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Preliminary Communication |

Hormone Replacement Therapy, Prothrombotic Mutations, and the Risk of Incident Nonfatal Myocardial Infarction in Postmenopausal Women FREE

Bruce M. Psaty, MD, PhD; Nicholas L. Smith, PhD; Rozenn N. Lemaitre, PhD; Hans L. Vos, PhD; Susan R. Heckbert, MD, PhD; Andrea Z. LaCroix, PhD; Frits R. Rosendaal, MD, PhD
[+] Author Affiliations

Author Affiliations: Departments of Medicine (Drs Psaty and Lemaitre), Epidemiology (Drs Psaty, Smith, Heckbert, LaCroix, and Rosendaal), and Health Services (Dr Psaty), Cardiovascular Health Research Unit, University of Washington, Seattle; Fred Hutchinson Cancer Research Center, Seattle, Wash (Dr LaCroix); Center for Health Studies, Group Health Cooperative, Seattle, Wash (Dr LaCroix); Department of Hematology (Drs Vos and Rosendaal), and Clinical Epidemiology (Dr Rosendaal), Leiden University Medical Center, Leiden, the Netherlands.


JAMA. 2001;285(7):906-913. doi:10.1001/jama.285.7.906.
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Published online

Context Estrogens are known to be prothrombotic, and findings from the Heart and Estrogen/progestin Replacement Study suggest that in women with clinically recognized heart disease, hormone replacement therapy (HRT) may be associated with early harm and late benefit in terms of coronary events.

Objective To assess whether, as hypothesized, prothrombotic mutations modify the association between HRT use and incidence of first myocardial infarction (MI).

Design and Setting Population-based, case-control study conducted in a Seattle-based health maintenance organization.

Participants Cases were 232 postmenopausal women aged 30 to 79 years who had their first nonfatal MI between 1995 and 1998. Controls were a stratified random sample of 723 postmenopausal women without MI who were frequency-matched to cases by age, calendar year, and hypertension status.

Main Outcome Measure Risk of first nonfatal MI based on current use of HRT and the presence or absence of coagulation factor V Leiden and prothrombin 20210 G→A variants among cases and controls, stratified by hypertension.

Results One hundred eight MI cases and 387 controls had hypertension and 124 MI cases and 336 controls did not. Among hypertensive women, the prothrombin variant was a risk factor for MI (odds ratio [OR], 4.32; 95% confidence interval [CI], 1.52-12.1) and, in this stratum, there was also a significant interaction between use of HRT and presence of the prothrombin variant on risk of MI. Compared with nonusers of HRT with wild-type genotype, women who were current users and who had the prothrombin variant (n = 8) had a nearly 11-fold increase in risk of a nonfatal MI (OR, 10.9; 95% CI, 2.15-55.2). The interaction with the prothrombin variant was more pronounced in analyses assuming 100% compliance than in those assuming 80% compliance with HRT. The interaction was absent among nonhypertensive women and was less pronounced if hypertensive and nonhypertensive women were combined into 1 group. No interaction was found for factor V Leiden in either hypertensive or nonhypertensive women. Among hypertensive women, the estimates were affected only in trivial ways by adjustment, and the interaction with the prothrombin variant was specific to HRT.

Conclusions Our results suggest that among postmenopausal hypertensive women, the association between HRT use and MI risk differed between those with and without the prothrombin 20210 G→A variant. If these findings are confirmed in other studies, screening for the prothrombin variant may permit a better assessment of the risks and benefits associated with HRT in postmenopausal women.

For many years, recommendations about the use of hormone replacement therapy (HRT) in postmenopausal women have been based largely on observational studies, which suggest that HRT reduces the risk of coronary heart disease.13 The likely mechanisms are numerous4 and include the beneficial effects of estrogens on lipids.5 But estrogens are also known to be prothrombotic.6 In men with prostate cancer or cardiovascular disease7,8 and in women on oral contraceptives,9 high doses or potent formulations of estrogens are associated with thrombotic complications, including myocardial infarction (MI), stroke, and venous thrombosis. In postmenopausal women, HRT is also a risk factor for venous thrombosis.1013

The results of the Heart and Estrogen/progestin Replacement Study (HERS) have renewed interest in the potential adverse effects of HRT.12,13 In this randomized clinical trial of secondary prevention, combined HRT was no better than placebo at preventing coronary events in postmenopausal women (relative risk [RR], 0.99; 95% confidence interval [CI], 0.81-1.22). In post-hoc analyses, treatment was associated with early harm during the first year of follow-up (RR, 1.52; 95% CI, 1.01-2.29) and a late benefit during follow-up years 4 and 5 (RR, 0.75; 95% CI, 0.50-1.13). One broad hypothesis offered to explain this pattern of risks was the possibility of "an immediate prothrombotic, proarrhythmic, or proischemic effect of treatment that is gradually outweighed by a beneficial effect on the underlying progression of atherosclerosis."12,13 According to this interpretation, a subgroup—perhaps defined by a clinical characteristic, an environmental exposure, or a genetic trait—is susceptible to an early adverse effect of estrogens while the rest of the population benefits from estrogen therapy. When a therapy produces effects that differ by more than chance variation in 2 subgroups, an interaction is present.

