.forename: Nilesh J
authors.initials: NJ
authors.lastname: Samani
authors.forename: Philippa J
authors.initials: PJ
authors.lastname: Talmud
mesh_terms: D000483:Alleles; D016022:Case-Control Studies; D003327:Coronary Disease / Q000097:blood / Q000201:enzymology* / Q000235:genetics*; D005838:Genotype; D054505:Group V Phospholipases A2 / Q000097:blood / Q000235:genetics*; D006801:Humans; D007527:Isoenzymes / Q000097:blood / Q000235:genetics; D057182:Mendelian Randomization Analysis; D020641:Polymorphism, Single Nucleotide
chemical_list: D007527:Isoenzymes; D054505:Group V Phospholipases A2; C516299:PLA2G5 protein, human
keywords: Mendelian randomization analysis