Published online before print April 30, 2007, doi: 10.1161/CIRCULATIONAHA.106.667584
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(Circulation. 2007;115:2490-2496.)
© 2007 American Heart Association, Inc.
Genetics |
Heritability of Platelet Responsiveness to Aspirin in Activation Pathways Directly and Indirectly Related to Cyclooxygenase-1
From the Department of Anesthesiology/Critical Care Medicine, Division of Cardiac Surgical Intensive Care (N.F.), Department of Medicine, Division of General Internal Medicine (L.R.Y., J.E.H.-G., D.V., T.F.M., D.M.B.), and Department of Medicine, Division of Cardiology (L.C.B.), Johns Hopkins Medical Institutions, Baltimore, Md; Inherited Disease Research Branch, National Human Genome Research Institute/National Institutes of Health, Baltimore, Md (R.M., A.F.W.); Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Md (M.D.F.); and Department of Medicine, Division of Hematology, Jefferson Medical College, Philadelphia, Pa (P.F.B.).
Correspondence to Nauder Faraday, MD, 298 Meyer Bldg, Johns Hopkins Hospital, 600 N Wolfe St, Baltimore, MD 21287. E-mail nfaraday{at}jhmi.edu
Received September 30, 2006; accepted February 23, 2007.
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Abstract |
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Background— The inability of aspirin (acetylsalicylic acid [ASA]) to adequately suppress platelet function is associated with future risk of myocardial infarction, stroke, and cardiovascular death. Genetic variation is a proposed but unproved mechanism for insufficient ASA responsiveness.
Methods and Results— We examined platelet ASA responsiveness in 1880 asymptomatic subjects (mean age, 44±13 years; 58% women) recruited from 309 white and 208 black families with premature coronary heart disease. Ex vivo platelet function was determined before and after ingestion of ASA (81 mg/d for 2 weeks) with the use of a panel of measures that assessed platelet activation in pathways directly and indirectly related to cyclooxygenase-1, the enzyme inhibited by ASA. The proportion of phenotypic variance related to CHD risk factor covariates was determined by multivariable regression. Heritability of phenotypes was determined with the use of variance components models unadjusted and adjusted for covariates. ASA inhibited arachidonic acid–induced aggregation and thromboxane B2 production by 
99% (P<0.0001). Inhibition of urinary thromboxane excretion and platelet activation in pathways indirectly related to cyclooxygenase-1 was less pronounced and more variable (inhibition of 0% to 100%). Measured covariates contributed modestly to variability in ASA response phenotypes (r2=0.001 to 0.133). Phenotypes indirectly related to cyclooxygenase-1 were strongly and consistently heritable across races (h2=0.266 to 0.762; P<0.01), but direct cyclooxygenase-1 phenotypes were not.
Conclusions— Heritable factors contribute prominently to variability in residual platelet function after ASA exposure. These data suggest a genetic basis for the adequacy of platelet suppression by ASA and potentially for differences in the clinical efficacy of ASA.
Key Words: antiplatelet agents • aspirin • genetics • platelets
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Introduction |
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Insufficient suppression of platelet function by aspirin (acetylsalicylic acid [ASA]) is associated with differences in cardiovascular outcome among individuals with atherosclerosis. In particular, individuals in whom ASA fails to suppress urinary thromboxane excretion,1 platelet aggregation,2 or platelet function analyzer (PFA) closure time3 are reported to be at increased risk of myocardial infarction, stroke, and cardiovascular death. Diminished suppression of urinary thromboxane excretion is also associated with a higher predicted risk of future cardiovascular events among asymptomatic subjects without manifest coronary heart disease (CHD).4
Editorial p 2468
Clinical Perspective p 2496
Multiple mechanisms are proposed to account for variability in the ability of ASA to suppress platelet function and reduce cardiovascular morbidity. Much attention has focused on variability in the ability of ASA to inhibit cyclooxygenase-1 (COX-1) and thromboxane-dependent platelet activation, which is the major mechanism of action of ASA.5 However, in the presence of sufficient ASA dosing and compliance,6–9 failure of ASA to inhibit COX-1–dependent platelet activation appears to be uncommon. Platelets may also be activated along pathways that are only partially dependent or independent of COX-1, and variability in residual platelet reactivity along these pathways may also contribute to differences in platelet function ex vivo and clinical outcome in vivo among ASA-treated individuals. Frelinger et al10 and Ohmori et al11 reported residual platelet activation in ASA-treated patients that was independent of COX activity, and residual activation in the collagen pathway was associated with an 8-fold excess in the occurrence of future cardiovascular morbidity.11
Genetic variation in the molecules responsible for platelet activation is an important potential contributor to the adequacy of the antiplatelet action of ASA. Thus far, small studies examining the relation between platelet function and specific gene variants in pathways directly12,13 and indirectly14–16 related to COX-1 have not provided consistent evidence for a gene-ASA response relation. To better understand whether genetic variation contributes to platelet ASA responsiveness, we determined the heritability of platelet response phenotypes in asymptomatic subjects recruited from white and black families with a history of premature CHD.