Genetic variants are excellent candidates for such interactions. Vandenbroucke et al14 have described an interaction between oral contraceptives and factor V Leiden on the risk of deep venous thrombosis. While factor V Leiden and the prothrombin 20210 G→A variant are clearly associated with the risk of venous thrombosis,15 reports of an association between these prothrombotic variants and coronary heart disease have been inconsistent, some finding an increased risk,1619 while others do not.2024 Whether HRT places women with either of these 2 prothrombotic variants at an especially high risk of MI remains unknown. Before the results of HERS were published or known to us, we initiated a population-based, case-control study to assess this interaction as an a priori hypothesis.

Setting

The setting for this project was Group Health Cooperative (GHC), a Seattle, Wash–based health maintenance organization with an enrollment of more than 400 000. The methods have been described previously25,26 and will be summarized only briefly here. The study was reviewed and approved by human subjects committees at both GHC and the University of Washington, Seattle. All subjects gave written informed consent before initiating the study. During the period of this study, the preferred oral estrogens at the GHC were esterified estrogens.

Identification of Cases and Controls

Cases were female GHC enrollees who survived an incident MI between January 1995 and December 1998. Potential cases were identified from 2 sources: (1) the computerized discharge abstracts for the 2 GHC hospitals; and (2) the GHC claims databases, which include bills for all services provided by non-GHC physicians and health care facilities. We have used and evaluated similar methods in previous case-control studies.2528 Due to different funding sources, cases were stratified on hypertension status as assessed by the computerized pharmacy database. Controls were a stratified random sample of postmenopausal female GHC enrollees sampled from the GHC computerized enrollment files on the basis of person-time.29 Controls were frequency matched to the cases by age (within decade), calendar year, and hypertension status at a ratio of approximately 3 to 1. Controls met the same eligibility criteria as the cases, but they had not had an MI. Grants from the National Institutes of Health and the American Heart Association funded primary data collection on cases with and without hypertension, respectively.

Index Dates and Eligibility

All women had an index date. For the cases, the index date was the date of admission for the first acute MI; and for the controls, the index date was a computer-generated random date within the same calendar year for which they had been chosen as controls. For all women, we only collected risk factor data available before the index date. This approach ensured that cases and controls met the same eligibility criteria. All women were aged 30 to 79 years at their index dates. For all subjects, we excluded women who were members of GHC for less than 1 year or who did not have at least 4 physician visits prior to their index dates; women who had had a prior MI; and women who were not postmenopausal. Additionally, we excluded cases whose index event was a complication of a procedure or a surgery.

Data Collection and Definition of HRT Use

Data collection included a review of the GHC outpatient medical record, a telephone interview, and a venous blood sample from women who consented to participate. Based on the medical record, research assistants determined eligibility and collected information about the following traditional risk factors for coronary heart disease: blood pressure and pulse; height and weight; cholesterol level, smoking status, family history, hysterectomy status, marital status, and use of health services; medical conditions such as angina, hypertension, diabetes, congestive heart failure, stroke, and peripheral vascular disease. Cardiovascular disease was defined as a history of angina, stroke, claudication, or vascular procedures, including coronary bypass, angioplasty, carotid endarterectomy, or peripheral vascular bypass. Research assistants were not blinded to case-control status.

The GHC computerized pharmacy database was used to assess current HRT use at the index date. Since 1976, the GHC pharmacy database has included a record for all prescriptions dispensed to GHC enrollees. Each pharmacy record includes a patient identifier, the drug type and dose, the date, the quantity dispensed, and dosing instructions. For determining current use, we searched the pharmacy data for the hormone prescription immediately preceding the reference date. When a woman (who was at least 80% compliant) received enough pills to last until her index date, she was counted as a current user; otherwise, she was counted as a nonuser. For 80% compliance, a woman who received 100 pills with instructions to take 1 pill per day was counted as a current user for 125 days (from 100/0.8) after the prescription dispensing date. Current progestin use was defined in the same way. In preplanned sensitivity analyses, we reanalyzed data that defined current HRT use assuming 100% rather than 80% compliance. For 100% compliance, a woman who received 100 pills with instructions to take 1 pill per day was counted as a current user for 100 days after the prescription dispensing date. Only users of oral estrogens with or without progestins were classified as users.

