Clinical Chemistry 54: 833-840, 2008.
First published March 20, 2008; 10.1373/clinchem.2007.096479
(Clinical Chemistry. 2008;54:833-840.)
© 2008 American Association for Clinical Chemistry, Inc.
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Molecular Diagnostics and Genetics |
Genetic Variants of Tumor Necrosis Factor Superfamily, Member 4 (TNFSF4), and Risk of Incident Atherothrombosis and Venous Thromboembolism
Anders Mälarstig1,
Per Eriksson1,
Lynda Rose2,
Kirsti A. Diehl2,
Anders Hamsten1,
Paul M Ridker2 and
Robert Y.L. Zee2,a
1 Atherosclerosis Research Unit, Department of Medicine, Karolinska Institute, Stockholm, Sweden; 2
Center for Cardiovascular Disease Prevention, and the Leducq Center for Molecular and Genetic Epidemiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA.
aAddress correspondence to this author at: Laboratory of Genetic and Molecular Epidemiology, Center for Cardiovascular Disease Prevention, Brigham and Women’s Hospital, 900 Commonwealth Avenue East, Boston, MA 02215. E-mail rzee{at}rics.bwh.harvard.edu.
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Abstract
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Background: Recent data have implicated tumor necrosis factor (ligand) superfamily, member 4 (TNFSF4) gene variation in myocardial infarction in women; however, no prospective data are available on either incident arterial or venous disorders.
Methods: We evaluated 2 previously characterized TNFSF4 gene variants (–921C>T and dbSNP rs3850641) with a) incident arterial events using a prospective case-cohort design with 344 incident CVD cases and 2254 control participants, all white, drawn from the Women’s Health Study cohort with 10 years of follow-up, and b) venous thromboembolism (VTE) risk using a nested, matched case-control design of 108 white male pairs (drawn from the Physicians’ Health Study cohort) and a case-cohort design of white female participants consisting of 125 cases and 2269 controls (drawn from the Women’s Health Study cohort), analyzed separately.
Results: Genotype distributions were in Hardy-Weinberg equilibrium. Results from a marker-by-marker regression analysis, adjusting for traditional risk factors, showed a significant association of –921C>T with an increased risk of VTE in women (additive: odds ratio 1.86; 95% CI 1.17–2.92, P = 0.008) in women. Furthermore, using a haplotype-based regression analysis, haplotype C-G was associated with a reduced risk of VTE relative to the referent haplotype, C-A (odds ratio 0.50; 95% CI 0.27–0.92; P = 0.02). In contrast, we found little evidence for an association of the variants/haplotypes with risk of VTE in men or CVD risk in women (as previously reported).
Conclusions: Our present findings, if corroborated in other prospective investigations, suggest that the TNFSF4 variants tested may be useful indicators for assessing the risk of venous thromboembolism.
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Introduction
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Vascular inflammation is a key component in the development and progression of cardiovascular disease (CVD)1
and venous thromboembolism (VTE). Understanding of the processes that initiate and maintain inflammation has increased with the characterization of new disease pathways in the adaptive and innate immune systems. One such pathway is the receptor-ligand pair Ox40-Ox40 ligand (Ox40L), which has shown association with atherosclerosis in both mouse and human(1). Interruption of the Ox40-Ox40L pathway attenuates atherogenesis in LDL receptor–deficient mice(2).
Ox40L is a 34-kDa glycoprotein belonging to the tumor necrosis superfamily. The expression of Ox40L has been observed in T cells, B lymphocytes, vascular endothelial cells, and importantly, dendritic cells(3)(4)(5). Cross-linking of Ox40L with Ox40 provides a T-cell costimulatory signal, resulting in increased proliferation and cytokine production(4)(5). In addition, there is evidence that Ox40L inhibits interleukin (IL)-10 production and suppresses the function of IL-10–producing T cells, which may be a unique function of Ox40L to regulate immunity and tolerance(2). Attributable to the immunoregulatory role of this pathway, interactions between Ox40 and Ox40L have the potential to enhance inflammatory responses in atherosclerotic plaque.
