Published online before print May 1, 2006, doi: 10.1161/CIRCULATIONAHA.106.615401
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(Circulation. 2006;113:2193-2200.)
© 2006 American Heart Association, Inc.
Genetics |
Polymorphism in the ß2-Adrenergic Receptor and Lipoprotein Lipase Genes as Risk Determinants for Idiopathic Venous Thromboembolism
A Multilocus, Population-Based, Prospective Genetic Analysis
From the Center for Cardiovascular Disease Prevention, Leducq Center for Molecular and Genetic Epidemiology, and Donald W. Reynolds Center for Cardiovascular Research, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass (R.Y.L.Z., N.R.C., P.M.R.); Department of Human Genetics, Roche Molecular Systems, Alameda, Calif (S.C., H.A.E.); and Roche Center for Medical Genomics, Basel, Switzerland (K.L.).
Correspondence to Robert Y.L. Zee, BDS, MPH, PhD, Laboratory of Genetic and Molecular Epidemiology, Brigham and Women’s Hospital, Harvard Medical School, 900 Commonwealth Ave E, Boston, MA 02215. E-mail rzee{at}rics.bwh.harvard.edu
Received January 19, 2006; revision received March 8, 2006; accepted March 10, 2006.
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Abstract |
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Background— Candidate genes in inflammation, thrombosis, coagulation, and lipid metabolism pathways have been implicated in venous thromboembolism (VTE).
Methods and Results— Using DNA samples collected at baseline in the Physicians’ Health Study cohort, we genotyped 92 polymorphisms from 56 candidate genes among 304 individuals who subsequently developed VTE (144 idiopathic, 156 secondary cases) and among 2070 individuals who remained free of reported vascular disease over a mean follow-up of 13.2 years to prospectively determine whether these gene polymorphisms contribute to the risk of VTE. For idiopathic VTE, in addition to the factor V (Leiden) mutation (odds ratio [OR], 5.13; 95% confidence interval [CI], 3.24 to 8.14; P<0.0001; false discovery rate [FDR], P<0.0001), an N291S lipoprotein lipase gene polymorphism (OR, 3.09; 95% CI, 1.56 to 6.09; P=0.001; FDR, P=0.036) and a Q27E ß2-adrenergic receptor gene polymorphism (OR, 1.40; 95% CI, 1.09 to 1.79; P=0.006; FDR, P=0.036) were found to be significantly associated with increased risk. For secondary VTE, a Q360H apolipoprotein A4 gene polymorphism (OR, 0.34; 95% CI, 0.18 to 0.65; P=0.001; FDR, P=0.07) and an I50V interleukin-4 receptor polymorphism (OR, 0.66; 95% CI, 0.52 to 0.84; P=0.0009; FDR, P=0.07) were moderately, but not statistically and significantly, associated with reduced risk after adjustment for multiple comparisons.
Conclusions– These present findings are hypothesis generating and require replication and confirmation in an independent investigation.
Key Words: genetics • multilocus • polymorphisms • risk factors • venous thromboembolism
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Introduction |
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Venous thromboembolism (VTE) is a major public health burden worldwide. Although conventional risk factors such as surgery, trauma, obesity, cancer, and rare genetic variants in the genes encoding antithrombin III, protein C, protein S, factor V (Leiden), and factor II (G20210A) mutations have been implicated in the disease process, VTE often occurs in the absence of known risk factors. It has thus been hypothesized that candidate genes associated with lipid metabolism, thrombosis and hemostasis, cell-matrix adhesion, and inflammation may be implicated in the pathogenesis of VTE. Therefore, we undertook an evaluation of 92 candidate gene polymorphisms (Table I in the online-only Data Supplement) related to these biological processes within a nested case-control sample from a prospective cohort of initially healthy men in the United States who were followed up over a 13.2-year period for the occurrence of first-ever venous thromboembolic event. The candidate genes examined were selected from biochemical pathways that have been implicated in the development and progression of vascular diseases, including VTE. In addition to the biological relevance of the selected candidate genes, the polymorphisms were further selected on the basis of prior evidence of potential functionality, validated allele frequency and heterozygosity, sequence-proven allelic variation, and confirmed mendelian segregation. The selected genetic polymorphisms focused broadly on the genes involved in lipid metabolism, inflammation, cell adhesion, thrombosis and hemostasis, and platelet function.