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Methods |
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Participants and Study Design
The study was approved by the Johns Hopkins institutional review board, and all subjects provided written informed consent. Subjects were identified from white and black families participating in a 24-year prospective study of apparently healthy siblings of patients with premature CHD (onset age <60 years). Siblings of index patients along with the sibling’s adult offspring and the offspring’s coparent were recruited. Subjects were eligible if they were free of CHD or any bleeding disorder or prior hemorrhagic event and had no serious comorbidity. Subjects were excluded if they had a history of ASA allergy or intolerance, baseline platelet count <100 000 or >500 000, hematocrit <30%, or white blood cell count >20 000. ASA and NSAID use were prohibited for 10 days before the baseline visit and throughout the study interval. Subjects were considered screen failures and excluded from analysis if aggregation to arachidonic acid in both whole blood and platelet-rich plasma (PRP) equaled zero at the baseline visit, suggesting intake of ASA or NSAIDs at baseline. Subjects were given a supply of 81-mg ASA tablets and instructed to take 1 pill each day for 14 days. Adherence to ASA use was assessed at the post-ASA visit by a modified Hill-Bone compliance questionnaire17 and pill counts.
Blood and Urine Sample Collection
Blood and urine were sampled at the same time of day before and after ASA use to reduce the effect of circadian rhythm on platelet function. Blood was collected via venipuncture into Vacutainer tubes containing EDTA, 3.2% sodium citrate, or serum separator as appropriate. Platelet counts were determined by automated cell counter (ACT-Diff, Beckman-Coulter, Miami, Fla). Platelet functional studies were completed within 2 hours of blood drawing. Plasma, serum, and urine were stored at –80°C until analyzed.
Assessment of Platelet Function
Optical aggregation was measured in PRP (200 000 platelets per microliter) in a PAP-4 Aggregometer (Horsham, Pa) after samples were stimulated with arachidonic acid (1.6 mmol/L; intra-assay coefficient of variation [CV]=7%), collagen (1, 2, 5 µg/mL; intra-assay CV=16%), ADP (2, 10 µmol/L; intra-assay CV=9%), or epinephrine (2, 10 µmol/L; intra-assay CV=20%). Whole blood impedance aggregation was measured in a Chrono-Log dual-channel lumiaggregometer (Havertown, Pa) after samples were stimulated with arachidonic acid (0.5 mmol/L, intra-assay CV=24%), collagen (1, 5 µg/mL; intra-assay CV=9%), or ADP (10 µmol/L; intra-assay CV=46%). For each subject, 1 whole blood sample was incubated with ASA in vitro (20 µmol/L for 15 minutes) before stimulation with arachidonic acid. Peak aggregation within 5 minutes of agonist stimulation was recorded as percent aggregation for PRP and as ohms for whole blood. Time from addition of collagen to start of aggregation was recorded as lag time (intra-assay CV=10%).
We measured platelet release of thromboxane B2 (TXB2) and ß-thromboglobulin ex vivo as follows: 5 minutes after whole blood aggregation was stimulated with collagen (1 µg/mL), samples were quenched with an equal volume of ice-cold acid-citrate-dextrose-indomethacin solution. Samples were centrifuged at 14 000g for 2 minutes, and the supernatant was frozen at –80°C. TXB2 (Assay Designs, Inc, Ann Arbor, Mich; intra-assay CV=15%) and ß-thromboglobulin (Diagnostica Stago, Asnieres, France; intra-assay CV=10%) were quantified by commercially available enzyme-linked immunosorbent assays, and results were normalized to platelet count.
