PLA2G7 Genotype, Lipoprotein-Associated Phospholipase A2 Activity, and Coronary Heart Disease Risk in 10 494 Cases and 15 624 Controls of European Ancestry
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.
Received November 13, 2009; accepted April 5, 2010.
Lipoprotein-associated phospholipase A2 (Lp-PLA2) is synthesized in macrophages and activated platelets, transported in the circulation on high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol particles, and present in atheromatous plaques. Its effects could be proatherogenic, through the generation of lysophosphatidylcholine and oxidized fatty acids, or antiatherogenic, through the hydrolysis of the proinflammatory mediator platelet-activating factor and its analogues formed on oxidation of LDL (reviewed by Karabina and Ninio1).
Clinical Perspective on p 2293
To date, >25 prospective cohort studies (of both general populations and individuals with established coronary heart disease [CHD]) have reported a consistent association of circulating Lp-PLA2 mass or activity with an increased risk of CHD. A literature-based meta-analysis of 14 studies reported an odds ratio (OR) of 1.21 (95% confidence interval [CI], 1.11 to 1.32) for a 1-SD increase in Lp-PLA2 mass and activity.2 Lp-PLA2 is also associated with other cardiovascular risk factors. For example, individuals with higher levels of Lp-PLA2 tend to be older and to have higher levels of total cholesterol, LDL cholesterol, triglycerides, and apolipoprotein B, higher blood pressure and body mass index, and lower levels of HDL cholesterol.3,4 However, it is uncertain whether ≥1 of these associated cardiovascular risk factors should be considered a mediator or confounder of the Lp-PLA2/CHD association.
Darapladib, the first specific inhibitor of Lp-PLA2 activity, reduced the volume of the necrotic core of atheromatous plaque in a pig model5 and in a randomized trial in humans in which intravascular coronary ultrasound was used to image coronary atheroma.6 This effect was achieved without an alteration in blood lipids. The effect of darapladib on cardiovascular events is currently being addressed in the ongoing Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy (STABILITY) trial (NCT00799903), a phase III outcome trial that will recruit up to 15 500 individuals.
In this study, we investigated the relationship between common variants at PLA2G7 (encoding Lp-PLA2) and Lp-PLA2 activity, cardiovascular risk factors, angiographic CHD, and coronary events in a large collaborative analysis of European populations, exploiting the randomized allocation of alleles7 to better understand the nature of the association between Lp-PLA2 and CHD.
Twelve studies were included in the analysis (full details from each study are provided in Methods and Table I in the online-only Data Supplement). Ethical approval from relevant ethical committees was obtained for all studies.
Four of the 5 prospective cohort studies used population-based sampling: the Second Northwick Park Heart Study (NPHS-II),8 the European Prospective Investigation Into Cancer and Nutrition Study, Norfolk-UK component (EPIC-Norfolk),9 the Edinburgh Artery Study (EAS),10 and the Cyprus study.11 In contrast, the Whitehall-II Study (WH-II) was workplace based.12 In EPIC-Norfolk, the analysis was based on a nested subset of CHD cases and controls matched for age, sex, and study enrollment date.
