Published online before print January 23, 2009, doi: 10.1161/CIRCGENETICS.108.801969
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Original Articles |
An Evaluation of Candidate Genes of Inflammation and Thrombosis in Relation to the Risk of Venous Thromboembolism
The Women’s Genome Health Study
From the Division of Preventive Medicine (R.Y.L.Z., R.J.G., L.R., P.M.R.), Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass; and Roche Molecular Systems, Inc (S.C., L.S.), Pleasanton, Calif.
Correspondence to Robert Y.L. Zee, BDS, MPH, PhD, Division of Preventive Medicine, Brigham and Women’s Hospital, Harvard Medical School, 900 Commonwealth Avenue East, Boston, MA 02215. E-mail rzee{at}rics.bwh.harvard.edu
Received June 25, 2008; accepted December 3, 2008.
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Abstract |
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Background— Although pathways associated with hemostasis and thrombosis are well documented to have an impact on venous thromboembolism (VTE), whether the inflammatory cascade also influences VTE risk is uncertain.
Methods and Results— We evaluated 51 polymorphisms from 32 inflammation-related genes (and an additional 19 polymorphisms from 15 thrombosis-related genes) as potential determinants of VTE in a prospective cohort of 22 413 white women followed over a 10-year period. Hazard ratios (HRs) for incident VTE according to the different genotypes were assessed by Cox proportional-hazards models. The false discovery rate (FDR) was used for correction for multiple testing with a 0.20 cut point. During follow-up, 158 idiopathic and 180 secondary VTE events occurred. As anticipated, factor V Leiden (HR, 3.22; 95% CI, 1.92 to 5.40; P<0.0001; FDR=0.004) and the prothrombin mutation (HR, 2.57; 95% CI, 1.64 to 4.02; P<0.0001; FDR=0.004) were both strongly associated with incident idiopathic VTE, as was the rs6046 polymorphism in the factor VII gene (HR, 0.54; 95% CI, 0.35 to 0.86; P=0.008; FDR, 0.12). With regard to polymorphism in the inflammatory genes, variation at rs1143634 in the IL-1β gene was associated with a reduced risk of idiopathic VTE (HR, 0.59; 95% CI, 0.44 to 0.80; P=0.0007; FDR=0.02), whereas variation at rs1800872 in the IL-10 gene was associated with increased risk (HR, 1.42; 95% CI, 1.12 to 1.80; P=0.004; FDR=0.07). By contrast, no significant associations were found for secondary VTE events.
Conclusion— In addition to previously reported polymorphisms associated with hemostasis and thrombosis, these prospective cohort data suggest that genetic variation in IL-1 β and IL-10 genes may also influence the risk of idiopathic VTE.
Key Words: genetics • VTE • polymorphisms • candidate genes • risk factors
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Introduction |
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Genetic variation in multiple genes associated with hemostasis and thrombosis are well documented to impact on rates of future idiopathic venous thromboembolism (VTE).1–7 However, recent work has also suggested that inflammatory processes related to innate immunity may also play a causal role in VTE.8–10 For example, systemic inflammation has been shown to be a potent prothrombotic stimulus, with effects including upregulation of procoagulant factors, downregulation of natural anticoagulants, inhibition of fibrinolytic activity, and modulation of platelet reactivity. Furthermore, inflammatory mediators in the tumor necrosis factor and interleukin families, and complement factors have been shown to influence the pathogenesis of thromboembolism.1–4
Clinical Perspective see p 57
Despite these data, data evaluating common genetic variants within the inflammatory/immune cascade and VTE risk are sparse. To address this issue, we evaluated potential associations of 51 polymorphisms from 32 inflammation-related genes with risk of incident VTE in the Women’s Genome Health Study (WGHS), a prospective cohort that included 22 413 initially healthy white women. As internal controls, we also evaluated 19 polymorphisms from 15 thrombosis-related genes, including factor V Leiden and the prothrombin mutation, 2 polymorphisms commonly ascertained in clinical practice.
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Methods |
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Study Participants
We studied DNA samples from a prospective cohort of apparently healthy women participating in the WGHS; a genetic substudy of the Women’s Health Study cohort, a recently completed randomized, double-blinded, placebo-controlled clinical trial of vitamin E and low-dose aspirin for the primary prevention of cardiovascular events and cancer among women.5,6 Details of the WGHS design have been described previously.6,7 In brief, the WGHS cohort consist of nearly 25 000 American women free of cardiovascular disease or cancer at study entry who have been followed prospectively for future vascular events, including VTE. For the purposes of this analysis, we limited the study cohort to those women who self-reported ethnicity as white and who had no prior history of deep vein thrombosis (DVT) nor pulmonary embolism (N=22 413). For any event of incident DVT or pulmonary embolism reported during study follow-up, medical records, death certificates, and autopsy reports were obtained and reviewed by an end points committee to confirm or reject each diagnosis. The diagnosis of DVT required a positive result on venography or ultrasonography. The diagnosis of pulmonary embolism required a positive (CT) angiogram or a ventilation-perfusion scan that showed at least 2 segmental perfusion defects without ventilation defects.