Shear-related platelet function was assessed by PFA-100 (Dade-Behring, Newark, Del). Whole blood was loaded into prefabricated proprietary cartridges (Dade-Behring) containing a combination of collagen and epinephrine, and closure time was recorded (maximum of 300 seconds; intra-assay CV=15%).
Thromboxane production in vivo was assessed by urinary 11-dehydro thromboxane B2 (Tx-M). Tx-M was quantified by commercially available enzyme-linked immunosorbent assays (Cayman Chemical Co., Ann Arbor, Mich; intra-assay CV=8%) and normalized to urinary creatinine.
Fibrinogen and von Willebrand factor (vWF) were measured to adjust for their potential confounding influences on platelet function. Plasma fibrinogen was measured by the Johns Hopkins clinical coagulation laboratory. Plasma vWF was quantified by commercially available enzyme-linked immunosorbent assays (DiaPharma, West Chester, Ohio; intra-assay CV=4%).
Assessment of Cardiac Risk Factors
Hypertension was considered present if the average of 4 resting blood pressures was 140/90 mm Hg and/or the patient was taking an antihypertensive medication. Current smoking was defined as any smoking within the past 30 days and was verified by exhaled CO levels. Height and weight were measured, and body mass index was calculated (kg/m2). Fasting plasma glucose and total cholesterol, high-density lipoprotein cholesterol, and triglycerides were measured with the use of a Cholestech LDX analyzer (Cholestech Corporation, Hayward, Calif). Low-density lipoprotein cholesterol was estimated by the Friedewald formula.18 Diabetes was defined as a fasting plasma glucose level 126 mg/dL and/or use of a hypoglycemic agent.19
Statistical Analysis
Data were analyzed with the use of SAS (version 9.1, 2002–2003, SAS Institute, Inc, Cary, NC). Means (±1 SD) and medians (interquartile ranges) of continuous variables were calculated. Variables that were nonnormal were transformed and normality confirmed by the Wilk-Shapiro test. Platelet function measurements, before and after ASA, were compared by paired t tests. The proportion of total phenotypic variance (r2) attributable to measured covariates was determined by multivariable linear regression, and partial r2 values were determined by type II sums of squares. Heritability estimates (h2) were calculated for each phenotypic trait with and without adjustment for cardiac risk factor covariates and baseline phenotype. The following cardiac risk factor covariates were included in multivariable r2 and h2 models: age, sex, hypertension, current smoking, body mass index, diabetes, low-density lipoprotein cholesterol, and fibrinogen levels. High-density lipoprotein and triglycerides were not included because they contributed <1% to variance of platelet phenotypes. vWF antigen was added as an additional covariate for analysis of PFA closure time only because it had no impact on the models for other platelet phenotypes. Simple bivariable relationships between the transformed and adjusted quantitative outcome measures and race were examined with the use of t tests.
Maximum-likelihood estimates of polygenic heritability were performed on the unadjusted and adjusted transformed traits with the use of variance components models in the ASSOC subroutine of SAGE.20 Briefly, we used a variance components model that partitions the total phenotypic variance of a trait (
2P) into components that correspond to additive genetic factors (2g) and unmeasured environmental factors (2e). With assumption of an additive nature of the 2 components, the estimate of heritability was calculated as 2g/2P. The significance of the heritability estimate was obtained with the use of a likelihood ratio test. All significance testing was 2-tailed with an 
of 0.05.
The authors had full access to and take full responsibility for the integrity of the data. All authors have read and agree to the manuscript as written.
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Results |
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A total of 1908 subjects were enrolled, and 28 were excluded because baseline platelet responses to arachidonic acid indicated ASA or NSAID ingestion. One thousand eight hundred eighty subjects from 309 white and 208 black families were included in the analysis. Overall, the mean age was 44±13 years, and 58% were women. Hypertension, cigarette smoking, and obesity were common in this highly selected sample (Table 1). Compliance with ASA ingestion was excellent, with 86% taking all 14 pills and 93% taking >12 pills.