The Hypercoagulability and Impaired Fibrinolytic Function Mechanisms Predisposing to MI (HIFMECH) study is a European multicenter case-control study of myocardial infarction (MI). A total of 527 cases (nonfatal events) and 566 controls were available for genotyping.13 AtheroGene3 had 1318 individuals with coronary artery disease (CAD), defined as a diameter stenosis ≥30% in at least 1 major coronary artery, and a total of 485 healthy individuals. In the Ludwigshafen Risk and Cardiovascular Health Study (LURIC), a CAD case was defined as having ≥20% coronary stenosis in at least 1 of 15 coronary segments; a control was free of angiographic evidence of coronary stenosis (731 controls and 2581 cases).14 Information from the Wellcome Trust Case-Control Study on CHD Infarction (WTCCC-CHD) was requested for single-nucleotide polymorphisms (SNPs) in strong linkage disequilibrium with the SNP rs1051931. This study contributed a total of 1988 CHD cases and 3004 controls.15
For the Southampton Atherosclerosis Study (SAS), 1164 individuals with stenosis ≥50% in at least 1 major epicardial coronary artery were included for genotyping. For SAS, the NPHS-II prospective study was utilized as the control population for SNP-disease associations. Both studies are based in the United Kingdom from similar geographic areas of recruitment.16
The UCL Diabetes and Cardiovascular Disease Study (UDACS) sought to evaluate cardiovascular risk factors for CHD in subjects with type 2 diabetes mellitus. In this study, only individuals of European descent (n=424) without CHD were included.17 For the Thrombogenic Factors and Recurrent Coronary Events Study (THROMBO)18 of MI survivors, 529 individuals with DNA information available were included in this analysis. Blood markers (including Lp-PLA2 activity) included in the THROMBO study and presented here were determined 2 months after the index MI. For the present analyses, only the baseline information was utilized because coronary events were recurrent instead of incident events.
Following a predetermined analysis plan, we obtained information on Lp-PLA2 activity, cardiovascular risk factors, PLA2G7 variants, and cardiovascular events from 11 participating studies within the collaboration. Unified definitions of all relevant variables utilized in the analysis were used. For a subset of predefined variables (Lp-PLA2 activity, C-reactive protein, and triglycerides), natural logarithmic transformations were used, and these variables were analyzed on a logarithmic scale. Covariates included in the different multivariate models utilized to calculate risk of CHD were coded homogeneously across all of the studies. We used study-specific definitions for cardiovascular events (Table I in the online-only Data Supplement). Studies were then divided into 2 categories: those with CHD events as an outcome (EPIC-Norfolk, NPHS-II, WH-II, EAS, Cyprus, HIFMECH, and WTCCC-CHD) and those with CAD defined by coronary angiography as an outcome (SAS, AtheroGene, and LURIC). All of the analyses were limited to individuals of identified European descent.
Information on Lp-PLA2 activity was available from 6 of the studies. To reduce interstudy variability, plasma Lp-PLA2 activity in AtheroGene, EPIC-Norfolk, NPHS-II, UDACS, and Cyprus was determined in a single laboratory (Dr Ewa Ninio at INSERM UMRS937, Paris, France) with the use of a radiometric assay, as reported previously.3,19 For these studies, a pool of plasma (always the same) was used to correct the data for interassay variability. For the THROMBO study, plasma Lp-PLA2 activity was determined by a commercial colorimetric assay (Cayman Chemical Co) with 2-thio-PAF as substrate and according to the manufacturer’s directions.18 For the LURIC study, Lp-PLA2 activity was measured by use of the Azwell Auto PAF-AH reagent set (Azwell).20 The within-assay variability was <10%.
Genotyping of SNPs in the PLA2G7 Gene
Within the NPHS-II study, 12 tagging SNPs were identified in PLA2G7 on the basis of a minor allele frequency (MAF) threshold >0.04 and r2>80% (Figure I in the online-only Data Supplement). In addition to rs1051931 (which encodes A379V), the SNPs rs974670, rs1421378, rs1805017 (R92H), and rs9381475 were chosen for further investigation on the basis of initial association of Lp-PLA2 activity in NPHS-II (Table II in the online-only Data Supplement) and the recent report by Sutton et al,21 which examined the association of PLA2G7 tagging SNPs and CHD risk. Genotype data on rs1051931 were available for 11 studies. The SNPs rs974670, rs1421378, rs1805017, and rs9381475 were previously genotyped in EPIC-Norfolk, EAS, Cyprus, AtheroGene, UDACS, and THROMBO. In addition, SNPs rs10948300 and rs2216465 were already genotyped in UDACS and EPIC-NORFOLK. For the WTCCC-CHD, we utilized the SNP rs9472819, which is in complete linkage disequilibrium (r2=1) with rs1051931. Details of the SNPs, genotyping methods, and MAFs are summarized in the Table.