Blood Collection and Laboratory Analysis

A blood specimen was drawn from the antecubital vein into tubes containing edetic acid and kept at 4°C until the blood was initially processed. Buffy coats were prepared, washed in saline, and stored at −70°C. Specimens were shipped on dry ice to the laboratory in Leiden, the Netherlands. The DNA was extracted from the white blood cells using standard salting-out procedures.30 The status of the prothrombin variant (20210 G→A) was assessed by the presence of a HindIII restriction site in the polymerase chain reaction fragment.31 The presence of factor V Leiden (1691 G→A) was assessed by the loss of an MnlI restriction site as originally described by Bertina et al.32 Laboratory personnel were blinded to case-control status and to HRT status.

Statistical Analysis

In comparing case and control characteristics, we used the t test for continuous variables, the χ2 test for categorical variables, and the Fisher exact test. Because of the stratified sampling, the analysis was stratified on hypertension status. Odds ratios (ORs) and CIs were estimated in the standard way,33,34 and logistic regression was used for multivariable analysis. The ORs estimating the association between HRT and MI were also calculated separately in the 2 strata defined by genotype: (1) women with a prothrombotic variant (susceptible women); and (2) women with the wild-type (normal) genotype (nonsusceptible women). All statistical tests were 2-tailed.

For the primary analysis, we classified women as current or not current users of HRT at their index dates by the 80% compliance method. The current users were compared with the noncurrent users. Women with a prothrombotic variant were compared with women with the wild-type genotype. Formal tests for interaction were carried out with both case-control and case-only methods,35,36 which are more efficient and powerful than case-control methods.37 Both methods estimate the synergy index (SI), which is a ratio of the OR in the susceptible women to the OR in the nonsusceptible women. An SI of 1 means that the ORs in the 2 subgroups were the same and that there was no interaction on the multiplicative scale; a SI of greater than 1 means that the joint effect of gene and the drug were supramultiplicative compared with their expected effect, which is the product of their individual effects.

Of the 955 women, 108 cases and 387 controls had hypertension, and 124 cases and 336 controls were in the stratum without hypertension. The control-to-case matching ratio was higher in the hypertensive (3.6:1) than in the nonhypertensive (2.7:1) women. Genotype assays were available for 950 women for factor V Leiden and for 953 women for the prothrombin variant. Factor V Leiden was present in 23 hypertensive and 25 nonhypertensive women, and no homozygotes were present. The prothrombin variant was present in 15 hypertensive and 15 nonhypertensive women. One additional nonhypertensive control was homozygous for the variant prothrombin allele.

Within each stratum, frequency matching produced a control group with a mean age close to that of the cases (Table 1). In both the hypertensive and the nonhypertensive strata, diabetes, smoking, physical activity, cholesterol, high-density lipoprotein cholesterol, glucose, family history, and a history of angina differed between cases and controls in the expected manner. Among nonhypertensive women, weight and systolic and diastolic blood pressure also differed significantly between cases and controls. Among the hypertensive women, weight, systolic blood pressure, and mean time enrolled in GHC were similar in the cases and controls.

Table Graphic Jump LocationTable 1. Characteristics of Cases and Controls Stratified on the Presence of Treated Hypertension

Table 2 summarizes the main effects of HRT, factor V Leiden, and the prothrombin variant on MI risk. Among hypertensive women, current HRT use and factor V Leiden were only weakly associated with MI risk. On the other hand, the prothrombin variant was associated with an increased risk of MI in hypertensive women (OR, 4.32; 95% CI, 1.52-12.1); after adjustment for covariates, the OR increased to 7.02 (95% CI, 2.27-21.8). Among nonhypertensive women, there was little association of HRT or either prothrombotic variant with case-control status, before or after adjustment for covariates.

Table Graphic Jump LocationTable 2. Association of Hormone Replacement Therapy, Factor V Leiden, and the Prothrombin Variant With First Nonfatal Myocardial Infarction

Table 3 summarizes the stratified analyses for the prothrombin variant. Hypertensive women who had the wild-type genotype for prothrombin and who were not current users of HRT served as the reference group. Among women with the wild-type genotype, HRT use was associated with a small reduction in the risk of nonfatal MI (OR, 0.89; 95% CI, 0.56-1.42). Compared with the reference group, women who had the prothrombin variant and who were not current users of HRT had only a small increase in the OR to 1.45 (95% CI, 0.28-7.66). In the absence of an interaction (on a multiplicative scale), the expected joint effects of the prothrombin variant and current HRT use would be 1.29. Compared with the reference group, the 8 women who had the prothrombin variant and who were current users of HRT had an almost 11-fold increase in the risk of MI (OR, 10.9; 95% CI, 2.15-55.2; P = .002).