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Platelet phenotypic traits were categorized as directly related to COX-1 if arachidonic acid was the agonist or a thromboxane metabolite was directly measured; they were characterized as indirectly related to COX-1 if collagen, ADP, or epinephrine was used to activate platelets. ASA markedly suppressed platelet function in all direct COX-1 assays. Whole blood and PRP aggregation to arachidonic acid were reduced to zero in the vast majority of both whites and blacks (P<0.0001 for pre- versus post-ASA). Only 6% of subjects had a whole blood aggregation response >0 (median=9 [interquartile range, 11]), which was further reduced to 0.4% after incubation with ASA in vitro. ASA inhibited ex vivo production of TXB2 an average of 99% in whites (45.9 [38.2] versus 0.30 [0.41] ng/108 platelets; P=0.0007 for pre- versus post-ASA, respectively) and blacks (53.6 [44.1] versus 0.34 [0.41] ng/108 platelets; P<0.0001 for pre- versus post-ASA, respectively). Average inhibition of Tx-M was less in magnitude and more variable than the other direct COX-1 measurements, averaging 76% in whites (132 [interquartile range, 127] versus 31 [interquartile range, 27] ng/mmol creatinine; P<0.0001 for pre- versus post-ASA, respectively) and 77% in blacks (137 [interquartile range, 155] versus 31 [interquartile range, 29] ng/mmol creatinine; P<0.0001 for pre- versus post-ASA, respectively). Variability in arachidonic acid aggregation after ASA was too limited to conduct further analyses.
The inhibitory effect of ASA on platelet phenotypes indirectly related to COX-1 was smaller and more variable than its effect on phenotypes directly related to COX-1 (Table 2). ASA led to minimal suppression of ADP-induced platelet activation in PRP and whole blood (
0% to 20% inhibition), moderate suppression of epinephrine-induced aggregation and ß-thromboglobulin release (40% to 50% inhibition), and strong suppression of collagen-epinephrine PFA closure time (2-fold increase). Inhibition of collagen-related platelet aggregation varied depending on the assay and was less in whole blood than in PRP and at higher collagen concentrations (Table 2).
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The total variance attributable to measured covariates in each post-ASA platelet phenotype was modest in both whites and blacks, ranging from <1% to 13% (r2; Table 3). Among cardiac risk factor covariates, age and sex contributed the most substantively to phenotypic variance. Depending on the specific ASA response phenotype, age accounted for up to 7% of variance in whites and 3% in blacks, and sex accounted for up to 11% in whites and 7% in blacks (Table IA and IB in the online-only Data Supplement). All other covariates accounted for <2% of phenotypic variance, except vWF levels for PFA phenotype (2% in whites, 7% in blacks). Baseline platelet phenotypes contributed strongly to variance in post-ASA phenotypes indirectly related to COX-1, accounting for up to 38% of the post-ASA variance (r2; Table 4; Table IIA and IIB in the online-only Data Supplement); however, baseline platelet phenotype accounted for 
2% of the variance in post-ASA phenotypes directly related to COX-1.
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Among direct COX-1 ASA response phenotypes, Tx-M was heritable in blacks and in unadjusted analysis for whites, TXB2 was heritable in whites only, and heritability of arachidonic acid aggregation was not measurable in either race (Table 3). In contrast, with the exception of PFA closure time, phenotypes indirectly related to COX-1 showed consistent heritability in both races, with heritable factors accounting for 27% to 77% of phenotypic variance in unadjusted analysis. Adjustment for measured covariates had minimal impact on heritability (Table 3), suggesting that the factors that contribute to heritability of ASA response phenotypes are distinct from cardiac risk factor covariates. For all measurements, the proportion of phenotypic variance attributable to heritable factors was greater than that due to measured covariates (Table 3).
Adjustment of post-ASA phenotype by baseline phenotype did not affect heritability of platelet phenotypes directly related to COX-1 (Table 4). Baseline platelet phenotype was a substantial contributor to heritability of post-ASA phenotypes indirectly related to COX-1; heritability estimates were reduced but remained significant for all phenotypes in whites and collagen aggregation in blacks (Table 4).
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Discussion |
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Effective suppression of platelet function is the mechanism through which low-dose ASA provides cardiovascular protection. The present study is the largest to characterize variability in platelet responsiveness to low-dose ASA in biologically important activation pathways that are both directly and indirectly related to COX-1. This is the first study to determine the contribution of cardiac risk factor covariates and polygenic heritability to variability in platelet function in response to ASA and to determine that heritable factors account for the largest proportion of variance in platelet ASA response phenotypes.