The association between Lp-PLA2 activity and CHD was assessed in the prospective NPHS-II and EPIC-Norfolk studies and pooled with the use of random effects models. Within each study, a hazard ratio (NPHS-II) and odds ratio (EPIC-Norfolk) and 95% CI for CHD by quartiles of Lp-PLA2 activity were obtained, with the bottom quartile used as the reference group. Progressive adjustment for potential confounders was made in 3 separate models, as follows: Model 1 included age (continuous) and sex plus enrollment date in EPIC-Norfolk and practice center in NPHS-II. Model 2 included these variables together with body mass index (continuous), smoking (current and ex-smoker versus never), diabetes mellitus (yes versus no), systolic blood pressure (continuous), fibrinogen (continuous), C-reactive protein (continuous log-transformed), and alcohol (continuous as units per week). Model 3 included all preceding covariates with the addition of total cholesterol (continuous), triglycerides (continuous log-transformed), apolipoprotein B (continuous), and apolipoprotein AI (continuous). Because complete genotype and phenotype data were not available for all 11 studies, the number included in the analysis of the relationship between PLA2G7 genotype and Lp-PLA2 activity, PLA2G7 genotype and other intermediate traits, and PLA2G7 genotype and CHD/angiographic CAD events differs. We detail, for each analysis, the number of studies and individuals included. The mean difference in log-Lp-PLA2 activity for each PLA2G7 SNP was obtained from 7 studies (NPHS-II, EPIC-Norfolk, Cyprus, UDACS, and THROMBO; for AtheroGene and LURIC, only the control group was used in this analysis) including up to 6094 individuals. The effect on cardiovascular risk factors of each PLA2G7 SNP was evaluated in all studies except SAS and WTCCC-CHD (10 studies and 13 544 individuals).
The association between PLA2G7 SNPs and CHD events was assessed in 10 studies (NPHS-II, EPIC-Norfolk, WH-II, HIFMECH, EAS, Cyprus, LURIC, AtheroGene, SAS, and WTCCC-CHD) for a total of up to 10 494 cases. The cross-sectional studies UDACS and THROMBO were not included in this analysis. Within each study, a log-OR and SE adjusted for age (continuous) and sex were obtained for each genotype comparison: subjects heterozygous versus individuals homozygous for the common allele (reference group), as well as those homozygous for the rare allele versus those homozygous for the common allele. For the WTCCC-CHD study, genotype counts were utilized to calculate an unadjusted OR for the different genotype comparisons. For all previous analyses, results across studies were pooled with the use of random effects models. No imputations for missing phenotype of genotype data were conducted. The outcome under evaluation (angiographic CAD versus CHD events) and study design (prospective versus case-control) were evaluated as potential sources of heterogeneity by meta-regression. With the combined data set, comprising 4971 cases of angiographic CAD, 5523 CHD events, and 15 624 controls, we had 95% power at P=0.001 to detect a per-allele OR of 1.2 (http://pngu.mgh.harvard.edu/≈purcell/gpc/).22
Lp-PLA2 Activity, Cardiovascular Risk Factors, and Risk of CHD
In 2 prospective studies (NPHS-II and EPIC-Norfolk) including 1030 cases and 3852 controls, body mass index, blood pressure, total cholesterol, LDL cholesterol, apolipoprotein B, and triglycerides were all higher by quartiles of increasing Lp-PLA2 activity. By contrast, Lp-PLA2 activity was inversely correlated with HDL cholesterol and apolipoprotein AI. No clear associations were observed with the emerging cardiovascular risk factors fibrinogen and C-reactive protein (Figure 1).
Higher Lp-PLA2 activity was associated with a graded increase in risk of CHD with no evidence of a threshold (Figure 2, left panel). Individuals in the top quartile had a hazard ratio for CHD of 1.61 (95% CI, 1.31 to 1.99) compared with individuals from the bottom quartile in a model adjusted for age, sex, and enrollment date (model 1). The magnitude of the Lp-PLA2/CHD association diminished slightly with additional adjustment for body mass index, smoking, diabetes mellitus, systolic blood pressure, C-reactive protein, fibrinogen, and alcohol consumption (model 2; hazard ratio of 1.56; 95% CI, 1.24 to 1.96). When additional adjustment was made for total cholesterol, apolipoprotein B, apolipoprotein AI, and triglycerides (model 3), the hazard ratio for CHD fell further to 1.17 (95% CI, 0.91 to 1.51) in individuals in the top quartile for Lp-PLA2 activity (Figure 2, right panel).