Idiopathic VTE was defined as occurring in the absence of a known malignant condition (diagnosed either before or up to 3 months after the VTE) or trauma, surgery, or hospitalization (lasting 3 or more days) within 3 months before the VTE. Secondary VTE included events that occurred in patients with cancer or during or up to 3 months after trauma, surgery, or hospitalization (lasting 3 or more days).8,9 The proportions for pulmonary embolism alone, DVT alone, and pulmonary embolism-DVT were 14.7%, 60.2%, and 25.1%, respectively. Women who did not develop a VTE event during follow-up (neither idiopathic nor secondary) were considered as controls.
The study was approved by the Brigham and Women’s Hospital Institutional Review Board for Human Subjects Research.
Selection of Candidate Gene Polymorphisms
A total of 70 polymorphisms from 47 candidate genes were examined in each study participant; 51 polymorphisms were from 32 inflammation-related candidate genes, and 19 polymorphisms were from 15 hemostatsis and thrombosis-related candidate genes. Polymorphisms were chosen based on prior evidence of potential functionality, validated allele frequency and heterozygosity, and sequence-proven allelic variation.
Genotype Determination
Genotyping was performed using a previously described and validated linear-array assays for candidate markers of cardiovascular disease, immune response, and inflammation (Roche Molecular Systems, Alameda, CA).10,11 In brief, each DNA sample was amplified in multiplex polymerase chain reactions (PCRs) using biotinylated primers. Each PCR 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. Genotype assignment was performed using the proprietary Roche molecular systems strip scan image processing software. To confirm genotype assignment, scoring was carried out by 2 independent observers. Discordant results (<1% of all scoring) were resolved by a joint reading, and where necessary, a repeat genotyping.
Statistical Analysis
We examined the association between each of the evaluated polymorphisms and risk of incident VTE in a multistage procedure. First, Hardy-Weinberg equilibrium was evaluated for each polymorphism using an exact test. The association of genotypes with VTE risk was evaluated using the Cox-proportional hazard regression analysis, assuming an additive model. All regression analyses were adjusted for age, body-mass index, treatment assignment, and use of hormone replacement therapy. Hazard ratios (HRs) and the corresponding 95% confidence interval (CI) were calculated. As both genetic and environmental determinants of idiopathic VTE are known to differ from that of secondary VTE, statistical analysis was performed for each clinical end point separately.
For the purposes of epidemiological comparison, we used the false discovery rate (FDR)12 to adjust for multiple hypothesis-testing. The FDR was applied to the adjusted models examining the additive effect of each gene variant on idiopathic and unprovoked VTE, separately, using the PROC MULT test of SAS version 9 (SAS Institute Inc, Cary, NC). Unlike common procedures such as the Bonferroni correction, the FDR method does not control the experimentwise error rate, but instead controls the expected proportion of false-positives among all positive results over multiple studies. Although no universal FDR significance threshold has been defined, a cut point of 0.20 has been suggested for candidate gene association studies,13 meaning that one should expect at most 20% of declared discoveries to be false.
The proportional hazards assumption was examined by including genotypic data by logarithm of time interaction into the model. All analyses were carried out using SAS/Genetics version 9 (SAS Institute Inc). A 2-tailed P value of 0.05 was considered as a statistically significant result.
All authors conceived and designed the study project. R.Y.L.Z. conducted the experiments. S.C. and L.S. contributed reagents/materials. R.Y.L.Z., R.J.G., and P.M.R. discussed and analyzed the data. R.Y.L.Z. prepared the manuscript draft. All authors finalized and approved the article. The authors had full access to the data and take full responsibility for its integrity. All authors have read and agreed to the manuscript as written.
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Results |
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Baseline characteristics of the study participants are shown in the Table 1. The 70 genetic variants from 47 genes examined in the present investigation are presented in Supplemental Table I, all in Hardy-Weinberg equilibrium after correction for multiple testing.
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The observed allele frequencies of the remaining genetic variants tested are comparable with those reported on the National Center for Biotechnology Information SNP database for white population (http://www.ncbi.nlm.nih.gov/sites/entrez?db=snp). Furthermore, at the 0.05
level, the polymorphisms tested were in proportional hazards assumption. For ease of presentation, the Table 2 presents those gene variants that were found to have a nominal P value <0.10 for the Cox regression analysis, in an additive model, for idiopathic, and secondary VTE, respectively. Supplemental Table II presents the nominal association results for all the gene variants tested.