Table Graphic Jump LocationTable 3. Association Among Hormone Use, Prothrombin Variant, and Risk of First Nonfatal Myocardial Infarction*

The analyses stratified on susceptibility also appear in Table 3. Among the 478 nonsusceptible, hypertensive women (with prothrombin wild type), HRT use was associated with a slight decrease in the risk of MI (OR, 0.89). Among the 15 susceptible, hypertensive women (with prothrombin variant), HRT use was associated with an increased risk of MI (OR, 7.50; 95% CI, 0.76-74.2; P = .10). The case-control estimate of the SI was 8.38 (95% CI, 0.81-86.8; P = .06). The case-only estimate of the SI was similar at 5.57 (95% CI, 1.07-29.1; P = .03) and indicated a significant interaction between HRT and the prothrombin variant on the risk of nonfatal MI among hypertensive women. When the analysis was restricted to whites only (data not shown), the case-control SI was 8.62 (95% CI, 0.83-89.4); the corresponding case-only SI was 5.38 (95% CI, 1.03-28.15). When we assumed 100% rather than 80% compliance, the evidence of an interaction became more pronounced with a case-control SI of 23.9 (95% CI, 1.61-354; P = .008).

Among women without hypertension, no cases had the prothrombin variant and used HRT. There was no evidence of an interaction. Combining estimates from these 2 strata, defined by hypertension status, did not appear to be appropriate. If hypertensive and nonhypertensive women were combined into a single group, the interaction would have been less pronounced (SI, 2.0; 95% CI, 0.45-8.95).

Table 4 summarizes the data for factor V Leiden in the same format used for the prothrombin variant. Again, women who were not current users by the 80% compliance method and who did not have factor V Leiden served as the reference group. Individually or jointly, there was little association between HRT use or factor V Leiden and MI risk. None of the CIs for these associations excluded the null hypothesis. The SIs estimated by both the case-control and the case-only methods were small and did not differ from the null hypothesis of no interaction.

Table Graphic Jump LocationTable 4. Association Among Hormone Use, Factor V Leiden, and Risk of First Nonfatal Myocardial Infarction

The small number of hypertensive women with the prothrombin variant (n = 15) limited the ability to adjust for potential confounding factors. Table 5 summarizes the effect of adjustment for a number of covariates one at a time. The unadjusted OR estimates are the same as in Table 3: 0.89 for HRT use, 1.45 for the prothrombin variant, and 10.9 for the combination of HRT use and the prothrombin variant. Adjustments for age, calendar year, race, smoking, diabetes, cardiovascular disease, systolic blood pressure, or cholesterol each had little effect on the point estimates. The lowest adjusted OR for the combination of HRT use and the prothrombin variant was 10.4, and the lower limit of the 95% CIs never went below 1.97.

Table Graphic Jump LocationTable 5. Effect of Adjustment on the Association of Hormone Use and Prothrombin Variant With the Risk of First Nonfatal Myocardial Infarction in Women With Hypertension*

Table 6 summarizes the findings of a series of analyses that attempted to identify other potential interactions with the prothrombin variant on the risk of MI, primarily among women with hypertension. The SIs for HRT use at 80% and 100% compliance were 8.38 (95% CI, 0.81-86.8) and 23.9 (95% CI, 1.61-354), respectively. No other characteristic was associated with such an elevated SI. For most of the characteristics, the ORs for MI risk were similar among those with and without the prothrombin variant. For the association between cardiovascular disease (such as angina) and MI risk, the OR was higher among those with the prothrombin variant (OR, 6.00; 95% CI, 0.48-75.4) than among those without the prothrombin variant (OR, 2.92; 95% CI, 1.79-4.78). The SI for cardiovascular disease was 2.05 (95% CI, 0.16-27.0). Zero entries precluded the ability to examine an interaction for smoking and for diabetes in the hypertensive women, but there was no evidence of an interaction in the population as a whole.

Table Graphic Jump LocationTable 6. Candidate Characteristics for Interaction With the Prothrombin Variant and Case-Control Status*

Among the controls, 85.7% of HRT users were taking esterified estrogens, and most of the others were taking conjugated estrogens. Estrogen patches were rarely used at GHC (2 cases and 2 controls). Among the 8 hypertensive women currently taking HRT and having the prothrombin variant, the 6 cases had a slightly smaller mean number of lifetime prescriptions for estrogens than the 2 controls (31 vs 39; P = .71). One of the 6 cases had started HRT 7 months prior to her MI while the other 5 had been regular users for a least 1 year before their MI event. Among the 6 hypertensive cases who had the prothrombin variant and who were current users of HRT, all 6 were using esterified estrogens; 5 of the 6 were taking estrogen alone rather than in combination with a progestin; and 5 were taking 0.625 mg/d and 1 was taking 0.3 mg/d. The antihypertensive medications used by these 6 women were similar to the agents typically used at GHC, and 3 of the 6 were taking atenolol.