In our sample of subjects from families with a history of premature CHD, 81 mg/d of ASA caused near total suppression of ex vivo platelet COX-1 activity, as measured by arachidonic acid–induced aggregation and TXB2 production, with little interindividual variation. These findings are consistent with results from smaller studies involving healthy volunteers6 and patients with overt CHD.20 In contrast, suppression of in vivo Tx-M production was incomplete (75% of baseline) and more variable than other direct COX-1 measures, and suppression of indirect COX-1 phenotypes varied even more dramatically. The difference in the ability of ASA to suppress production of TXB2 ex vivo and Tx-M in vivo is important because it suggests that nonblood cells (eg, endothelial cells)21,22 and/or non–COX-1 pathways (eg, nonenzymatic)23 may contribute to thromboxane production in vivo and that this thromboxane production is not fully suppressed by 81 mg/d of ASA. Overall, our results indicate that biochemical failure of ASA at 81 mg/d to inhibit platelet COX-1 and platelet thromboxane production is uncommon. It remains unclear whether higher ASA doses would have a greater suppressive effect on Tx-M production in vivo or on indirect COX-1 pathways and the clinical significance, if any, of the incremental suppression.
Age,4,24 sex,4,9 cigarette smoking,25,26 diabetes,27,28 obesity,29,30 and cholesterol31,32 are reported to modify platelet responsiveness to ASA. We quantified the contribution of these cardiac risk factors to variability in platelet ASA response phenotypes and found that the total variance attributable to these factors was small. Among cardiac risk factors, only age and sex contributed consistently to phenotypic variation in ASA responsiveness, most prominently in indirect COX-1 pathways, with lesser platelet suppression associated with increased age and female sex. Older patients are known to experience a higher rate of recurrent cardiovascular events despite ASA treatment,33 and recent data suggest that ASA may be less effective in women than men for primary cardiovascular disease prevention.34 Greater residual platelet reactivity in older patients and women, particularly in indirect COX-1 pathways, may be a mechanism to explain these findings.
The present study demonstrates that heritable factors contribute strongly and significantly to residual platelet reactivity after ASA exposure, accounting for a much larger proportion of the variance in platelet phenotype than cardiac risk factor covariates. In addition, heritability estimates were relatively unaffected by adjustment for measured covariates, which suggests that the factors that contribute to heritability of ASA responsiveness are distinct from traditional cardiac risk factors. In the Framingham Heart Study, heritable factors contributed more strongly than environmental covariates to platelet aggregability (to ADP and epinephrine) and lag time (to collagen) in the absence of ASA.35 Studies examining the individual contribution of single gene variants to platelet functional responses to ASA have thus far been equivocal,12–16 probably because the specific variants studied are not related to phenotype or because the individual contribution of these single gene variants to overall phenotypic variance is too low to accurately quantify. Results of the present study suggest a genetic cause for differences among individuals in ASA responsiveness and support the search for specific genes and gene-gene interactions that determine platelet responsiveness to ASA therapy.
We noted that the heritability of platelet ASA response phenotypes indirectly related to COX-1 was stronger and more consistent than phenotypes directly related to COX-1. Limited variability in arachidonic acid aggregation and TXB2 phenotypes likely contributes to this finding. We also noted that baseline platelet function contributed prominently to heritability of post-ASA phenotypes indirectly related to COX-1 but not to those directly related to COX-1. These findings suggest that the same factors that contribute to variability in indirect COX-1 phenotypes before ASA also contribute to variability after ASA, and ASA has limited impact on this variance. It is possible that phenotypes before and after ASA are controlled by the same genetic factors. This is in contrast to direct COX-1 pathways, in which residual platelet function and heritability of response after ASA are lower and appear to be largely independent of baseline platelet function. One clinical implication for this finding is that individuals who have greater platelet reactivity in indirect COX-1 pathways at baseline are likely to retain greater reactivity despite ASA treatment and might receive less cardioprotection from ASA therapy. This also suggests that assessment of multiple platelet activation pathways may be required to fully characterize interindividual variability in platelet responsiveness to ASA and to clarify the relation between ex vivo ASA response measures and in vivo cardiovascular morbidity.
