TY - JOUR
T1 - Novel genetic approach to investigate the role of plasma secretory phospholipase a2 (spla2)-v isoenzyme in coronary heart disease
AU - Holmes, Michael V.
AU - Exeter, Holly J.
AU - Folkersen, Lasse
AU - Nelson, Christopher P.
AU - Guardiola, Montse
AU - Cooper, Jackie A.
AU - Sofat, Reecha
AU - Boekholdt, S. Matthijs
AU - Khaw, Kay Tee
AU - Li, Ka Wah
AU - Smith, Andrew J.P.
AU - Van't Hooft, Ferdinand
AU - Eriksson, Per
AU - Franco-Cereceda, Anders
AU - Asselbergs, Folkert W.
AU - Boer, Jolanda M.A.
AU - Onland-Moret, N. Charlotte
AU - Hofker, Marten
AU - Erdmann, Jeanette
AU - Kivimaki, Mika
AU - Kumari, Meena
AU - Reiner, Alex P.
AU - Keating, Brendan J.
AU - Humphries, Steve E.
AU - Hingorani, Aroon D.
AU - Mallat, Ziad
AU - Samani, Nilesh J.
AU - Talmud, Philippa J.
PY - 2014/4/1
Y1 - 2014/4/1
N2 - 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. Methods and 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.
AB - 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. Methods and 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.
UR - http://www.scopus.com/inward/record.url?scp=84902185272&partnerID=8YFLogxK
U2 - 10.1161/CIRCGENETICS.113.000271
DO - 10.1161/CIRCGENETICS.113.000271
M3 - Journal articles
C2 - 24563418
AN - SCOPUS:84902185272
SN - 1942-325X
VL - 7
SP - 144
EP - 150
JO - Circulation: Cardiovascular Genetics
JF - Circulation: Cardiovascular Genetics
IS - 2
ER -