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. |
Publication Type | Journal Article |
Year of Publication | 2014 |
Authors | Holmes MV, Exeter HJ, Folkersen L, Nelson CP, Guardiola M, Cooper JA, Sofat R, S Boekholdt M, Khaw K-T, Li K-W, Smith AJP, Hooft FVan't, Eriksson P, Franco-Cereceda A, Asselbergs FW, Boer JMA, Onland-Moret CN, Hofker M, Erdmann J, Kivimaki M, Kumari M, Reiner AP, Keating BJ, Humphries SE, Hingorani AD, Mallat Z, Samani NJ |
Secondary Authors | Talmud PJ |
Corporate Authors | CARDIoGRAM Consortium |
Journal | Circ Cardiovasc Genet |
Volume | 7 |
Issue | 2 |
Pagination | 144-50 |
Date Published | 2014 Apr |
ISSN | 1942-3268 |
Keywords | Alleles, Case-Control Studies, Coronary Disease, Genotype, Group V Phospholipases A2, Humans, Isoenzymes, Mendelian Randomization Analysis, Polymorphism, Single Nucleotide |
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. 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. |
DOI | 10.1161/CIRCGENETICS.113.000271 |
Alternate Journal | Circ Cardiovasc Genet |
PubMed ID | 24563418 |
PubMed Central ID | PMC4212409 |
Grant List | R01 HL-81680 / HL / NHLBI NIH HHS / United States RG/08/008/25291 / / British Heart Foundation / United Kingdom G0802432 / / Medical Research Council / United Kingdom R01 HL036310 / HL / NHLBI NIH HHS / United States P01 HL-49058 / HL / NHLBI NIH HHS / United States R01 HL-64035 / HL / NHLBI NIH HHS / United States G1000143 / / Medical Research Council / United Kingdom P01 HL-62426 / HL / NHLBI NIH HHS / United States FS/13/6/29977 / / British Heart Foundation / United Kingdom RG/10/001/27643 / / British Heart Foundation / United Kingdom R01 HL-105924 / HL / NHLBI NIH HHS / United States T32 HL-07692 / HL / NHLBI NIH HHS / United States G0401527 / / Medical Research Council / United Kingdom R01 HL-91056 / HL / NHLBI NIH HHS / United States MR/K006584/1 / / Medical Research Council / United Kingdom MR/K013351/1 / / Medical Research Council / United Kingdom P01 HL-077101 / HL / NHLBI NIH HHS / United States RG/10/12/28456 / / British Heart Foundation / United Kingdom |