Although the failure of ASA to suppress platelet activation in pathways directly and indirectly related to COX-1 is associated with excess cardiovascular morbidity,1–3,11 the present study is limited because the sensitivity and specificity of ex vivo measurements for cardiovascular risk prediction are not known, and the therapeutic implication of inadequate platelet suppression is not clear.
In summary, the present study demonstrates that ex vivo measures of platelet ASA responsiveness are highly heritable, particularly those phenotypes related indirectly to COX-1, and that heritable factors contribute more prominently to phenotypic variability in ASA responsiveness than cardiac risk factor covariates. Additional studies are needed to identify the precise gene variants associated with each ASA response phenotype and the relation among genotype, ex vivo phenotype, and clinical cardiovascular outcome.
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Acknowledgments |
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Sources of Funding
This work was supported by grants from the National Institutes of Health/National Heart, Lung, and Blood Institute (U01 HL72518 and HL65229); by a grant from the National Institutes of Health/National Center for Research Resources (M01-RR000052) to the Johns Hopkins General Clinical Research Center; and by the Intramural Research Program of the National Institutes of Health/National Human Genome Research Institute. Aspirin tablets were provided by McNeil Consumer and Specialty Pharmaceuticals (Fort Washington, Pa). Discounts on urinary thromboxane assays were provided by AspirinWorks (Broomfield, Colo). Some of the results of this report were obtained by using the program package SAGE, which is supported by a US Public Health Service resource grant (RR03655) from the National Center for Research Resources.
Disclosures
Dr Faraday has received additional research support from NovoNordisk. Dr L. Becker and Dr D. Becker have received research support from McNeil Consumer and Specialty Pharmaceuticals (Fort Washington, Pa) and AspirinWorks (Broomfield, Colo). The other authors report no conflicts.
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- Ridker PM, Cook NR, Lee IM, Gordon D, Gaziano JM, Manson JE, Hennekens CH, Buring JE. A randomized trial of low dose aspirin in the primary prevention of cardiovascular disease in women. N Engl J Med. 2005; 352: 1293–1304.
[Abstract/Free Full Text] - O’Donnell CJ, Larson MG, Feng D, Sutherland PA, Lindpaintner K, Myers RH, D’Agostino RA, Levy D, Tofler GH. Genetic and environmental contributions to platelet aggregation: the Framingham Heart Study. Circulation. 2001; 103: 3051–3056.
[Abstract/Free Full Text]
CLINICAL PERSPECTIVE
Insufficient suppression of platelet function by aspirin (acetylsalicylic acid [ASA]) is associated with excess cardiovascular morbidity. Variability in the ability of ASA to suppress platelet activation pathways that are directly and indirectly related to cyclooxygenase-1 and genetic variation in the molecules involved in these activation pathways are proposed mechanisms for ASA treatment failure. This study examined platelet ASA responsiveness in 1880 asymptomatic subjects recruited from 309 white and 208 black families with premature coronary heart disease. Ex vivo platelet function was determined before and after ingestion of ASA (81 mg/d for 2 weeks) with the use of a panel of measures that assessed platelet function in pathways directly and indirectly related to cyclooxygenase-1. This is the first study to demonstrate that platelet responsiveness to ASA is a highly heritable trait, particularly phenotypic responses in activation pathways that are indirectly related to cyclooxygenase-1. It is also the first to demonstrate that heritable factors contribute much more strongly than traditional cardiac risk factors (hypertension, diabetes mellitus, hypercholesterolemia, cigarette smoking, obesity) to interindividual variability in residual platelet function after ASA exposure. These findings suggest that a genetic basis exists for response to ASA therapy and that inadequate responsiveness runs in families. It also suggests that assessment of multiple platelet activation pathways may be required to fully characterize interindividual variability in platelet responsiveness to ASA. Additional studies are needed to determine the relation among specific gene variants, ex vivo platelet phenotype, and clinical cardiovascular outcome before clinicians will be able to use assays of ASA responsiveness to direct antiplatelet therapy.
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The online-only Data Supplement, consisting of tables, is available with this article at http://circ.ahajournals.org/cgi/content/full/ CIRCULATIONAHA.106.667584/DC1.
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