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The F11 gene encodes factor (F)XI, a component of the intrinsic coagulation pathway. Single nucleotide polymorphisms (SNPs) in the F11 gene and high FXI antigen levels are associated with venous thrombosis (VT) [1,2]. Two F11 variants were found to be associated with VT in a recent fine mapping study conducted in the Leiden Thrombophilia Study and in the Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis (MEGA) study: rs2289252 (22771 T/C) in intron 12 and rs2036914 (7872 C/T) in intron 2 [3]. Carriers of two risk alleles, compared with those who carried no risk alleles, had odds ratios (OR) for VT of 1.84 [95% confidence interval (CI), 1.62–2.10] for rs2289252 and 1.84 (95% CI, 1.61–2.10) for rs2036914, and for carriers of one risk allele the OR was 1.41 (95% CI, 1.27–1.57) for rs2289252 and 1.42 (95% CI, 1.26–1.61) for rs2036914 [3]. Although these two F11 SNPs were associated with FXI levels, they remained associated with VT after adjustment for FXI levels [3].

Several studies have shown that users of statins (a class of lipid-lowering HMG-CoA reductase inhibitors) have approximately 50% fewer VT events than non-users have [4–7]. In the MEGA study, we asked whether carriers of the rs2289252 and rs2036914 risk alleles, compared with non-carriers, were at an increased risk for VT among statin users and also among nonusers.

The MEGA study recruited consecutive patients aged 18–70 years with a first diagnosis of VT (deep vein thrombosis of the leg, venous thrombosis of the arm or pulmonary embolism) from six anticoagulation clinics in the Netherlands between 1 March 1999 and 31 May 31 2004 [8]. Partners of patients were invited to take part as control participants. Additional controls were recruited from the same geographical region by a random digit dialing method and were frequency matched to patients by age and sex [9]. Information on risk factors for VT and medication use (including statins) before their VT event for cases or before enrollment for controls was obtained from questionnaires completed by the participants. Participants also provided a blood or buccal swab sample for DNA extraction [8]. Genotypes were determined in a core laboratory that was blinded to case–control status [10]. All study participants provided written informed consent. The MEGA study was approved by the Medical Ethics Committee of the Leiden University Medical Center, Leiden, The Netherlands.

DNA was available for 9803 participants. Because active cancer is a strong risk factor for VT that might mask other associations, participants with a known malignancy or missing malignancy status were excluded from the current analysis (n = 708); participants without medication use information were also excluded (n = 204); thus, 3698 cases with VT and 4473 controls with no history of VT were investigated in the current study. Of these 8171 study participants, 384 (5%) were self-reported statin users (125 cases and 259 controls). Logistic regression models that adjusted for age and gender were used to assess the association between genotype and VT in statin users and non-users separately using sas software (version 9.1) (SAS Institute Inc., Cary, NC, USA).

Cases and controls did not differ appreciably in mean age (cases, 47.2 years [standard deviation, 12.9]; controls, 47.6 years [standard deviation, 12.3]) or gender (45.6% of cases and 47.2% of controls were male). In the controls of MEGA the genotype frequencies for rs2289252 were 17.1% (TT), 47.1% (TC) and 35.8% (CC) and for rs2036914 were 27.4% (CC), 49.3% (CT) and 23.3% (TT). Genotype distributions for the two SNPs in MEGA did not deviate from Hardy-Weinberg expectations among controls[11] (P > 0.25). The linkage disequilibrium between rs2289252 and rs2036914 was moderate (r= 0.38) in the HapMap CEPH population (Utah residents with ancestry from northern and western Europe) [12].

Among statin non-users of MEGA, the rs2289252 and rs2036914 SNPs were associated with VT (Fig. 1): for participants carrying two risk alleles, compared with those carrying no risk alleles, the OR for VT was 1.83 (95% CI, 1.60–2.08) for rs2289252 and 1.75 (95% CI, 1.54–1.98) for rs2036914. For participants with one risk allele, the OR was 1.39 (95% CI, 1.26–1.55) for rs2289252 and 1.30 (95% CI, 1.15–1.46) for rs2036914, again compared with participants carrying no risk alleles.

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Figure 1.  Risk of venous thrombosis (VT) according to statin use for rs2289252 genotypes, compared with the minor homozygote (CC), and for rs2036914 genotypes, compared with the minor homozygote (TT). The odds ratios (ORs) [shown with 95% confidence intervals] were adjusted for gender and age.

