title: Type II secretory phospholipase A2 and prognosis in patients with stable coronary heart disease: mendelian randomization study.
abstract: BACKGROUND
  Serum type II secretory phospholipase A(2) (sPLA(2)-IIa) has been found to be predictive of adverse outcomes in patients with stable coronary heart disease. Compounds targeting sPLA(2)-IIa are already under development. This study investigated if an association of sPLA(2)-IIa with secondary cardiovascular disease (CVD) events may be of causal nature or mainly a matter of confounding by correlated cardiovascular risk markers.
  
  
  RESULTS
  Eight-year follow-up data of a prospective cohort study (KAROLA) of patients who underwent in-patient rehabilitation after an acute cardiovascular event were analysed. Associations of polymorphisms (SNP) in the sPLA(2)-IIa-coding gene PLA2G2A with serum sPLA(2)-IIa and secondary fatal or non-fatal CVD events were examined by multiple regression. Hazard ratios (HR) were compared with those expected if the association between sPLA(2)-IIa and CVD were causal. The strongest determinants of sPLA(2)-IIa (rs4744 and rs10732279) were associated with an increase of serum concentrations by 81% and 73% per variant allele. HRs (95% confidence intervals) estimating the associations of the SNPs with secondary CVD events were increased, but not statistically significant (1.16 [0.89-1.51] and 1.18 [0.91-1.52] per variant allele, respectively). However, these estimates were very similar to those expected when assuming causality (1.18 and 1.17), based on an association of natural log-transformed sPLA(2)-IIa concentration with secondary events with HR = 1.33 per unit.
  
  
  CONCLUSIONS
  The present findings regarding genetic polymorphisms, determination of serum sPLA(2)-IIa, and prognosis in CVD patients are consistent with a genuine causal relationship and thus might point to a valid drug target for prevention of secondary CVD events.
authors.affiliation: Division C070 Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany. l.breitling@fkfz-heidelberg.de
authors.forename: Lutz P
authors.initials: LP
authors.lastname: Breitling
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Koenig
authors.forename: Marcus
authors.initials: M
authors.lastname: Fischer
authors.forename: Ziad
authors.initials: Z
authors.lastname: Mallat
authors.forename: Christian
authors.initials: C
authors.lastname: Hengstenberg
authors.forename: Dietrich
authors.initials: D
authors.lastname: Rothenbacher
authors.forename: Hermann
authors.initials: H
authors.lastname: Brenner
mesh_terms: D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000097:blood / Q000378:metabolism; D002318:Cardiovascular Diseases / Q000150:complications / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics; D015331:Cohort Studies; D003327:Coronary Disease / Q000175:diagnosis* / Q000201:enzymology* / Q000453:epidemiology / Q000235:genetics; D005260:Female; D005500:Follow-Up Studies; D054501:Group II Phospholipases A2 / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D057182:Mendelian Randomization Analysis; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis
chemical_list: D015415:Biomarkers; D054501:Group II Phospholipases A2; C516287:PLA2G2A protein, human