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As anticipated, both the well-recognized prothrombin mutation (rs1799963: HR, 3.2; 95% CI, 1.9 to 5.4; P<0.0001; q=0.0035) and factor V Leiden (rs6025: HR, 2.6; 95% CI, 1.6 to 4.0; P<0.0001; q=0.0035) were significantly associated with incident idiopathic VTE at low FDR. Among the remaining variants ascertained in the hemostatic and thrombotic genes, significant association with idiopathic VTE was also observed for factor VII rs6046 (HR, 0.55; 95% CI, 0.35 to 0.86; P=0.0084; q=0.12; Table 2).
With regard to the inflammatory genes, 2 novel associations were found, a protective effect for polymorphism at rs1143634 in the IL-1β gene (HR, 0.59; 95% CI, 0.44 to 0.80; P=0.0007; q=0.016) and a net hazard for rs1800872 in the IL-10 gene (HR, 1.42; 95% CI, 1.12 to 1.80; P=0.0038; q=0.07; Table 2). In addition to these statistically robust findings, nominal associations with idiopathic VTE were also observed for factor VII rs5742910 (HR, 0.60; 95% CI, 0.40 to 0.92; P=0.018; q=0.20) and for IL-6 rs1800796 (HR, 1.60, 95% CI, 1.07 to 2.38; P=0.022; q=0.22; Table 2).
We found no evidence of association for any of the polymorphisms tested with secondary VTE risk (Table 2).
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Discussion |
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In this prospective study, in addition to the well-recognized prothrombin mutation and factor V Leiden, we found variation in 2 inflammatory genes (IL-1β rs1143634 and IL-10 rs1800872) to significantly associate with risk of incident idiopathic VTE. In addition, corroborating our own prior work in men,11 we also found significant association between factor VII rs6046 and idiopathic VTE; of interest, the magnitude and direction of effect for rs6046 in the current data for women is almost identical to that previously reported in men. However, we found no evidence for an association of any gene evaluated with secondary VTE risk.
With regard to our novel findings, the protein encoded by the IL-1β gene is a member of the IL-1 cytokine family. This cytokine family is produced by activated macrophages as a proprotein, an important mediator of the inflammatory response and a procoagulant factor and is involved in a variety of cellular activities, including cell proliferation, differentiation, and apoptosis, and tissue-factor expression on endothelial cells and monocytes.14–16 As noted previously,15–17 IL-1 has been shown to stimulate procoagulant activity and leukocyte adhesion in human endothelial cells cultured from both umbilical veins and adult saphenous veins but not in other cultured cell types. Similar actions of IL-1 on vascular endothelium in vivo may contribute to the development of intravascular coagulation and enhanced leukocyte-vessel wall adhesion at sites of inflammation.15–17
As for IL-10, the protein encoded by this gene is a cytokine produced primarily by monocytes and to a lesser extent by lymphocytes. These inflammatory proteins participate in the underlying pathophysiology of venous thrombosis through the induction of procoagulation and inhibition of anticoagulation.4,18,19 A study by Downing et al2 showed that IL-10 was elevated in the vein wall during venous thrombosis. Neutralization of IL-10 increased inflammation, whereas supplementation with rIL-10 demonstrated a dose- and time-dependent decrease in inflammation. These data demonstrate an anti-inflammatory property of IL-10 in the regulation of thrombus-associated inflammation and thrombosis and suggest that IL-10 could be used as a therapeutic agent in the treatment of venous thrombosis. Furthermore, a recent study by Reitsma and Rosendaal (Leiden Thrombophilia Study)4 has shown that levels of various cytokines, including IL-1β and IL-10, were risk determinants for venous thrombosis.
In a study by Pieroni et al20, evaluating the variation at TNF- –308G>A (rs1800629), LT 252A>G (rs909253), IL-6 –174G>C (rs1800769), IL-1ra 86bp VNTR, IL-10 –1082G>A (rs1800896), and CD-31 125C>G (also known as PECAM1 rs668) polymorphisms, no evidence of altered VTE risk was observed although coinheritance of LT 252A>G and IL-10 –1082G>A was associated with a 2-fold increase in thrombotic risk. Other studies examining several inflammatory markers, including C-reactive protein and IL-6, showed little evidence of an association with VTE risk.21–24 Taken together, our present and previous investigations suggest that the release of cytokines may be important in mediating the activation of both the coagulation and the fibrinolytic mechanisms in thrombosis.