Single nucleotide polymorphisms (SNPs) in the tumor necrosis factor (ligand) superfamily, member 4 (TNFSF4)2
gene, encoding Ox40L, have been associated with increased risk of myocardial infarction (MI) in women(1). In contrast, the role of inflammatory genes in VTE is less explored. More importantly, the long-term risk of thromboembolic events associated with TNFSF4 variants and, hence, their predictive power remain unknown. We therefore investigated the associations of 2 previously characterized TNFSF4 variants (–921C>T and dbSNP rs3850641) with a) risk of incident arterial events using a prospective, case-cohort design with 344 incident CVD cases and 2386 control participants drawn from the Women’s Health Study (WHS) and b) VTE risk in men and women drawn from the Physicians’ Health Study (PHS) cohort and the WHS cohort, respectively.
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Materials and Methods
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study design
Physicians’ Health Study.
We employed a nested case-control design within the PHS, a randomized, double-blinded, placebo-controlled trial of aspirin and β-carotene initiated in 1982 among 22 071 male, predominantly white (>94%) U.S. physicians, 40–84 years of age at study entry(6). Before randomization, 14 916 participants provided an EDTA-anticoagulated blood sample, which was stored for genetic analysis. All participants were free of prior MI, stroke, transient ischemic attacks, deep venous thrombosis/pulmonary embolism (DVT/PE), and cancer at study entry. Yearly follow-up self-report questionnaires provided reliable updated information on newly developed diseases and the presence or absence of other cardiovascular risk factors. A history of cardiovascular risk factors, such as hypertension, diabetes, or hyperlipidemia, was defined by self-report of diagnosis at entry into the study. For all reported incident vascular events occurring after study enrollment, hospital records, death certificates, and autopsy reports were requested and reviewed by an end-points committee using standardized diagnostic criteria.
A diagnosis of DVT was confirmed by a positive report of venous ultrasound or venography, whereas the diagnosis of PE was confirmed in the presence of either a positive angiogram or a ventilation-perfusion scan with 2 or more mismatched defects. Idiopathic (primary/unprovoked) DVT/PE was defined as occurring in the absence of known malignancy, recent trauma, or surgery(7). For each case, a control matched by age, smoking history, and length of follow-up was chosen among those subjects who remained free of vascular diseases; 108 case-control pairs were identified for the present investigation, all white men.
The study was approved by the Brigham and Women’s Hospital Institutional Review Board for Human Subjects Research.
Women’s Health Study.
We employed a case-cohort design within the WHS cohort, a recently completed randomized, double-blinded, placebo-controlled clinical trial of low-dose aspirin and vitamin E aimed at assessing the hypothesis of primary prevention of CVD and cancer in U.S. female healthcare professionals through this intervention(8). Eligible participants were apparently healthy women, age 45 years or older, who were free of self-reported CVD or cancer at study entry (1992–1995), with follow-up for incident CVD through February 2005. At the time of enrollment, participants provided written informed consent; completed questionnaires on racial/ethnic status, demographic variables, medical history, medication use, dietary and lifestyle variables; and were asked to provide a blood sample.
Participants were followed for the composite end point of incident CVD (nonfatal MI, nonfatal ischemic stroke, coronary revascularization, or cardiovascular death) and the individual endpoints of nonfatal MI and nonfatal ischemic stroke. Medical records were obtained and reviewed for confirmation of events as described(8). Deaths from cardiovascular causes were identified by reports from family members, postal authorities, and a search of the National Death Index and were confirmed by autopsy reports, death certificates, and medical records. For the composite endpoint of incident VTE (DVT/PE), medical records were obtained and reviewed for confirmation of events as described(9). Deaths from vascular causes were identified by reports from family members, postal authorities, and a search of the National Death Index and were confirmed by autopsy reports, death certificates, and medical records.