Of the 4 SNPs in which genotype data were available from the 12 studies (Table), only on 4 occasions was a borderline lack of Hardy-Weinberg equilibrium observed, with P=0.05 to P=0.03. Because by chance alone we would expect 2 SNPs not to be in Hardy-Weinberg equilibrium, the borderline deviation from Hardy-Weinberg proportions is unlikely to affect the pooled analysis.
PLA2G7 Variants and Lp-PLA2 Activity
The studies NPHS-II, EPIC-Norfolk, Cyprus, UDACS, AtheroGene, LURIC, and THROMBO contributed information on ≥1 of 7 PLA2G7 SNPs and Lp-PLA2 activity levels (expressed as a log-ratio) (Figure 3).
Using individuals homozygous for the common allele in each case as the reference group, we observed a statistically significant additive increase in Lp-PLA2 activity in individuals carrying rs1051931 (A379V; n=5801). Compared with those homozygous for the common allele (AA), individuals homozygous for the rare allele (VV) had a relative difference in Lp-PLA2 activity of 7.2%, and heterozygous subjects (AV) had a 3% relative difference. A trend was observed toward an inverse association with Lp-PLA2 activity for the following gene variants: rs1421378 (n=5141), rs1805017 (R92H; n=6094), and rs2216465 (n=3471). None of these variants exhibited strong linkage disequilibrium (r2<0.2) with the rs1051931. A null association with the levels of Lp-PLA2 activity was observed for the variants rs974670, rs9381475, and rs10948300 (Figure 3). For all previous analyses, the exclusion of the THROMBO study did not modify the results (data available on request).
PLA2G7 Variants and Cardiovascular Risk Factors
The SNP rs1051931, with the largest effect on Lp-PLA2 activity, was not associated with any of the cardiovascular risk factors correlated with Lp-PLA2 activity itself, despite a large data set for body mass index (n=4036), systolic blood pressure (n=4036), LDL cholesterol (n=3292), and HDL cholesterol (n=3387) (Figure 4). We observed no effect of the rs1051931 variant on additional cardiovascular risk factors such as diastolic blood pressure, glucose, and homocysteine (data available on request).
PLA2G7 Gene Variants and Risk of CHD
In pooled analysis of data from 10 studies (NPHS-II, EPIC-Norfolk, Cyprus, AtheroGene, LURIC, THROMBO, WH-II, SAS, EAS, and WTCCC-CHD), with the total number of combined outcomes ranging from 1627 to 10 494, there was no clear association of any of the 7 PLA2G7 variants with risk of CHD (Figure 5A), including rs1051931 (10 494 events), which was consistently associated with a modest difference in Lp-PLA2 activity (Figure 3). The null association of the rs1051931 variant was preserved when CHD events and angiographically evaluated CAD were analyzed separately. No significant heterogeneity was observed according to the outcome evaluated (CHD event versus angiographic CAD) or according to study design (prospective versus case-control). All P values, derived from meta-regression, for the different genotype comparisons were >0.1 (Figure 5B).
In this analysis of pooled data from 12 studies with 26 118 participants, we identified a clear association of Lp-PLA2 activity with risk of CHD, but the effect size was sensitive to the degree of adjustment for covariables including blood lipids, with which Lp-PLA2 activity is also associated. Several PLA2G7 variants that were associated with Lp-PLA2 activity did not exhibit any association with a wide range of established and novel cardiovascular risk factors, suggesting that their association with CHD events or angiographic CHD should be less prone to confounding. Despite some of the variants showing association with Lp-PLA2 activity, none showed a clear association with angiographic coronary disease or CHD events. However, this null result needs to be interpreted in the light of the relatively weak influence of these SNPs on Lp-PLA2 activity, the available sample size, and therefore the statistical power of the study.
