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

被引：19

作者：

Holmes, Michael V. ^{[1
,2
]}

Exeter, Holly J. ^{[3
]}

Folkersen, Lasse ^{[6
]}

Nelson, Christopher P. ^{[7
,8
]}

Guardiola, Montse ^{[3
,9
]}

Cooper, Jackie A. ^{[3
]}

Sofat, Reecha ^{[5
]}

Boekholdt, S. Matthijs ^{[10
]}

Khaw, Kay-Tee ^{[11
]}

Li, Ka-Wah ^{[3
]}

Smith, Andrew J. P. ^{[3
]}

van't Hooft, Ferdinand ^{[12
,14
]}

Eriksson, Per ^{[12
,14
]}

Franco-Cereceda, Anders ^{[13
]}

Asselbergs, Folkert W. ^{[4
,15
,17
]}

Boer, Jolanda M. A. ^{[18
]}

Onland-Moret, N. Charlotte ^{[16
,17
]}

Hofker, Marten ^{[19
]}

Erdmann, Jeanette ^{[20
]}

Kivimaki, Mika ^{[2
]}

Kumari, Meena ^{[2
]}

Reiner, Alex P. ^{[21
]}

Keating, Brendan J. ^{[1
,22
]}

Humphries, Steve E. ^{[3
]}

Hingorani, Aroon D. ^{[2
]}

Mallat, Ziad ^{[23
]}

Samani, Nilesh J. ^{[7
,8
]}

Talmud, Philippa J. ^{[3
]}

机构：

[1] Univ Penn, Perelman Sch Med, Div Transplant Surg, Philadelphia, PA 19104 USA

[2] UCL, Genet Epidemiol Grp, London WC1E 6JF, England

[3] UCL, Ctr Cardiovasc Genet, London WC1E 6JF, England

[4] UCL, Fac Populat Hlth Sci, Inst Cardiovasc Sci, London WC1E 6JF, England

[5] UCL, Div Med, London WC1E 6JF, England

[6] Novo Nordisk, Dept Mol Genet, Copenhagen, Denmark

[7] Univ Leicester, Dept Cardiovasc Sci, Leicester, Leics, England

[8] Glenfield Hosp, NIHR Leicester Cardiovasc Biomed Res Unit, Leicester, Leics, England

[9] Univ Rovira & Virgili, CIBERDEM, Unitat Recerca Lipids & Arteriosclerosi, E-43201 Reus, Spain

[10] Univ Amsterdam, Acad Med Ctr, Dept Cardiol, NL-1105 AZ Amsterdam, Netherlands

[11] Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England

[12] Karolinska Inst, Atherosclerosis Res Unit, Dept Med Solna, Stockholm, Sweden

[13] Karolinska Inst, Dept Mol Med & Surg, Cardiothorac Surg Unit, Stockholm, Sweden

[14] Karolinska Univ Hosp Solna, Ctr Mol Med, Stockholm, Sweden

[15] Univ Med Ctr Utrecht, Dept Cardiol, Div Heart & Lungs, Utrecht, Netherlands

[16] Univ Med Ctr Utrecht, Dept Med Genet, Utrecht, Netherlands

[17] ICIN Netherlands Heart Inst, Durrer Ctr Cardiogenet Res, Utrecht, Netherlands

[18] Natl Inst Publ Hlth & Environm RIVM, Bilthoven, Netherlands

[19] Univ Groningen, Univ Med Ctr Groningen, Dept Mol Genet, Groningen, Netherlands

[20] Med Univ Lubeck, Med Klin 2, D-23538 Lubeck, Germany

[21] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA

[22] Childrens Hosp Philadelphia, Ctr Appl Genom, Philadelphia, PA 19104 USA

[23] Univ Cambridge, Addenbrookes Hosp, Div Cardiovasc Med, Cambridge CB2 2QQ, England

来源：

CIRCULATION-CARDIOVASCULAR GENETICS | 2014年 / 7卷 / 02期

基金：

英国医学研究理事会; 美国国家卫生研究院;

关键词：

Mendelian randomization analysis; GROUP-V; CARDIOVASCULAR-DISEASE; ARTERY-DISEASE; EPIC-NORFOLK; HEALTHY-MEN; A(2); ASSOCIATION; ATHEROSCLEROSIS; EVENTS; RISK;

D O I：

10.1161/CIRCGENETICS.113.000271

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Background- Secretory phospholipase A(2) (sPLA(2)) enzymes are considered to play a role in atherosclerosis. sPLA(2) activity encompasses several sPLA(2) isoenzymes, including sPLA(2)-V. Although observational studies show a strong association between elevated sPLA(2) activity and CHD, no assay to measure sPLA(2)-V levels exists, and the only evidence linking the sPLA(2)-V isoform to atherosclerosis progression comes from animal studies. In the absence of an assay that directly quantifies sPLA(2)-V levels, we used PLA2G5 mRNA levels in a novel, modified Mendelian randomization approach to investigate the hypothesized causal role of sPLA(2)-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 sPLA(2)-V levels. We tested the association of this SNP with sPLA(2) 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=5.1x10(-6)). There was no association of rs525380C > A with plasma sPLA(2) activity (difference in geometric mean of sPLA(2) 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 sPLA(2)-V levels) and CHD events. The evidence does not support a causal role for sPLA(2)-V in CHD.

引用

页码：144 / 150

页数：7