In a recent study by Smith et al,13 examining the association of common variants in 24 clotting-related candidate genes with risk of incident venous thrombosis in 2029 postmenopausal women, only the tissue factor pathway inhibitor gene demonstrated global association (q=0.13). In their single-marker analysis, 5 gene variants were found with a q value less than 0.20 (factor V rs4524, factor XI rs2289252, and protein C rs1799810, rs2069915, and rs5937). More recently, a report by Bezemer et al25 evaluating more than 19 000 gene-centric variants with risk of DVT in 3 case-control sample series and using a q value of 0.20 as cut point, 3 gene variants (CYP4V2 rs13146272, SERPINC1 rs2227589, and GP6 rs1613662) were identified with q values less than 0.10. However, as our gene-panel was initiated before these reports and did not include these gene variants, direct comparisons could not be made.
The candidate gene approach relies on prior knowledge of biological pathways and its associations with the phenotype of interest. In recent years, genome-wide association studies of common, complex diseases have become available, and have provided insights in the underlying pathophysiologic mechanisms of several common disorders. Unfortunately, to date, no large genome-wide association investigations have been conducted in relation to VTE, thus, highlighting the need for large-scale, prospective studies in this important clinical condition. In this context, in addition to the candidate gene set described here, the WGHS project will eventually include full genome-wide scan data (estimated completion March 2009); thus, more detailed results regarding other potential genetic predispositions to VTE are expected in future analyses.7
Strengths of the present study are the overall sample size, the biological relevance of the polymorphisms considered, the prospective design and the complete long-term follow-up. 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 one specific finding. Nonetheless, some potential limitations of our study require discussion. First, this study included only white female health professionals, and our findings may not be generalizable to other populations, and with different socioeconomic background. Furthermore, participants used in the present study were drawn from a clinical trial population (WGHS), which is inherently different from a population-based study. Of note, although we observed only modest, nonsignificant associations of the factor V Leiden and prothrombin mutation with provoked/secondary VTE risk, CIs for these estimated associations were wide and consistent with those observed in many previous studies.26–31 Discrepancies among reports could be due to differences in study design, the definition of VTE events in varying settings, methods of surveillance for events, and/or chance. In the present study, the increased hazards of provoked events associated with each of the factor V Leiden and prothrombin mutation were not significantly different from the observed HRs for idiopathic events (P=0.13 for factor V Leiden HRs, provoked versus idiopathic events; P=0.10 for the prothrombin mutation HRs, provoked versus idiopathic events).32 Thus, further prospective investigation of the factor V Leiden and prothrombin mutation in provoked/secondary VTE is warranted.
It is also possible that one or more of the observed associations is the result of linkage disequilibrium with a yet-to-be-identified nearby susceptibility locus or gene. As previously described, the polymorphisms tested in our study were solely selected based on prior evidence of potential functionality, validated allele frequency and heterozygosity, and sequence-proven allelic variation, and thus linkage disequilibrium/haplotype structure was not considered. Hence, further studies using linkage disequilibrium/haplotype-SNP tagging information from public genome databases such as HapMap, SeattleSNPs, are warranted; In this regard, the HapMap linkage disequilibrium (r-squared) plots for the ±10 kb region of IL1B rs1143634, and IL10 rs1800872 are presented in Supplemental Figures I and II, respectively. More importantly, replication of our present findings in different populations is required, despite the low FDRs observed and the high level of significance found in our regression analyses.
In our study, we had the ability to detect, based on the present sample sizes, assuming 80% power, at an of 0.05, a hazards ratio greater than 1.42 (idiopathic VTE) and 1.40 (secondary VTE) if the minor allele frequency is 0.50, and a hazards ratio greater than 2.62 (idiopathic VTE) and 2.58 (secondary VTE) if the minor allele frequency is 0.01 assuming a univariable-additive model. Thus, we cannot rule out a modest risk of VTE associated with the polymorphisms tested. Hence, based on the observed hazards ratios and the corresponding CIs, polymorphisms that are potentially false-negatives after our multiple-testing correction warrant further investigation; as an example, IL-6 rs1800796 has been implicated in various vascular conditions including venous thrombosis.4,33
In conclusion, this prospective investigation among initially healthy white US women indicates that genetic variations in factor VII, IL-1β, and IL-10 may play a critical role in the pathogenesis of incident idiopathic VTE. Additional large-scale studies using comprehensive genome-wide analysis are needed to further elucidate the pathogenesis of VTE.
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Acknowledgments |
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Sources of Funding
This study was supported by grants AG031061, HL-43851, HL-80467, and CA-47988 from the National Heart, Lung, and Blood Institute and the National Cancer Institute. Roche Molecular Systems and F. Hoffmann La-Roche supported the genotype determinations financially and with in-kind contribution of reagents and consumables.
Disclosures
None.
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Footnotes |
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Guest editor for this article was Teri A. Manolio, MD, PhD.
The online-only Data Supplement is available at http://circgenetics.ahajournals.org/cgi/content/full/CIRCGENETICS.108.801969/DC1.
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