The present case-cohort study consisted of white women who were not current smokers, and not hormone replacement therapy (HRT) users: 344 incident CVD cases (including 91 MI and 95 ischemic stroke) and 2254 subcohort controls were available for the arterial investigation; and 125 incident DVT/PE cases and 2269 subcohort controls were available for the venous investigation.
The study was approved by the Brigham and Women’s Hospital Institutional Review Board for Human Subjects Research.
snp selection and genotype determination
The rs3850641 SNP is positioned in intron 1 and was chosen for its strong association with MI in a previous study(1). We also selected the –921C>T variant, positioned in the TNFSF4 promoter, for its putative role in transcription regulation(10). We determined genotype using a fluorescence-based allelic discrimination method (Applied Biosystems)(11). Each 10-mL amplification reaction volume contained 1x Universal Master Mix (ABgene Inc.) and 10 ng template DNA. Amplification reactions were carried out on an ABI 7900HT Sequence Detection System according to the manufacturer’s specifications. 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 if necessary, a repeat genotyping. In addition, quality control (duplicate-genotyping) was performed on 5% randomly selected samples, and 100% concordance on genotype assignment was observed. Results were scored blinded as to case-control status.
statistical analysis
WHS.
We compared allele and genotype frequencies among cases and controls with values predicted by Hardy-Weinberg equilibrium using the 
2 test. Hazard ratios (HRs) of total CVD, MI, ischemic stroke, or VTE associated with each polymorphism were calculated separately by a weighted Cox proportional-hazards analysis using Barlow’s method(12)(13) with adjustment for age and further adjustment for traditional CVD risk factors or potential confounders [randomized treatment assignment, body mass index (BMI), history of hypertension (
140/90 mm Hg or on antihypertensive medications or physician’s diagnosis), presence or absence of diabetes, hyperlipidemia [plasma cholesterol 6.21 mmol/L (240 mg/dL)], and the use of hormone replacement therapy], assuming an additive, dominant, or recessive mode of inheritance. Because the TT-homozygote for –921C>T was quite rare, analysis assuming a recessive model was not performed. We examined pairwise linkage disequilibrium (LD) as described by Devlin and Risch(14) and performed haplotype inference and frequency estimation using Phase v2.1.1(15)(16). In addition, we examined the relationship between haplotypes and each prespecified clinical endpoint (MI, or ischemic stroke) separately using a haplotype-based weighted Cox proportional-hazards analysis with baseline parameterization(17), adjusting for the same potential risk factors or confounders. For each HR, we calculated 95% CIs.
PHS.
We compared allele and genotype frequencies among cases and controls with values predicted by Hardy-Weinberg equilibrium using the 2 test. Relative risks of VTE associated with each genotype were calculated separately by conditional logistic regression analysis conditioning on the matching by age, smoking status, and length of follow-up since randomization and further controlling for randomized treatment assignment, history of hypertension, diabetes, and BMI, assuming additive, dominant, or recessive mode of inheritance. Because the TT-homozygote for –921C>T was quite rare, analysis assuming a recessive model was not performed. We examined pairwise LD as described by Devlin and Risch(14) and determined haplotype estimation and inference using Phase v2.1.1(15)(16). We examined haplotype distributions between cases and controls by permutation test. In addition, we examined the relationship between haplotypes and incident VTE using a haplotype-based logistic regression analysis(17), adjusting for the same potential risk factors.
All analyses were carried out using SAS/Genetics 9.1 package (SAS Institute Inc.). For each odds ratio, we calculated 95% CIs. A 2-tailed P value of 0.05 was considered statistically significant.
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Results
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arterial events
Baseline characteristics of the study participants are shown in Table 1
. As expected, the case participants had a higher prevalence of traditional cardiovascular risk factors at baseline compared with controls. Genotype frequencies for the polymorphisms tested in the subcohort group were in Hardy-Weinberg equilibrium.