The association of Lp-PLA2 activity with CHD risk was modified by the adjustment for other cardiovascular risk factors in a multivariate analysis, with the attenuation in effect size being most marked when blood lipids were entered into the model. This involves a judgment on which variables should be considered potential mediators of the association and which should be considered confounders. Confounding factors should be balanced among groups of individuals categorized by genotype for common SNPs in PLA2G7 that affect Lp-PLA2 activity because genotype is determined by randomized allocation at conception. We therefore identified variants in PLA2G7 associated with Lp-PLA2 activity and studied their effect on other cardiovascular risk factors and CHD events. A careful selection of the PLA2G7 SNPs was conducted to minimize the likelihood of a false-negative finding because of inadequate selection of genetic tools. This included the identification of common tag SNPs for individuals of European descent who were initially evaluated in the NPHS-II study and whose results were then complemented with published evidence on the effects of PLA2G7 variants on Lp-PLA2 activity and disease risk,21 enabling a final selection of the 7 variants utilized in the genetic component of the analysis. Of the 7 SNPs used, 4 (rs1051931, rs1421378, rs1805017, and rs2216465) exhibited association with Lp-PLA2 activity (Figure 3), although the magnitude of these associations was small to moderate. Indeed, rs1051931, which showed the strongest association, displayed only a relative difference on Lp-PLA2 activity of 7.2% and 3% for rare allele homozygotes and heterozygotes, respectively (Figure 3); the other variants showed associations of similar or lower magnitude.
Lp-PLA2 activity itself was correlated with a range of blood lipids in the present analysis, and the findings are consistent with those of the Framingham Heart Study.23 However, we found that rs1051931, which displayed the largest effect on Lp-PLA2 activity, showed no association with blood lipids. This observation is consistent with data from the 2 short-term randomized trials in humans in which the Lp-PLA2 inhibitor darapladib was used.6,24 Even though Lp-PLA2 activity was reduced by ≈60% (at a dose of 160 mg daily), darapladib did not modify the concentrations of the lipid particles (LDL cholesterol, HDL cholesterol, or triglycerides). These findings in combination suggest that blood lipids may be confounders rather than mediators for the association between Lp-PLA2 activity and CHD risk.
In the present study, variants that affect Lp-PLA2 activity were not associated with coronary atheroma detected by angiography. The absence of an effect on the degree of coronary stenosis could be consistent with experimental studies in a pig model of diabetic hyperlipidemia and a human trial of darapladib.5,6,24 In the pig study, 24-week treatment with darapladib led to only a modest reduction in coronary lesion size, but treated animals showed a significant alteration in their plaque composition with a smaller necrotic core populated by fewer inflammatory cells, suggesting that darapladib treatment may reduce plaque composition and vulnerability independent of blood lipid changes. Similarly, in human studies of darapladib, there were detectable reductions in the area of the necrotic core of atheromatous plaques in coronary arteries of patients receiving the drug.24 The hypothesis that this may translate to a reduction in plaque rupture and clinical events is now being tested in the STABILITY trial.
There was no clear signal for an effect of PLA2G7 variants on CHD, despite the inclusion of >10 494 cases (Figure 5A and 5B). However, given the small to modest effect of common alleles at the PLA2G7 locus on Lp-PLA2 activity, and when one considers the strength of the association of Lp-PLA2 activity and CHD risk (Figure 2), a per-allele OR as low as 1.05 (which we were insufficiently powered to detect) could still be compatible with a contributory role of Lp-PLA2 to CHD. Other genetic studies examining this question have yielded inconsistent findings.25,26 In a Taiwanese study of MIs before the age of 45 years, the rare allele of rs1051931 was associated with increased risk of an event (OR=1.66 [95% CI, 1.14.1 to 5.80]), despite being associated with lower Lp-PLA2 activity, whereas the V279F variant showed no association with enzyme activity or risk of MI.27 In a case-control study in Chinese subjects of the 7 SNPs in PLA2G7 studied singly or as haplotypes, only the promoter SNP rs13210554 (not included in our analysis) was associated with increased CHD risk, whereas the V279F variant and rs1805018 (but not rs1805017 or rs1051931) showed an association with lower Lp-PLA2 activity but were not associated with CHD risk.28 However, Sutton et al21 reported a significant association of PLA2G7 variants, including rs1805017 and rs1051931, with CHD risk in 2 multiethnic studies.