In this population-based, case-control study, the prothrombin 20210 G→A variant was a risk factor for MI among hypertensive women. There was also a significant interaction between the use of HRT and the prothrombin variant on the risk of MI among women with hypertension. Compared with the reference group, the 8 women who were current HRT users and who had the prothrombin variant had a nearly 11-fold increase in the risk of a nonfatal MI (OR, 10.9; 95% CI, 2.15-55.2). The 95% CI of the SI as assessed by the more powerful case-only method, a formal test for a multiplicative interaction, excluded the null hypothesis (Table 3). The interaction was more pronounced for the 100% compliance method than for the 80% compliance method of defining current HRT use (Table 3). No such interaction was found for nonhypertensive women (Table 3) or for factor V Leiden in either the hypertensive or the nonhypertensive women (Table 4). Among the hypertensive women, the estimates were affected only in trivial ways by adjustment for potential confounding factors (Table 5). The interaction with the prothrombin variant was specific to HRT use and not to other characteristics (Table 6).

The prothrombin variant has been associated with an increased incidence of venous thrombosis and with elevated levels of prothrombin in plasma.31 In other observational studies, the prothrombin variant has been associated with the incidence of MI in some studies1719 but not in others.20,2224 While previous studies have identified potential interactions of oral contraceptive use with factor V Leiden14 and of HRT use with activated protein C resistance38 on the incidence of venous thrombosis, there are no previous epidemiologic reports of an interaction between HRT use and prothrombotic variants on the risk of MI. The only cross-sectional analysis, conducted in women with hyperlipidemia, assessed HRT use at the time of the clinic visit rather than at the time of the cardiovascular event.39

This study had a number of limitations. Due to the low prevalence of the prothrombin variant, it was not possible to adjust simultaneously for multiple potential confounding factors in a single model.40 While the healthy user effect is often invoked to explain the association between HRT use and a decreased risk of cardiovascular events,41,42 such biases are less likely to be important in studies of genetic variants as risk factors. In addition to the possibility of confounding, potential alternative explanations for the findings of genetic association studies include linkage disequilibrium and population admixture. The results were also based on a small number of women with the genetic variant, so there remained considerable statistical uncertainty around the risk estimates reported in this study.

For both the prothrombin variant and factor V Leiden, we had expected, but did not find, similar interactions with HRT use. The cases in this study all represent survivors of an MI, and it is possible that the interaction may affect mortality rather than disease incidence. If, for instance, the joint effects of factor V Leiden and HRT use are associated with a high case-fatality rate, a case-control study of nonfatal MI would fail to detect an interaction. On the other hand, survival bias is unlikely to induce the interaction seen with the prothrombin variant and HRT use in this study.

For the prothrombin variant, the findings of an interaction among those with hypertension were not confirmed by the findings among those without hypertension. Several explanations, including chance, are possible. Three of the 6 hypertensive cases who had the prothrombin variant and who were HRT users were also taking the β-blocker atenolol, which may have improved their post-MI survival. In hypertensive patients, moreover, the presence and the severity of target organ disease is strongly associated with several prothrombotic abnormalities, including elevated levels of D-dimer.43,44 As we have previously hypothesized,6 the presence of subclinical or clinical cardiovascular disease, such as angina or hypertensive disease, may be important in initiating the prothrombotic effects of estrogens, including any potential interaction with the prothrombin variant. Rosendaal15 has described the risk of venous thrombosis in terms of multiple interacting causes, and a similar model may be relevant for arterial thrombotic disease.

In this case-control study, which excluded women with a previous MI, the interaction with the prothrombin variant was associated with current use of HRT rather than with recent initiation of therapy as in HERS. If a prothrombotic third factor such as coronary atherosclerosis or hypertensive target organ disease is also required,43,44 the onset of the thrombotic event may be delayed until that third factor progresses far enough or becomes severe enough, in the presence of the prothrombin variant and HRT use, to precipitate an MI. If this third-factor hypothesis is true, the findings of this study would be expected to differ from those of HERS in terms of the time relationship between MI events and the initiation of HRT. HERS was a secondary prevention trial that enrolled only women with clinical coronary disease so that the hypothetical third factor was already present from the outset when participants were randomized and began taking HRT.

