PLA2G7 Genotype, Lipoprotein-Associated Phospholipase A2 Activity, and Coronary Heart Disease Risk in 10 494 Cases and 15 624 Controls of European Ancestry

被引：96

作者：

Casas, Juan P. ^{[1
,2
,13
]}

Ninio, Ewa ^{[3
,4
]}

Panayiotou, Andrie ^{[5
]}

Palmen, Jutta ^{[6
]}

Cooper, Jackie A. ^{[6
]}

Ricketts, Sally L. ^{[8
]}

Sofat, Reecha ^{[10
]}

Nicolaides, Andrew N. ^{[5
,11
,12
]}

Corsetti, James P.

Fowkes, F. Gerry R. ^{[14
]}

Tzoulaki, Ioanna ^{[15
]}

Kumari, Meena ^{[2
]}

Brunner, Eric J. ^{[2
]}

Kivimaki, Mika ^{[2
]}

Marmot, Michael G. ^{[2
]}

Hoffmann, Michael M. ^{[16
]}

Winkler, Karl ^{[16
]}

Maerz, Winfred ^{[17
]}

Ye, Shu ^{[18
]}

Stirnadel, Heide A. ^{[19
]}

Khaw, Kay-Tee ^{[7
]}

Humphries, Steve E. ^{[6
]}

Sandhu, Manjinder S. ^{[7
,9
]}

Hingorani, Aroon D. ^{[2
,10
]}

Talmud, Philippa J. ^{[6
]}

机构：

[1] London Sch Hyg & Trop Med, Dept Epidemiol & Populat Hlth, London WC1E 7HT, England

[2] UCL, Dept Epidemiol & Publ Hlth, Genet Epidemiol Grp, London, England

[3] Univ Paris 06, INSERM, UMRS937, Paris, France

[4] Fac Med Pierre & Marie Curie, Paris, France

[5] Univ Cyprus, Dept Biol Sci, Nicosia, Cyprus

[6] UCL, Div Cardiovasc Genet, Dept Med, London, England

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

[8] Univ Cambridge, Strangeways Res Lab, Cambridge, England

[9] Wellcome Trust Sanger Inst, Cambridge, England

[10] UCL, Ctr Clin Pharmacol, British Heart Fdn Labs, London, England

[11] Cyprus Cardiovasc Dis Educ & Res Trust, Nicosia, Cyprus

[12] Univ London Imperial Coll Sci Technol & Med, Dept Vasc Surg, London, England

[13] Univ Rochester, Sch Med & Dent, Dept Pathol & Lab Med, Rochester, NY USA

[14] Univ Edinburgh, Ctr Populat Hlth Sci, Edinburgh, Midlothian, Scotland

[15] Univ London Imperial Coll Sci Technol & Med, Div Epidemiol Publ Hlth & Primary Care, London, England

[16] Univ Klinikum Freiburg, Klin Chem Abt, Freiburg, Germany

[17] Synlab Med Versorgungszentrum Lab Diagnost Heidel, Heidelberg, Germany

[18] Queen Mary Univ London, William Harvey Res Inst, Barts & London Sch Med & Dent, London, England

[19] GlaxoSmithKline R&D, Worldwide Epidemiol, Harlow, Essex, England

来源：

CIRCULATION | 2010年 / 121卷 / 21期

基金：

英国医学研究理事会; 英国惠康基金; 美国国家卫生研究院;

关键词：

epidemiology; genetics; mendelian randomization analysis; risk factors; ACTIVATING-FACTOR-ACETYLHYDROLASE; PLASMA PAF-ACETYLHYDROLASE; CARDIOVASCULAR-DISEASE; MYOCARDIAL-INFARCTION; ARTERY-DISEASE; ATHEROSCLEROTIC PLAQUE; GENE; MEN; VARIANT; DEFICIENCY;