Using a marker-by-marker approach, genotype and allele distributions were similar between cases and controls (Table 2
). Results from the adjusted Cox regression analysis showed no evidence for an association of the variants tested with total CVD events, MI, or ischemic stroke (Table 3
). Overall, the variants were in strong pairwise LD (D' = 0.95), and similar haplotype distribution was observed between cases and subcohort controls (see Supplementary Table 1 in the Data Supplement that accompanies the online version of this article at http://www.clinchem.org/content/vol54/issue5). Further analysis using a haplotype-based approach again yielded similar null findings (see Supplementary Table 2 in the online Data Supplement).
venous events
Baseline characteristics of the sample populations are shown in Table 4
. As expected, the case participants had a higher prevalence of BMI at baseline compared with subcohort controls. Genotype frequencies for the polymorphisms tested in the control/subcohort group were in Hardy-Weinberg equilibrium.
Using a marker-by-marker approach, genotype and allele distributions for –921C>T were significantly different between cases and subcohort controls in women (Table 5
), but not men. Results from the adjusted regression analysis showed an association of –921C>T with increased risk of VTE (additive: HR 1.86, 95% CI 1.17–2.92, P = 0.008; Table 6
). However, no association of rs3850641 with VTE risk was found (Table 6
). As previously described, the WHS sample population consisted of nonsmokers. We thus reran the entire regression analysis limited to nonsmokers in the PHS nested case-control sample population for direct comparison. Similar null findings were obtained in men (Table 6
). The polymorphisms tested were in strong pairwise LD (PHS: D' = 1.00; WHS: D' = 1.00). Again, the haplotype distribution was significantly different between cases and subcohort controls in women, but not men (see Supplementary Table 3 in the online Data Supplement). The most frequent haplotype was 1–1 [C-A], which was thus used as the referent.
Results from the adjusted haplotype-based regression analysis showed an association of haplotype 1–2 [C-G] with lower risk of VTE relative to the referent-haplotype 1–1 [C-A] in women (HR 0.50, 95% CI 0.27–0.92, P = 0.02; Supplementary Data Table 4). Again, in an analysis limited to nonsmokers, no significant association of the haplotypes examined with risk of VTE was detected in men (see Supplementary Table 4 in the online Data Supplement). Furthermore, additional adjustment for factor V Leiden and prothrombin-mutation carrier status showed similar null (PHS) and significant (WHS) findings (data not shown).
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Discussion
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Our data indicate no relationship between 2 genetic variants in TNFSF4 and risk of future cardiovascular events in apparently healthy women. Thus, the result of our study does not support previous studies associating SNPs in TNFSF4 with atherothrombotic disease(1)(18). The WHS study differs from previous cardiovascular case-control studies targeting TNFSF4 variants in some aspects. The most important is that the WHS study enrolled individuals with distinct socioeconomic status (health professionals) and excluded smoking individuals and HRT users. Therefore, a cardiovascular risk conferred by gene–environment interactions between TNFSF4 variants and risk factors related with lifestyle would not be detectable in the present WHS study. Gene–environment interactions have been suggested to underlie a considerable part of the variability observed at quantitative trait loci and may thus substantially influence genotype–disease associations(19). In this context, it is interesting that a recent study demonstrated association of a TNFSF4 variant with cerebrovascular disease in diabetic patients only(20).
We demonstrate here, however, that the promoter variant –921C>T in TNFSF4 is significantly associated with the risk of incident VTE in women, but not men. To the best of our knowledge, the present investigation is the first to examine specific TNFSF4 variants with risk of incident VTE in men and women. Thus, the present findings implicate a relative differential contribution of traditional risk factors between arterial and venous thrombosis, including nonclassic atherosclerotic mechanisms and differential effects of plasma lipids on atherogenesis in the venous bed vs coronary vascular bed. Moreover, unidentified environmental factors that modify TNFSF4 effects are likely to differ between the pathogenesis of arterial and venous disorders. Furthermore, there are no data supporting a gender-specific genetic association in VTE. As discussed elsewhere(21), our observed association with VTE risk in women requires confirmation in other studies.