Among hypertensive controls, the prothrombin variant was present in only 1.8% of women. An uncommon susceptibility factor, such as the prothrombin variant or another associated with a high risk of events among HRT users, might account in part for the pattern of early harm and late benefit seen in the HERS trials.12,13 Simulation studies suggest that the putative unknown susceptibility factor has to exhibit both a prevalence of 3% to 5% and a risk ratio of 13 to 25 in HRT users to reproduce the pattern of early harm and late benefit seen in HERS. While the prothrombin variant is a good candidate, other susceptibility factors are also likely to be important.

The long-term goal of research in the area of pharmacogenetics is to help clinicians individualize treatment for their patients and select drug therapies that maximize either effectiveness, or safety, or both. If the HERS findings are indeed the result of an interaction between HRT and a susceptibility factor, there is an urgent public health need to identify the putative susceptibility factor. Based on their biology and prevalence, the prothrombin variant and factor V Leiden were both reasonable candidates. The findings of this study suggest the possibility of an interaction between the prothrombin variant and HRT use on the incidence of MI among women with hypertension, but they need to be confirmed in other settings. If the findings are confirmed, or if other drug-gene interactions are identified, clinicians may eventually screen postmenopausal women for selected genetic variants that help characterize a woman's expected risk or benefit from HRT for a variety of outcomes, including MI, stroke, and venous thrombosis.

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Psaty BM, Heckbert SR, Koepsell TD.  et al.  The risk of myocardial infarction associated with anti-hypertensive drug therapies.  JAMA.1995;274:620-625.
Psaty BM, Koepsell TD, LoGerfo JP, Wagner EH, Inui TS. β-Blockers and primary prevention of coronary heart disease in patients with high blood pressure.  JAMA.1989;261:2087-2094.
Psaty BM, Koepsell TD, Siscovick D.  et al.  An approach to several problems in the use of large databases for population-based case-control studies of the therapeutic efficacy and safety of anti-hypertensive medicines.  Stat Med.1991;10:653-662.
Pearce N. What does the odds ratio estimate in a case-control study?  Int J Epidemiol.1993;22:1189-1192.
Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells.  Nucleic Acids Res.1988;16:1215.
Poort SR, Rosendaal FR, Reitsma PH, Bertina RM. A common genetic variation in the 3′-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis.  Blood.1996;88:3698-3703.
Bertina RM, Koeleman BPC, Koster T.  et al.  Mutation in blood coagulation factor V associated with resistance to activated protein C.  Nature.1994;369:64-67.
Schlesselman JJ. Case-Control Studies: Design, Conduct, Analysis. New York, NY: Oxford University Press; 1982.
Breslow NE, Day NE. Statistical Methods in Cancer Research: Volume 1—The Analysis of Case-Control Studies. Lyon, France: International Agency for Research on Cancer; 1980. IARC scientific publications No. 32.
Smith PG, Day NE. The design of case-control studies: the influence of confounding and interaction effects.  Int J Epidemiol.1984;13:356-365.
Khoury MJ, Flanders WD. Nontraditional epidemiologic approaches in the analysis of gene-environment interaction: case-control studies with no controls.  Am J Epidemiol.1996;144:207-213.
Yang Q, Khoury MJ, Flanders WD. Sample size requirements in case-only designs to detect gene-environment interaction.  Am J Epidemiol.1997;146:713-720.
Lowe G, Woodward M, Vessey M, Rumley A, Gough P, Daly E. Thrombotic variables and risk of idiopathic venous thromboembolism in women aged 45-64 years: relationships to hormone replacement therapy.  Thromb Haemost.2000;83:530-535.
Glueck CJ, Wang P, Fontaine RN, Tracy T, Sieve-Smith L, Lang JE. Effect of exogenous estrogen on atherothrombotic vascular disease risk related to the presence or absence of factor V Leiden (resistance to activated protein C).  Am J Cardiol.1999;84:549-554.
Peduzzi P, Concato J, Kemper E, Holford TR, Feinstein AR. A simulation study of the number of events per variable in logistic regression analysis.  J Clin Epidemiol.1996;49:1373-1379.
Barrett Connor E. Postmenopausal estrogen and prevention bias.  Ann Intern Med.1991;115:455-456.
Matthews KA, Kuller LH, Wing RR, Meilahn EN, Plantinga P. Prior to use of estrogen replacement therapy, are users healthier than nonusers?  Am J Epidemiol.1996;143:971-978.
Sechi LA, Zingaro L, Catena C, Casaccio D, Demarchi S. Relationship of fibrinogen levels and hemostatic abnormalities with organ damage in hypertension.  Hypertension.2000;36:978-985.
Lip GYH. Target organ damage and the prothrombotic state in hypertension.  Hypertension.2000;36:975-977.

