Genetic variation in the first-pass metabolism of ethinylestradiol, sex hormone binding globulin levels and venous thrombosis risk.
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Stegeman BH, Vos HL, Helmerhorst FM, Rosendaal FR, Reitsma PH, van Hylckama Vlieg A
Genetic variation in the first-pass metabolism of ethinylestradiol, sex hormone binding globulin levels and venous thrombosis risk.
Eur J Intern Med. 2017 Jul;42:54-60. doi: 10.1016/j.ejim.2017.05.019. Epub 2017 Jun 1.
- PubMed ID
- 28579309 [ View in PubMed]
- 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 27.6nmol/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.
DrugBank Data that Cites this Article
- Drugs
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Ethinylestradiol Catechol O-methyltransferase Protein Humans UnknownSubstrateDetails Ethinylestradiol Cytochrome P450 3A5 Protein Humans UnknownSubstrateDetails Ethinylestradiol UDP-glucuronosyltransferase 1-3 Protein Humans UnknownNot Available Details Ethinylestradiol UDP-glucuronosyltransferase 2B7 Protein Humans UnknownSubstrateDetails - Drug Reactions
Reaction Details Details Details Details Details Details