Clinical Perspective p 2200
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Methods |
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Study Population
We evaluated potential associations between a panel of 92 candidate gene polymorphisms (Data Supplement Table I) and the risk of incident deep venous thrombosis/pulmonary embolism (DVT/PE) by studying prospectively collected DNA samples from a cohort of apparently healthy middle-aged men participating in the prospective Physicians’ Health Study, a randomized, double-blind, placebo-controlled trial of aspirin and beta-carotene for the primary prevention of cardiovascular disease and cancer.1
The study protocol has previously been described. In brief, 22 071 predominantly white US male physicians 40 to 84 years of age who were free of prior myocardial infarction, stroke, transient ischemic attack, and cancer were enrolled; 14 916 (68%) provided baseline blood samples that were subsequently used for genetic analysis. All participants were followed up for the occurrence of symptomatic DVT/PE. Each reported clinical end point was confirmed by detailed review of hospital records, death certificates, and autopsy reports by a committee of physicians using prespecified standard criteria. The diagnosis of DVT required a positive result on venography or ultrasonography. The diagnosis of PE required a positive angiogram or a ventilation-perfusion scan that showed at least 2 segmental perfusion defects without ventilation defects. The study was approved by the Brigham and Women’s Hospital Institutional Review Board for Human Subjects Research.
According to the study design, each participant who provided an adequate sample of whole blood at baseline and had any confirmed incident cardiovascular event during follow-up, including myocardial infarction, stroke, or DVT/PE, was matched to control participants who also provided a baseline blood sample for genomic analysis and had remained free of any reported cardiovascular disease at the time the index event occurred in the case patient. Controls were selected at random from among those participants who met the matching criteria of age (±2 years), smoking habits (former, current, or never smoker), and time since study entry. To increase power for statistical comparison, all controls were pooled in a common-reference group for the present analysis; a total of 304 incident DVT/PE (144 idiopathic/unprovoked, and 156 secondary/provoked) cases and 2070 controls were available and underwent genotyping for each of these 92 candidate gene polymorphisms within 56 genes.
Genotyping was performed with previously described and validated linear-array assays for candidate markers of cardiovascular disease, immune response, and inflammation (Roche Molecular Systems, Alameda, Calif).2,3 In brief, each DNA sample was amplified in multiplex polymerase chain reactions through the use of biotinylated primers. Each polymerase chain reaction product pool was then hybridized to the corresponding panel of sequence-specific oligonucleotide probe that had been immobilized in a linear array on nylon membrane strips. The colorimetric detection method was based on the use of streptavidin-horseradish peroxidase conjugate with hydrogen peroxide and 3,3',5,5'-tetramethylbenzidine as substrates.
Statistical Approach, Adjustment for Multiple Comparisons, and Methods for Discrimination Analyses
As previously described,3 the aim of pooled controls in a common-reference group was to provide more stable estimates of background allele and genotype frequencies and to increase the power for statistical comparisons. Furthermore, to address the use of a pooled control group, all logistic regression analyses were unmatched and adjusted for age and smoking status. We examined the association between each of the 92 polymorphisms evaluated and the risk of DVT/PE in a multistage procedure. First, Hardy-Weinberg equilibrium was evaluated for each polymorphism using a 1-df goodness-of-fit test among controls after exclusion of rare alleles (frequency <0.05). Genotype frequencies between cases and controls were then compared by logistic regression analyses adjusted for age and smoking status to compute relative risks and 95% confidence intervals (CIs). All initial analyses were performed assuming dominant, additive, or recessive mode for each polymorphism. For the purposes of epidemiological comparison, we used the false discovery rate (FDR)4 to adjust for multiple hypothesis testing. The FDR was applied to the age- and smoking-adjusted univariable models examining the additive effect of each gene polymorphism, on the overall sample population, and within each stratum (idiopathic/secondary VTE) separately using the PROC MULTTEST of SAS, version 8 (SAS Institute Inc, Cary, NC). Unlike common procedures such as the Bonferroni adjustment, the FDR method does not control the experiment-wise error rate, instead, it controls the expected proportion of false-positives among all positive results over multiple studies. Second, we performed forward-stepwise multivariable logistic regression analyses to evaluate evidence that specific polymorphisms might be independently associated with the disease outcome with a nominal value of P=0.10 as the criterion for entry to the model and a final cut point of P=0.05 to remain. We further controlled for body mass index (kg/m2), history of hypertension, history of hyperlipidemia, and the presence or absence of diabetes. Furthermore, we used the Bayesian information criterion to select variables for inclusion after adjustment for the number of terms selected.5 In addition, we carried out the same analysis for idiopathic and secondary DVT/PE separately. All regression analyses were controlled for randomized treatment assignments, and all probability values are 2 tailed. We used c statistics, representing the area under the receiver-operating characteristic curve, to estimate model discrimination. Because these data were partially matched by age and smoking, c statistics do not reflect the overall fit of a predictive model including these terms. A comparison of c statistics, however, can indicate the genetic contribution to model fit.6
All authors conceived and designed the study project. Dr Zee conducted the experiments. Drs Cheng, Erlich, and Lindpaintner contributed reagents or materials. All authors discussed and analyzed the data. All authors prepared, wrote, and approved the article. The authors had full access to the data and take full responsibility for their integrity. All authors have read and agree to the manuscript as written.