Figures

Tables

Table Graphic Jump LocationTable 1. Characteristics of Cases and Controls Stratified on the Presence of Treated Hypertension
Table Graphic Jump LocationTable 2. Association of Hormone Replacement Therapy, Factor V Leiden, and the Prothrombin Variant With First Nonfatal Myocardial Infarction
Table Graphic Jump LocationTable 3. Association Among Hormone Use, Prothrombin Variant, and Risk of First Nonfatal Myocardial Infarction*
Table Graphic Jump LocationTable 4. Association Among Hormone Use, Factor V Leiden, and Risk of First Nonfatal Myocardial Infarction
Table Graphic Jump LocationTable 5. Effect of Adjustment on the Association of Hormone Use and Prothrombin Variant With the Risk of First Nonfatal Myocardial Infarction in Women With Hypertension*
Table Graphic Jump LocationTable 6. Candidate Characteristics for Interaction With the Prothrombin Variant and Case-Control Status*

References

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Stampfer MJ, Colditz GA. Estrogen replacement and coronary heart disease: a quantitative assessment of the epidemiologic evidence.  Prev Med.1991;20:47-63.
Barrett-Connor E, Grady D. Hormone replacement therapy, heart disease, and other considerations.  Annu Rev Public Health.1998;19:35-72.
Mendelsohn ME, Karas RH. The protective effects of estrogen on the cardiovascular system.  N Engl J Med.1999;340:1801-1811.
Writing Group for the PEPI Trial.  Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women: the Postmenopausal Estrogen/Progestin Intervention (PEPI) Trial.  JAMA.1995;273:199-208.
Psaty BM, Heckbert SR, Atkins D.  et al.  A review of the association of estrogens and progestins with cardiovascular disease in post-menopausal women.  Arch Intern Med.1993;153:1421-1427.
Sotaniemi EA, Kontturi MJ. Serum lipid levels and thromboembolic complications during estrogen therapy of prostatic cancer.  Scand J Urol Nephrol.1975;9:89-93.
Coronary Drug Project Research Group.  The coronary drug project: initial findings leading to modifications of its research protocol.  JAMA.1970;214:1303-1313.
Inman WHW, Vessey MP, Westerholm B, Engelund A. Thromboembolic disease and the steroidal content of oral contraceptives: a report to the committee on safety of drugs.  BMJ.1970;2:203-209.
Daly E, Vessey MP, Hawkins MM, Carson JL, Gough P, Marsh S. Risk of venous thromboembolism in users of hormone replacement therapy.  Lancet.1996;348:977-980.
Grodstein F, Stampfer MJ, Goldhaber SZ.  et al.  Prospective study of exogenous hormones and risk of pulmonary embolism in women.  Lancet.1996;348:983-987.
Hulley S, Grady D, Bush T.for the Heart and Estrogen/progestin Replacement Study (HERS) Research Group.  Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women.  JAMA.1998;280:605-613.
 Final tables from the Heart and Estrogen/progestin Replacement Study (HERS). Available at: http://www.epibiostat.ucsf.edu/HERS/ptable2-5.html. Accessed February 8, 2000.
Vandenbroucke JP, Koster T, Briët E, Reitsma PH, Bertina RM, Rosendaal FR. Increased risk of venous thrombosis in oral-contraceptive users who are carriers of factor V Leiden mutation.  Lancet.1994;344:1453-1457.
Rosendaal FR. Venous thrombosis: a multicausal disease.  Lancet.1999;353:1167-1173.
Rosendaal FR, Siscovick DS, Schwartz SM.  et al.  Factor V Leiden (resistance to activated protein C) increases the risk of myocardial infarction in young women.  Blood.1997;89:2817-2821.
Rosendaal FR, Siscovick DS, Schwartz SM, Psaty BM, Raghunathan TE, Vos HL. A common prothrombin variant (20210 G to A) increases the risk of myocardial infarction in young women.  Blood.1997;90:1747-1750.
Franco RF, Trip MD, ten Cate H.  et al.  The 20210 G→A mutation in the 3′-untranslated region of the prothrombin gene and the risk for arterial thrombotic disease.  Br J Haematol.1999;104:50-54.
Arruda VR, Siquiera LH, Chiaparini LC.  et al.  Prevalence of the prothrombin gene variant 20210 G→A among patients with myocardial infarction.  Cardiovasc Res.1998;37:42-45.
Doggen CJ, Cats VM, Bertina RM, Rosendaal FR. Interaction of coagulation defects and cardiovascular risk factors: increased risk of myocardial infarction associated with factor V Leiden or prothrombin 20210A.  Circulation.1998;97:1037-1041.
