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Novel Genetic Approach to Investigate the Role of Plasma Secretory Phospholipase A2 (sPLA <sub>2</sub> )-V Isoenzyme in Coronary Heart Disease

Holmes, Michael V and Exeter, Holly J and Folkersen, Lasse and Nelson, Christopher P and Guardiola, Montse and Cooper, Jackie A and Sofat, Reecha and Boekholdt, S Matthijs and Khaw, Kay-Tee and Li, Ka-Wah and Smith, Andrew JP and van’t Hooft, Ferdinand and Eriksson, Per and Franco-Cereceda, Anders and Asselbergs, Folkert W and Boer, Jolanda MA and Onland-Moret, N Charlotte and Hofker, Marten and Erdmann, Jeanette and Kivimaki, Mika and Kumari, Meena and Reiner, Alex P and Keating, Brendan J and Humphries, Steve E and Hingorani, Aroon D and Mallat, Ziad and Samani, Nilesh J and Talmud, Philippa J (2014) 'Novel Genetic Approach to Investigate the Role of Plasma Secretory Phospholipase A2 (sPLA <sub>2</sub> )-V Isoenzyme in Coronary Heart Disease.' Circulation: Cardiovascular Genetics, 7 (2). pp. 144-150. ISSN 1942-325X

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Abstract

<jats:sec> <jats:title>Background—</jats:title> <jats:p> Secretory phospholipase A <jats:sub>2</jats:sub> (sPLA <jats:sub>2</jats:sub> ) enzymes are considered to play a role in atherosclerosis. sPLA <jats:sub>2</jats:sub> activity encompasses several sPLA <jats:sub>2</jats:sub> isoenzymes, including sPLA <jats:sub>2</jats:sub> -V. Although observational studies show a strong association between elevated sPLA <jats:sub>2</jats:sub> activity and CHD, no assay to measure sPLA <jats:sub>2</jats:sub> -V levels exists, and the only evidence linking the sPLA <jats:sub>2</jats:sub> -V isoform to atherosclerosis progression comes from animal studies. In the absence of an assay that directly quantifies sPLA <jats:sub>2</jats:sub> -V levels, we used <jats:italic>PLA2G5</jats:italic> mRNA levels in a novel, modified Mendelian randomization approach to investigate the hypothesized causal role of sPLA <jats:sub>2</jats:sub> -V in coronary heart disease (CHD) pathogenesis. </jats:p> </jats:sec> <jats:sec> <jats:title>Methods and Results—</jats:title> <jats:p> Using data from the Advanced Study of Aortic Pathology, we identified the single-nucleotide polymorphism in <jats:italic>PLA2G5</jats:italic> showing the strongest association with <jats:italic>PLA2G5</jats:italic> mRNA expression levels as a proxy for sPLA <jats:sub>2</jats:sub> -V levels. We tested the association of this SNP with sPLA <jats:sub>2</jats:sub> activity and CHD events in 4 prospective and 14 case–control studies with 27 230 events and 70 500 controls. rs525380C&gt;A showed the strongest association with <jats:italic>PLA2G5</jats:italic> mRNA expression ( <jats:italic>P</jats:italic> =5.1×10 <jats:sup>−6</jats:sup> ). There was no association of rs525380C&gt;A with plasma sPLA <jats:sub>2</jats:sub> activity (difference in geometric mean of sPLA <jats:sub>2</jats:sub> activity per rs525380 A-allele 0.4% (95% confidence intervals [−0.9%, 1.6%]; <jats:italic>P</jats:italic> =0.56). In meta-analyses, the odds ratio for CHD per A-allele was 1.02 (95% confidence intervals [0.99, 1.04]; <jats:italic>P</jats:italic> =0.20). </jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions—</jats:title> <jats:p> 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 <jats:italic>PLA2G5</jats:italic> expression, a surrogate for sPLA <jats:sub>2</jats:sub> -V levels) and CHD events. The evidence does not support a causal role for sPLA <jats:sub>2</jats:sub> -V in CHD. </jats:p> </jats:sec>

Item Type: Article
Uncontrolled Keywords: Mendelian randomization analysis
Subjects: H Social Sciences > H Social Sciences (General)
R Medicine > R Medicine (General)
Divisions: Faculty of Social Sciences
Faculty of Social Sciences > Institute for Social and Economic Research
SWORD Depositor: Elements
Depositing User: Elements
Date Deposited: 29 Sep 2015 13:57
Last Modified: 18 Aug 2022 12:09
URI: http://repository.essex.ac.uk/id/eprint/15172

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