Lp-PLA2 activity levels are stable among healthy subjects or patients with stable coronary disease.29 It is important to consider whether other genetic variants might help to delineate the mechanisms underlying the association between Lp-PLA2 activity and CHD. Genetic variants other than in PLA2G7 itself, in the genes MEF2A, CXCL12, VEGF, PTGIS, and CD44 (presumably acting in trans), may influence Lp-PLA2 activity.23 We also reported previously that variants in the APOE cluster explained ≈4% of the variance in Lp-PLA2.30 However, variants in the vicinity of PLA2G7 itself (acting in cis) provide a much more specific genetic tool than variants located outside this gene that could influence other pathways. A number of approaches could be undertaken to overcome the problem that the PLA2G7 SNPs studied thus far are weak genetic instruments, which compromises statistical power. These include expanding the data set of European subjects included in a mendelian randomization analysis; resequencing of the PLA2G7 gene in individuals of European ancestry to identify less frequent variants with more extreme effects on Lp-PLA2 activity; and undertaking more studies in subjects of Asian ancestry, among whom there is a common loss-of-function variant (V279F) associated with a very substantial reduction in enzyme activity with a frequency of heterozygotes of 25% and homozygotes of 1% to 4%.31,32 The results from the association studies on this V279F variant have thus far been inconclusive. Earlier hospital-based studies have indicated that subjects carrying the mutant allele are at higher risk of arterial events (MI or stroke), as indicated in the study by Yamada et al33 including up to 850 cases and 1684 controls. However, more recently, a Korean case-control study (532 cases and 670 controls) showed opposite results,34 and a Chinese study of 827 cases and 947 controls did not find a significant association between the null variant and CHD.28
In summary, in a tagging SNP approach with the use of common PLA2G7 variants in a large-scale collaboration including ≈26 000 European individuals, 4 SNPs were identified with small to moderate association with Lp-PLA2 activity but with no effect on lipid variables or CHD risk. However, the modest effect of these variants on Lp-PLA2 activity means that their expected effect on CHD risk, were Lp-PLA2 to be contributory, would be predicted to be small, and even though the collaboration included >10 400 cases, it may lack sufficient power to detect a genetic effect consistent with a causal role for Lp-PLA2 in CHD. The STABILITY trial should provide information on the efficacy and safety of darapladib in particular and Lp-PLA2 inhibition in general for the prevention of CHD events in a number of ethnic groups.
We would like to thank Hervé Durand and Sofie Ashford for excellent technical assistance. This study makes use of data generated by the Wellcome Trust Case-Control Consortium. A full list of the investigators who contributed to the generation of the data is available from http://www.wtccc.org.uk.
Sources of Funding
Funding for Wellcome Trust Case-Control Consortium was provided by the Wellcome Trust under award 085475. In France, this work was supported by the Institut National de la Santé et de la Recherche Médicale. Dr Ninio is Director of Research of Centre National de la Recherche Scientifique. This work was supported by an educational grant from GlaxoSmithKline (Drs Talmud and Sandhu) and by the British Heart Foundation Program grant RG05/014 and a senior fellowship to Dr Hingorani (FS2005/125). Dr Ricketts is funded by the British Heart Foundation. Dr Sofat is a British Heart Foundation (Schillingford) Clinical Training Fellow (FS/07/011). The Cyprus study was supported by a joint Cyprus Research Promotion Foundation, Ministry of Health, and Cyprus Heart Foundation grant (41/5PE). Dr Ye thanks support from the British Heart Foundation (PG98/183). The Whitehall II study has been supported by grants from the Medical Research Council; British Heart Foundation; Health and Safety Executive; Department of Health; National Institute on Aging (AG13196), US National Institutes of Health; Agency for Health Care Policy Research (HS06516); and the John D. and Catherine T. MacArthur Foundation Research Networks on Successful Midlife Development and Socioeconomic Status and Health.