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The observed frequency of the less common (or minor) allele at each site among the controls has previously been reported.3 After Bonferroni adjustment, all alleles tested (those with frequency >0.05) demonstrated Hardy-Weinberg equilibrium.3
Baseline characteristics of participants who subsequently developed DVT/PE (cases) and of those who remained free of cardiovascular disease during follow-up (controls) are shown in Table 1.
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A full list of genotype frequencies for the case and control participants and calculated odds ratios (ORs) assuming an additive, dominant, or recessive mode of inheritance for the polymorphisms evaluated is available from the authors in electronic format. For ease of presentation, Table 2 presents those polymorphisms that were found to have a nominal univariable value of P<0.10 for association, in any mode of inheritance, with all incident DVT/PE. Results for the additive mode and the associated FDR also are presented. Of the polymorphisms examined, 10 (Table 2) were found to be independent genetic predictors of risk in the traditional age- and smoking-adjusted stepwise selection multivariable models with a value of P<0.05. However, when a Bayes information criterion was used as the selection criterion, only 5 remained significant. These 5 included the dominant mode of the apolipoprotein A4 Q360H polymorphism, the dominant mode of the interleukin-4 receptor I50V polymorphism, the dominant mode of the factor II G20210A polymorphism, the additive mode of the factor V Leiden, and the additive mode of the E-selectin L554F polymorphism.
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Following our a priori analysis plan, 1 marker association remained statistically significant after full adjustment for multiple comparisons and after adjustment for potential confounders: the additive effect of factor V Leiden. In a stepwise multivariable risk factor–adjusted analysis (Table 2), factor V Leiden (OR, 3.74; 95% CI, 2.54 to 5.50; P<0.0001) was found to be an independent predictor of total incident VTE. For this, the P value for FDR was <0.0001, reconfirming our earlier findings in participants from the same PHS cohort.7
Using a stratified analysis, we found 3 associations with idiopathic VTE that remained statistically significant after full adjustment for multiple comparisons and for potential confounders. As shown in Table 3, a stepwise multivariable risk factor–adjusted analysis indicated the following to be independent predictors of increased risk: the lipoprotein lipase (LPL) N291S gene variant (OR, 3.09; 95% CI, 1.56 to 6.09; P=0.001), the ß2-adrenergic receptor Q27E gene polymorphism (OR, 1.40; 95% CI, 1.09 to 1.79; P=0.006), and factor V Leiden (OR, 5.13; 95% CI, 3.24 to 8.14; P<0.0001). For these, the FDRs were 0.036, 0.036, and <0.0001, respectively. In the stepwise Bayes information criterion analysis, the c statistic for the final risk-prediction model was 0.714 compared with 0.627 for the risk-prediction model based only on the demographic/clinical risk factors.
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For secondary VTE, none of the marker associations remained statistically significant after adjustment for multiple comparisons and after adjustment for potential confounders (Table 4). However, 2 markers achieved borderline association: the apolipoprotein A4 Q360H gene variant (FDR, 0.07) and the interleukin 4 receptor I50V gene polymorphism (FDR, 0.07). As shown in Table 4, in a stepwise multivariable risk factor–adjusted analysis, the additive effect of the apolipoprotein A4 Q360H gene variant (OR, 0.34; 95% CI, 0.18 to 0.65; P=0.001) and the additive effect of the interleukin-4 receptor I50V gene polymorphism (OR, 0.66; 95% CI, 0.52 to 0.84; P=0.0009) were observed to be associated with reduced risk of secondary VTE. Of note, although nominally significant, the FDR for the factor V Leiden mutation did not reach the 0.05 level (P=0.28; Table 4), nor did the factor II G20210A variant (Table 3; P=0.28 in Table 4).