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In contrast, among statin users carriers of rs2289252 were not at increased risk for VT. For participants carrying two risk alleles, compared with those carrying no risk alleles, the OR for VT was 1.06 (95% CI, 0.66–1.71); for those carrying one risk allele the OR was 1.10 (95% CI, 0.57–2.10); and for carriers of 1 or 2 risk alleles, the OR was 1.07 (95% CI, 0.68–1.68). Similarly, among statin users carriers of two rs2036914 risk alleles were also not at an increased risk for VT: the OR was 1.03 (95% CI, 0.53–1.99); however, carriers of one risk allele were at a nominally increased risk for VT: the OR was 1.46 (95% CI, 0.83–2.57).

We also asked whether the association between factor (F)V Leiden and VT differed according to statin use. For FV Leiden the ORs for VT were not appreciably different between statin users and nonusers. Among statin users, for carriers of factor V Leiden, compared with non-carriers, the OR was 4.94 (95% CI, 2.37–10.30) and among non-users the OR was 3.64 (95% CI, 3.09–4.29).

Thus, among MEGA participants who were statin non-users, we found that carriers compared with non-carriers of the risk alleles of rs2289252 and rs2036914 had an increased risk for VT. In contrast, among statin users, carriers of two risk alleles for either SNP were not at an increased risk for VT.

A pathophysiological explanation remains to be found for why the risk associated with these SNPs differs according to statin use. Statins could preferentially suppress the risk for VT in those who carry the risk allele of these SNPs by either (i) inhibiting the increase in FXI levels associated with the risk alleles or (ii) inhibiting the mechanism by which these higher FXI levels increase VT risk. The first possibility could be investigated by determining whether statin use reduces FXI levels preferentially in carriers of the risk alleles; however, the effect of statins on FXI levels has not been reported. The effect of statin use on FXI levels would best be explored in a prospective study because, for example, in the MEGA study statins were likely prescribed to subjects with cardiovascular disease, a population reported to have high FXI levels [13]. An example of the second possibility would be the inhibition of the conversion of FXI into FXIa (as elevated FXI levels can only the increase risk for VT if FXI is activated). An important physiological site of FXI activation is reported to be the surface of activated platelets [14–16], and statins have been reported to inhibit platelet activation [17].

Although anticoagulant therapy reduces the risk for VT events by about 80% [18], anticoagulant therapy also causes life-threatening bleeding events [19–21]. Thus, if statins were shown in a randomized study to effectively reduce VT events, statin therapy may be a useful treatment option when there are particular concerns about bleeding risk or when the risk of VT is modest. The genetic risk for VT from these F11 variants exposes patients to a modest lifelong increase in risk for VT, and in this study of MEGA, the risk for VT in carriers of two alleles of the F11 variants was attenuated by statin use. However, given that the incidence of VT in the general population is approximately 1–2 per 1000 persons per year [22] our results would not justify indiscriminate long-term statin use by carriers of the rs2289252 or rs2036914 risk allele. But future studies could investigate whether carriers of rs2289252 or rs2036914 risk alleles who are in high-risk groups, such as hospitalized patients or patients with a previous VT events, would benefit from statin use.

The present study has several limitations. It is subject to recall bias as medication use was self-reported; however, the risk estimates in MEGA for the association between statin use and VT is consistent with other published studies [4–7]. Furthermore, associations with VT would be underestimated if patients had reported medication use more accurately than control subjects. Multiple statins were used in the study; thus, our results might not be generalizable to all statins. The number of statin users in MEGA was limited; thus, to rule out false-positive associations, the different risk estimates for VT in statin users and nonusers for rs2289252 and rs2036914 should be investigated in an additional study.

In conclusion, although rs2289252 and rs2036914 are associated with a risk of VT, the present study did not find carriers of these risk alleles to be at higher risk of VT among statin users. A randomized trial of statin therapy for the prevention of VT events would provide a better estimate of the clinical benefit of treating carriers of the risk alleles for rs2289252 and rs2036914 with statins to reduce VT events.

Disclosure of Conflict of Interests

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L.A. Bare, A.R. Arellano, C.H. Tong and J.J. Devlin are employees of Celera. LUMC and Celera hold patents or patent applications related to SNPs in F11 and venous thrombosis.

References

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  2. Disclosure of Conflict of Interests
  3. References