D O I：

10.1161/CIRCULATIONAHA.109.923383

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Background-Higher lipoprotein-associated phospholipase A2 (Lp-PLA2) activity is associated with increased risk of coronary heart disease (CHD), making Lp-PLA2 a potential therapeutic target. PLA2G7 variants associated with Lp-PLA2 activity could evaluate whether this relationship is causal. Methods and Results-A meta-analysis including a total of 12 studies (5 prospective, 4 case-control, 1 case-only, and 2 cross-sectional studies; n = 26 118) was undertaken to examine the association of the following: (1) Lp-PLA2 activity versus cardiovascular biomarkers and risk factors and CHD events (2 prospective studies; n = 4884); (2) PLA2G7 single-nucleotide polymorphisms and Lp-PLA2 activity (3 prospective, 2 case-control, 2 cross-sectional studies; up to n = 6094); and (3) PLA2G7 single-nucleotide polymorphisms and angiographic coronary artery disease (2 case-control, 1 case-only study; n = 4971 cases) and CHD events (5 prospective, 2 case-control studies; n = 5523). Lp-PLA2 activity correlated with several CHD risk markers. Hazard ratios for CHD events for the top versus bottom quartile of Lp-PLA2 activity were 1.61 (95% confidence interval, 1.31 to 1.99) and 1.17 (95% confidence interval, 0.91 to 1.51) after adjustment for baseline traits. Of 7 single-nucleotide polymorphisms, rs1051931 (A379V) showed the strongest association with Lp-PLA2 activity, with VV subjects having 7.2% higher activity than AAs. Genotype was not associated with risk markers, angiographic coronary disease (odds ratio, 1.03; 95% confidence interval, 0.80 to 1.32), or CHD events (odds ratio, 0.98; 95% confidence interval, 0.82 to 1.17). Conclusions-Unlike Lp-PLA2 activity, PLA2G7 variants associated with modest effects on Lp-PLA2 activity were not associated with cardiovascular risk markers, coronary atheroma, or CHD. Larger association studies, identification of single-nucleotide polymorphisms with larger effects, or randomized trials of specific Lp-PLA2 inhibitors are needed to confirm or refute a contributory role for Lp-PLA2 in CHD. (Circulation. 2010; 121: 2284-2293.)

引用

页码：2284 / U74

页数：21

共 34 条

[1] Association between the Ala379Val variant of the lipoprotein associated phospholipase A2 and risk of myocardial infarction in the north and south of Europe [J].

Abuzeid, AM ;

Hawe, E ;

Humphries, SE ;

Talmud, PJ .

ATHEROSCLEROSIS, 2003, 168 (02) :283-288

[2]

[Anonymous], 2007, NATURE, V447, P661, DOI DOI 10.1038/NATURE05911

[3] Lipoprotein-associated phospholipase A2, high-sensitivity C-reactive protein, and risk for incident coronary heart disease in middle-aged men and women in the Atherosclerosis Risk in Communities (ARIC) study [J].

Ballantyne, CM ;

Hoogeveen, RC ;

Bang, H ;

Coresh, J ;

Folsom, AR ;

Heiss, G ;

Sharrett, AR .

CIRCULATION, 2004, 109 (07) :837-842

[4] Plasma PAF-acetylhydrolase in patients with coronary artery disease: results of a cross-sectional analysis [J].

Blankenberg, S ;

Stengel, D ;

Rupprecht, HJ ;

Bickel, C ;

Meyer, J ;

Cambien, F ;

Tiret, L ;

Ninio, E .

JOURNAL OF LIPID RESEARCH, 2003, 44 (07) :1381-1386

[5] High lipoprotein-associated phospholipase A2 is a risk factor for recurrent coronary events in postinfarction patients [J].

Corsetti, JP ;

Rainwater, DL ;

Moss, AJ ;

Zareba, W ;

Sparks, CE .

CLINICAL CHEMISTRY, 2006, 52 (07) :1331-1338

[6]

Day N, 1999, BRIT J CANCER, V80, P95

[7] Integrated associations of genotypes with multiple blood biomarkers linked to coronary heart disease risk [J].

Drenos, Fotios ;

Talmud, Philippa J. ;

Casas, Juan P. ;

Smeeth, Liam ;

Palmen, Jutta ;

Humphries, Steve E. ;

Hingorani, Aroon D. .

HUMAN MOLECULAR GENETICS, 2009, 18 (12) :2305-2316

[8]

Garza CA, 2007, MAYO CLIN PROC, V82, P159

[9] Nature's randomised trials [J].

Hingorani, A ;

Humphries, S .

LANCET, 2005, 366 (9501) :1906-1908

[10] Genetic variants and haplotypes of lipoprotein associated phospholipase A2 and their influence on cardiovascular disease (The Ludwigshafen Risk and Cardiovascular Health Study) [J].

Hoffmann, M. M. ;

Winkler, K. ;

Renner, W. ;

Winkelmann, B. R. ;

Seelhorst, U. ;

Wellnitz, B. ;

Boehm, B. O. ;

Maerz, W. .

JOURNAL OF THROMBOSIS AND HAEMOSTASIS, 2009, 7 (01) :41-48

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