The inflammatory component of VTE is evident in the immune response that follows an acute VTE event. Less is known of the relationship between chronic inflammation and future VTE risk. Interaction between Ox40 on T cells and Ox40L on vascular endothelial cells induces the production of RANTES (regulated on activation, normal T expressed and secreted), which recruits more T cells to the endothelium, thereby promoting a local proinflammatory state(22). The present data further highlight the potential involvement of inflammation in the pathogenesis of VTE in addition to the commonly perceived coagulation and fibrinolytic mechanisms(23)(24)(25).
The use of 2 closed population sampling schemes—nested case-control and case-cohort—in which subsequent case status was determined solely by the development of disease, strongly reduces the possibility that our findings are due to bias. In essence, a case-cohort study is comparable to a case-control study in which every person in the source population has the same chance of being included as a control, regardless of how much time that person has contributed to the person-time experience of the cohort(26). Although a recent simulation study with respect to analysis and efficiency suggested that a case-cohort sampling from the full cohort may be more efficient than using a comparable nested case-control design(13), in many instances there may be little difference between the 2 schemes(13)(26). Our study cohorts consist entirely of white subjects with distinct socioeconomic status (healthcare professionals), so our data cannot be generalized to other ethnic groups and other populations. Of note, functional analyses of both genetic variants examined in the present study, using haplotype-specific chromatin immunoprecipitation of activated polymerase II as a measure of transcriptional activity in vivo and electromobility shift assay to analyze allele-specific binding of transcription factors in vitro, have indicated that the –921C>T polymorphism is functionally important(27).
In our study, based on the present case-cohort size and the observed allele frequencies and assuming 80% power and an 
value of 0.05, we had the ability to detect a risk ratio (for total incident CVD events) of equal or >1.8 and of 1.5 for the –921C>T and rs3850641 variants, respectively, assuming an additive model. Power will be less for other individual clinical endpoints. Thus, we cannot rule out that a modest risk of cardiovascular disease was associated with the polymorphisms/haplotypes tested in this study population.
Future molecular genetics studies targeting the Ox40-Ox40L pathway will need to address issues of gene–environment interactions and moderate effect sizes and investigate several related clinical phenotypes, which will determine the usefulness of TNFSF4 variants in the prediction of future thromboembolic risk.
In conclusion, the present investigation provides no evidence for an association of TNFSF4 variation with incident CVD in women, which is in contrast to previous findings. However, an association of a TNFSF4 promoter gene variant with an increased risk of incident VTE was found in women but not men. More importantly, our present findings require replication/confirmation in other prospective studies.
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Acknowledgments
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Grant/Funding Support: This study was supported by grants from the National Heart, Lung, and Blood Institute (HL-58755 and HL-63293); the Leducq Transatlantic Networks of Excellence for Cardiovascular Research Program; the Doris Duke Charitable Foundation; the American Heart Association; the Donald W. Reynolds Foundation, Las Vegas, Nevada; the European Commission (LSHM-CT-2007-037273); the Swedish Research Council (project 8691); the Swedish Heart-Lung Foundation; and the Stockholm County Council (project 20050210).
Financial Disclosures: None declared.
Acknowledgments: The authors thank the investigators, staff, and participants of the Women’s Health Study for their valuable contributions.
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Footnotes
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1 Nonstandard abbreviations: CVD, cardiovascular disease; VTE, venous thromboembolism; Ox40L, Ox40 ligand; IL, interleukin; SNP, single nucleotide polymorphism; MI, myocardial infarction; WHS, Women’s Health Study; PHS, Physicians’ Health Study; DVT, deep venous thrombosis; PE, pulmonary embolism; LD, linkage disequilibrium. 
2 Human genes: TNFSF4, tumor necrosis factor (ligand) superfamily, member 4.
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Abstract
Introduction