Professor Hingorani is a member of the Editorial Board of Drug and Therapeutics Bulletin and has provided nonremunerated advice to London Genetics and GlaxoSmithKline. Dr Stirnadel is an employee of GlaxoSmithKline.
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Lipoprotein-associated phospholipase A2 (Lp-PLA2) is transported in the circulation on high-density lipoprotein and low-density lipoprotein cholesterol particles and is present in atheromatous plaques, where it may exert proatherogenic effects through generation of lysophosphatidylcholine and oxidized fatty acids. Higher Lp-PLA2 activity is associated with increased risk of coronary heart disease (CHD) in observational studies, making Lp-PLA2 a potential therapeutic target. However, higher Lp-PLA2 activity may simply mark alterations in blood lipids and other CHD risk factors, reflect (rather than contribute to) plaque, or even play an antiatherogenic role through the hydrolysis of the proinflammatory mediator platelet-activating factor and its analogues formed on oxidation of low-density lipoprotein cholesterol. We identified common variants of the PLA2G7 gene that encodes Lp-PLA2 associated with Lp-PLA2 activity and used these to clarify the nature of the association of Lp-PLA2 with other putative risk factors and CHD events using mendelian randomization. Genetic variants associated with modest effects on Lp-PLA2 activity were not associated with major alterations in cardiovascular risk factors, coronary atheroma, or CHD events. Larger mendelian randomization analyses, perhaps with the use of variants associated with larger effects on Lp-PLA2 activity, and randomized trials of specific Lp-PLA2 inhibitors will be needed to confirm or refute a contributory role for Lp-PLA2 in CHD.
From the Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, UK (J.P.C.); Genetic Epidemiology Group, Department of Epidemiology and Public Health, University College London, London, UK (J.P.C., M. Kumari, E.J.B., M. Kivimaki, M.G.M., A.D.H.); INSERM UMRS937, UPMC University Paris 06 and Faculté de Médecine Pierre et Marie Curie, Paris, France (E.N.); Department of Biological Sciences, University of Cyprus, Nicosia, Cyprus (A.P., A.N.N.); Division of Cardiovascular Genetics, Department of Medicine, University College London, London, UK (J.P., J.A.C., S.E.H., P.J.T.); Department of Public Health and Primary Care (K.K., M.S.S.), Strangeways Research Laboratory (S.L.R.), University of Cambridge, Cambridge, UK; Genetic Epidemiology, Wellcome Trust Sanger Institute, Cambridge, UK (M.S.S.); Centre for Clinical Pharmacology, British Heart Foundation Laboratories at University College London, London, UK (R.S., A.D.H.); Cyprus Cardiovascular Disease Educational and Research Trust, Nicosia, Cyprus (A.N.N.); Department of Vascular Surgery, Imperial College, London, UK (A.N.N.); Department of Pathology and Laboratory Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY (J.P.C.); Centre for Population Health Sciences, University of Edinburgh, Teviot Place, Edinburgh, UK (F.G.R.F.); Division of Epidemiology, Public Health and Primary Care, Imperial College, St Mary’s Campus, London, UK (I.T.); Abteilung für Klinische Chemie, Innere Medizin, Universitätsklinikum Freiburg, Freiburg, Germany (M.M.H., K.W.); Synlab Medizinisches Versorgungszentrum für Labordiagnostik Heidelberg, Heidelberg, Germany (W.M.); William Harvey Research Institute, Barts, and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK (S.Y.); and Worldwide Epidemiology, GlaxoSmithKline R&D, Harlow, UK (H.A.S.).
The online-only Data Supplement is available with this article at http://circ.ahajournals.org/cgi/content/full/CIRCULATIONAHA.109.923383/DC1.
Correspondence to Dr Juan P. Casas, Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, Keppel St, London WC1E 7HT, London, UK. E-mail Juan.firstname.lastname@example.org