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As presented elsewhere, we used Bayesian genomic control analysis (with Markov chain Monte Carlo algorithms) to examine the potential impact of population stratification and cryptic relatedness in our investigation.8,9 In these data, the median 
2 value for additive effects of all 92 polymorphisms was 0.38, which is <1, indicating that no correction was necessary.3
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Discussion |
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In this report from a prospective, population-based, genetic epidemiological evaluation of initially healthy American men, we found 3 polymorphisms to be strongly associated with idiopathic incident VTE after adjustment for multiple comparisons. One of these, the factor V (Leiden) mutation, is widely recognized as a major risk factor for idiopathic DVT. The other 2, polymorphisms in the ß2-adrenoreceptor and LPL genes, raise interesting issues with respect to the pathogenesis of VTE.
ß2-Adrenergic receptor (ADRB2) is a member of the G protein–coupled receptor superfamily. This receptor is directly associated with one of its ultimate effectors, the class C L-type calcium channel Ca(V)1.2. This receptor-channel complex also contains a G protein, an adenylyl cyclase, cAMP-dependent kinase, and the counterbalancing phosphatase PP2A. The assembly of the signaling complex provides a mechanism that ensures specific and rapid signaling by this G protein–coupled receptor.10 The ADRB2 is widely expressed in various tissue types in which catecholamines exert their effects, including lipoprotein metabolism, glucose homeostasis, and vascular tone. Different sequence variants of the ADRB2 gene (GeneID 154; chromosome 5q31–32) are associated with nocturnal asthma, obesity, and type 2 diabetes.10,11 Our recent data and data from others have shown that the ADRB2 G16R and Q27E contribute to metabolic syndrome susceptibility12 and myocardial infarction13 in men. Although the present prospective analysis found a statistically significant association between this ADRB2 variation and incident idiopathic VTE, this has not been observed in at least 1 other setting.14 Whether these differences reflect the play of chance or suggest true differences between populations requires confirmation in future analysis of independent cohorts.
LPL (GeneID 4023; chromosome 8p22), which is expressed in heart, muscle, and adipose tissue, is an enzyme that functions as a homodimer and has the dual functions of triglyceride hydrolase and ligand/bridging factor for receptor-mediated lipoprotein uptake. The gene encoding LPL contains 10 exons spanning 30 kb. Several common polymorphisms have been described on the LPL gene, and most of them are synonymous variants. Severe mutations that cause LPL deficiency result in type I hyperlipoproteinemia, whereas less extreme mutations in LPL are linked to many disorders of lipoprotein metabolism. In particular, the N291S variant has been associated with decreased LPL activity, lower levels of high-density lipoprotein (HDL) cholesterol,15 and increased triglycerides.16 Recently, data from the Veterans Affairs HDL Intervention Trial have shown that in men with low HDL cholesterol and coronary heart disease, the 291S allele was more frequent than in coronary heart disease–free men with normal HDL cholesterol.17 More recently, data from the Regression Growth Evaluation Statin Study (REGRESS) have found the LPL N291S gene polymorphism to be independently associated with fasting plasma levels of triglycerides in men with coronary artery disease.18 Taken together, these prior data suggest a potential role of the LPL N291S gene variant in arterial thrombosis; in contrast, we are not aware of other genetic epidemiological data or functional characteristic studies evaluating these newly described polymorphisms for idiopathic venous thromboembolic events.
