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Genetic variation in the first-pass metabolism of ethinylestradiol, sex hormone binding globulin levels and venous thrombosis risk

  • Bernardine H. Stegeman
    Affiliations
    Department of Thrombosis and Haemostasis, Leiden University Medical Center, Leiden 2333 ZA, The Netherlands

    Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden 2333 ZA, The Netherlands
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  • Hans L. Vos
    Affiliations
    Department of Thrombosis and Haemostasis, Leiden University Medical Center, Leiden 2333 ZA, The Netherlands

    Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden 2333 ZA, The Netherlands
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  • Frans M. Helmerhorst
    Affiliations
    Department of Gynaecology and Reproductive Medicine, Leiden University Medical Center, Leiden 2333 ZA, The Netherlands

    Department of Clinical Epidemiology, Leiden University Medical Center, Leiden 2333 ZA, The Netherlands
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  • Frits R. Rosendaal
    Affiliations
    Department of Clinical Epidemiology, Leiden University Medical Center, Leiden 2333 ZA, The Netherlands
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  • Pieter H. Reitsma
    Affiliations
    Department of Thrombosis and Haemostasis, Leiden University Medical Center, Leiden 2333 ZA, The Netherlands

    Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden 2333 ZA, The Netherlands
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  • Astrid van Hylckama Vlieg
    Correspondence
    Corresponding author at: Department of Clinical Epidemiology C7-P, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands.
    Affiliations
    Department of Clinical Epidemiology, Leiden University Medical Center, Leiden 2333 ZA, The Netherlands
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      Highlights

      • The susceptibility to the prothrombotic effect of oral contraceptives (OC) differs.
      • The role of the first pass-metabolism of ethinylestradiol therefore was studied.
      • Genetic variation in UGT2B7 may, in part, explain thrombosis risk in OC users.

      Abstract

      Background

      Use of ethinylestradiol, one of the active ingredients in combined oral contraceptives, affects the incidence of venous thrombosis. To explain why some women develop thrombosis when using oral contraceptives and others do not, we hypothesized a role for the first-pass metabolism of ethinylestradiol in the liver. We set out to determine the association between genetic variation in the first-pass metabolism of ethinylestradiol, venous thrombosis risk and the effect on Sex-hormone-binding-globulin (SHBG) levels.

      Methods

      Premenopausal women were included from two case-control studies: LETS (103 cases; 159 controls) and MEGA (397 cases; 796 controls). Haplotype-tagging SNPs were selected in 11 candidate genes; COMT, CYP1A2, CYP2C9, CYP3A4, CYP3A5, SULT1A1, SULT1E1, UGT1A1, UGT1A3, UGT1A9, UGT2B7. Venous thrombosis risk was expressed as odds ratios (OR) with 95% confidence intervals (CI). For SHBG levels, mean differences with 95%CI were estimated in combined oral contraceptive-using control subjects from the MEGA study.

      Results

      Two copies of haplotype D in the UGT2B7 gene increased venous thrombosis risk (ORLETS: 3.78; ORMEGA: 2.61) as well as SHBG levels (mean difference 27.6 nmol/L, 95%CI: −61.7 to 116.9 compared with no copies) in oral contraceptive users and not in non-users. In oral contraceptive users, haplotype A and B in the CYP3A4 gene were associated with venous thrombosis risk, but not in non-users; however, the effect on SHBG levels was not directional with the risk. None of the other haplotypes were associated with venous thrombosis.

      Conclusion

      Genetic variation in the UGT2B7 gene may, in part, explain venous thrombosis risk in combined oral contraceptive users.

      Keywords

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