Cushman M, Rosendaal FR, Psaty BM.  et al.  Factor V Leiden is not a risk factor for arterial vascular disease in the elderly: results from the Cardiovascular Health Study.  Thromb Haemost.1998;79:912-915.
Ridker PM, Hennekens CH, Miletich JP. G20210A mutation in prothrombin gene and risk of myocardial infarction, stroke, and venous thrombosis in a large cohort of US men.  Circulation.1999;99:999-1004.
Redondo M, Watzke HH, Stucki B.  et al.  Coagulation factors II, V, VII and X, prothrombin gene 20210G→A transition, and factor V Leiden in coronary artery disease: high factor V clotting activity is an independent risk factor for myocardial infarction.  Arterioscler Thromb Vasc Biol.1999;19:1020-1025.
Gardemann A, Arsic T, Katz N, Tillmanns H, Hehrlein FW, Haberbosch W. The factor II G20210A and factor V G1691A gene transitions and coronary heart disease.  Thromb Haemost.1999;81:208-213.
Psaty BM, Heckbert SR, Atkins D.  et al.  The risk of myocardial infarction associated with the combined use of estrogens and progestins in post-menopausal women.  Arch Intern Med.1994;154:1333-1339.
Psaty BM, Heckbert SR, Koepsell TD.  et al.  The risk of myocardial infarction associated with anti-hypertensive drug therapies.  JAMA.1995;274:620-625.
Psaty BM, Koepsell TD, LoGerfo JP, Wagner EH, Inui TS. β-Blockers and primary prevention of coronary heart disease in patients with high blood pressure.  JAMA.1989;261:2087-2094.
Psaty BM, Koepsell TD, Siscovick D.  et al.  An approach to several problems in the use of large databases for population-based case-control studies of the therapeutic efficacy and safety of anti-hypertensive medicines.  Stat Med.1991;10:653-662.
Pearce N. What does the odds ratio estimate in a case-control study?  Int J Epidemiol.1993;22:1189-1192.
Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells.  Nucleic Acids Res.1988;16:1215.
Poort SR, Rosendaal FR, Reitsma PH, Bertina RM. A common genetic variation in the 3′-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis.  Blood.1996;88:3698-3703.
Bertina RM, Koeleman BPC, Koster T.  et al.  Mutation in blood coagulation factor V associated with resistance to activated protein C.  Nature.1994;369:64-67.
Schlesselman JJ. Case-Control Studies: Design, Conduct, Analysis. New York, NY: Oxford University Press; 1982.
Breslow NE, Day NE. Statistical Methods in Cancer Research: Volume 1—The Analysis of Case-Control Studies. Lyon, France: International Agency for Research on Cancer; 1980. IARC scientific publications No. 32.
Smith PG, Day NE. The design of case-control studies: the influence of confounding and interaction effects.  Int J Epidemiol.1984;13:356-365.
Khoury MJ, Flanders WD. Nontraditional epidemiologic approaches in the analysis of gene-environment interaction: case-control studies with no controls.  Am J Epidemiol.1996;144:207-213.
Yang Q, Khoury MJ, Flanders WD. Sample size requirements in case-only designs to detect gene-environment interaction.  Am J Epidemiol.1997;146:713-720.
Lowe G, Woodward M, Vessey M, Rumley A, Gough P, Daly E. Thrombotic variables and risk of idiopathic venous thromboembolism in women aged 45-64 years: relationships to hormone replacement therapy.  Thromb Haemost.2000;83:530-535.
Glueck CJ, Wang P, Fontaine RN, Tracy T, Sieve-Smith L, Lang JE. Effect of exogenous estrogen on atherothrombotic vascular disease risk related to the presence or absence of factor V Leiden (resistance to activated protein C).  Am J Cardiol.1999;84:549-554.
Peduzzi P, Concato J, Kemper E, Holford TR, Feinstein AR. A simulation study of the number of events per variable in logistic regression analysis.  J Clin Epidemiol.1996;49:1373-1379.
Barrett Connor E. Postmenopausal estrogen and prevention bias.  Ann Intern Med.1991;115:455-456.
Matthews KA, Kuller LH, Wing RR, Meilahn EN, Plantinga P. Prior to use of estrogen replacement therapy, are users healthier than nonusers?  Am J Epidemiol.1996;143:971-978.
Sechi LA, Zingaro L, Catena C, Casaccio D, Demarchi S. Relationship of fibrinogen levels and hemostatic abnormalities with organ damage in hypertension.  Hypertension.2000;36:978-985.
Lip GYH. Target organ damage and the prothrombotic state in hypertension.  Hypertension.2000;36:975-977.
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