In the analysis of secondary/provoked VTE, although none of the polymorphisms examined achieved significance after adjustment for multiple comparisons, 2 potential candidates, associated with inflammation and lipid metabolism, were found to be modestly associated with reduced risk, albeit at nominal significant levels. One of these, a Q360H polymorphism in the apolipoprotein A4 gene (APOA4; GeneID 337; chromosome 11q23) has been reported to be associated with cerebrovascular disease, obesity, and depression in a Brazilian elderly population.19 A recent meta-analysis found a significant lowering effect of the APOA4 N291S variant on plasma levels of triglycerides.20 More recently, several studies provided the first evidence for the hypothesis that APOA4 is an endogenous antiinflammatory protein.21,22 Thus, together with our present findings, these data further suggest a potential role of this polymorphism as a risk determinant for venous thrombosis. We also found a suggestive association of an I50V polymorphism in the interleukin-4 receptor gene (IL4R; GeneID 3566; chromosome 16p11.2–12.1) with reduced risk of secondary VTE. Allelic variations in this gene have been associated with atopy,23 type 1 diabetes mellitus,24,25 serum IgE response,26,27 and osteoarthritis.28 However, future studies are needed to provide further evidence for an association.
Despite the intriguing nature of our findings, we believe appropriate clinical caution should be used when interpreting positive results from any association study; epidemiological limitations of association studies potentially leading to false-positive findings include inadequate sample size, failure to ensure that affected and unaffected subjects derive from the same source population, overreliance on post hoc subgroup analyses, and selective presentation of results without consideration of the adverse effects that can arise as a result of multiple comparisons. With regard to these concerns, strengths of our study design include its sample size and the fact that we used a closed prospective cohort in which the determination of case status was based solely on the subsequent development of disease rather than on any arbitrary selection criteria designed by the investigators. Furthermore, our genomic control analysis revealed no evidence of population stratification in these data. We also chose, on an a priori basis, to adjust for multiple comparisons and to present all our data simultaneously rather than focusing on any 1 specific finding. We recognize that it is also possible that 1 or more of the observed associations is the result of linkage disequilibrium with a yet-to-be-identified nearby susceptibility locus (loci) or gene (genes). As such, confirmation of these findings in different populations is required, despite the low FDRs observed and the high level of significance found in our regression analyses. With regard to power, from our total sample size, at a nominal alpha level of 0.05, in a univariable setting, our study had 80% power to detect an OR of >1.41 with a minor allele frequency of 0.50 and an OR of >1.97 with a minor allele frequency of 0.05. Thus, polymorphisms that are potentially false negatives after our multiple comparison adjustment also may be worthy of further investigation. Because we do not have data available on baseline plasma ADRB2 or LPL levels on our study participants, the impact of these intermediate phenotypes cannot be examined within the context of the present investigation.
In conclusion, in this prospective, population-based study, several candidate gene polymorphisms were identified that were independently associated with risk of incident VTE. It is particularly interesting and encouraging that apart from the widely documented prothrombotic effect of the factor V Leiden mutation, polymorphisms in ADRB2 (an important inflammatory mediator) and LPL (a key player in lipid metabolism) genes are known to play central roles in vascular biology. The present findings should be viewed as hypothesis generating and exploratory and require validation and replication in other prospective studies.
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Acknowledgments |
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This work was supported by grants from the National Heart Lung and Blood Institute (HL-58755, HL-63293), the Doris Duke Charitable Foundation, and the Donald W. Reynolds Foundation. We thank the participants, staff, and investigators of the Physicians’ Health Study for their long-term commitment to this project. We also thank Michael Grow and Arkadiy Silbergleit for their work in developing and optimizing the Roche Molecular Systems Cardiovascular Disease panel, and Rebecca Reynolds, Lori Steiner, Karen Walker and Gabriele Zangenberg (Beer) for their work in developing and optimizing the RMS Infla panel used for this study.
Disclosures
None.
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CLINICAL PERSPECTIVE
The present investigation highlights the importance of combining both an a priori selection of polymorphisms based on prior clinical and biological implications and an a priori application of rigorous statistical approaches when studying the genetic epidemiology of common complex disorders, including venous thromboembolism. Furthermore, it emphasizes the need to investigate genetic risk factors in a prospective setting using large, homogenous populations to minimize background noises such as population admixture and genetic/allelic heterogeneity. Although the present findings account for a fraction of the overall genetic variance of the trait of interest, our findings were derived from a modest number of genes, indicating the value and utility of multilocus candidate gene association study. Of note, our present data have limited practical applicability; however, we believe they point the way toward a future feasibility of creating comprehensive genetic risk factor panels and their application in medical practice.
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Footnotes |
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The online-only Data Supplement can be found at http://circ.ahajournals.org/cgi/content/full/CIRCULATIONAHA.106.615401/DC1.
Guest Editor for this article was Burton E. Sobel, MD.
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