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Estrogen-metabolizing gene polymorphisms and lipid levels in women with different hormonal status

The Pharmacogenomics Journal volume 5, pages 346–351 (2005)Cite this article

Abstract

Endogenous and exogenous sex steroid hormones have multiple effects on lipid and lipoprotein metabolism. It is also known that estrogen has antiatherogenic actions, therefore we considered examining whether there was any association between polymorphisms in estrogen-metabolizing genes and lipid levels in women. We investigated the association between variants in genes related to estrogen biosynthesis (CYP19-TTTAn) and estrogen catabolism (CYP1A1*2A, CYP1A1*2C, CYP1A2-Asn516Asn, CYP3A4*1B, and COMT-Val158Met) with serum lipid levels in a cross-sectional study with 472 Brazilian women of European descent. They were divided into three subgroups according to their hormonal status: premenopausal women (n=187), postmenopausal women exposed to hormonal replacement therapy (HRT) (n=118), and postmenopausal women unexposed to HRT (n=167). The postmenopausal women receiving HRT who were carriers of the CYP3A4*1B variant showed lower low-density lipoprotein cholesterol levels than wild-type homozygotes. Premenopausal women homozygous for the CYP1A1*2C allele had higher high-density lipoprotein cholesterol levels than heterozygotes. While the CYP1A1*2C variant probably has a higher catalytic activity, the functional implications of the CYP3A4 polymorphism are still uncertain. These data are the first attempt to associate estrogen metabolism genes to lipid levels in women.

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Abbreviations

ANOVA:

one-way analysis of variance

COMT :

catechol-O-methyltransferase

CYP450:

cytochrome P450

CYP19 :

cytochrome P450, family 19

CYP1A1 :

cytochrome P450, family 1, subfamily A, polypeptide 1

CYP1A2 :

cytochrome P450, family 1, subfamily A, polypeptide 2

CYP3A4 :

cytochrome P450, family 3, subfamily A, polypeptide 4

E1:

estrone

E2:

17β-estradiol

ERT:

estrogen replacement therapy

ESR1:

estrogen receptor 1

ESR2:

estrogen receptor 2

HDL-C:

high-density lipoprotein cholesterol

HRT:

hormone replacement therapy

LDL-C:

low-density lipoprotein cholesterol

SD:

standard deviation

SNPs:

single nucleotide polymorphisms

T-chol:

total cholesterol

TG:

triglyceride

References

  1. Godsland IF . Effects of postmenopausal hormone replacement therapy on lipid, lipoprotein, and apolipoprotein (a) concentrations: analysis of studies published from 1974–2000. Fertil Steril 2001; 75: 898–915.

    Article  CAS  Google Scholar 

  2. Herrington DM, Klein KP . Invited review: pharmacogenetics of estrogen replacement therapy. J Appl Physiol 2001; 91: 2776–2784.

    Article  CAS  Google Scholar 

  3. Tempfer CB, Riener EK, Hefler LA, Huber JC, Muendlein A . DNA microarray-based analysis of single nucleotide polymorphisms may be useful for assessing the risks and benefits of hormone therapy. Fertil Steril 2004; 82: 132–137.

    Article  CAS  Google Scholar 

  4. Cavalli SA, Hirata MH, Hirata RD . Detection of MboII polymorphism at the 5′ promoter region of CYP3A4. Clin Chem 2001; 47: 348–351.

    CAS  PubMed  Google Scholar 

  5. Neven P . The origin of postmenopausal oestrogens. Eur J Cancer 2002; 38: S29–S30.

    Article  Google Scholar 

  6. Kurosaki K, Saitoh H, Oota H, Watanabe Y, Kiuchi M, Ueda S . Combined polymorphism associated with a 3-bp deletion in the 5′-flanking region of a tetrameric short tandem repeat at the CYP19 locus. Nippon Hoigaku Zasshi 1997; 51: 191–195.

    CAS  PubMed  Google Scholar 

  7. Polymeropoulos MH, Xiao H, Rath DS, Merril CR . Tetranucleotide repeat polymorphism at the human prostatic acid phosphatase (ACPP) gene. Nucleic Acids Res 1991; 19: 4792.

    PubMed  PubMed Central  Google Scholar 

  8. Tworoger SS, Chubak J, Aiello EJ, Ulrich CM, Atkinson C, Potter JD et al. Association of CYP17, CYP19, CYPB1, and COMT polymorphisms with serum and urinary sex hormone concentrations in postmenopausal women. Cancer Epidemiol Biomarkers Prevent 2004; 13: 94–101.

    Article  CAS  Google Scholar 

  9. Badawi AF, Cavalieri EL, Rogan EG . Role of human cytochrome P450 1A1, 1A2, 1B1, and 3A4 in the 2-, 4-, and 16alpha-hydroxylation of 17beta-estradiol. Metabolism 2001; 50: 1001–1003.

    Article  CAS  Google Scholar 

  10. Lee AJ, Cai MX, Thomas PE, Conney AH, Zhu BT . Characterization of the oxidative metabolites of 17beta-estradiol and estrone formed by 15 selectively expressed human cytochrome p450 isoforms. Endocrinology 2003; 144: 3382–3398.

    Article  CAS  Google Scholar 

  11. Matsui A, Ikeda T, Enomoto K, Nakashima H, Omae K, Watanabe M et al. Progression of human breast cancers to the metastatic state is linked to genotypes of catechol-O-methyltransferase. Cancer Lett 2000; 150: 23–31.

    Article  CAS  Google Scholar 

  12. Quinones L, Lucas D, Godoy J, Caceres D, Berthou F, Varela N et al. CYP1A1, CYP2E1 and GSTM1 genetic polymorphisms. The effect of single and combined genotypes on lung cancer susceptibility in Chilean people. Cancer Lett 2001; 174: 35–44.

    Article  CAS  Google Scholar 

  13. Spurr NK, Gough AC, Stevenson K, Wolf CR . Msp-1 polymorphism detected with a cDNA probe for the P-450 I family on chromosome 15. Nucleic Acids Res 1987; 15: 5901.

    Article  CAS  Google Scholar 

  14. http://www.imm.ki.se/CyPalleles.

  15. Hayashi S, Watanabe J, Nakachi K, Kawajiri K . PCR detection, of an A/G polymorphism within exon 7 of the CYP1A1 gene. Nucleic Acids Res 1991; 19: 4797.

    Article  CAS  Google Scholar 

  16. Garte S . The role of ethnicity in cancer susceptibility gene polymorphisms: the example of CYP1A1. Carcinogenesis 1998; 19: 1329–1332.

    Article  CAS  Google Scholar 

  17. Shimada T, Yamazaki H, Mimura M, Inui Y, Guengerich FP . Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians. J Pharmacol Exp Ther 1994; 270: 414–423.

    CAS  Google Scholar 

  18. Rebbeck TR, Jaffe JM, Walker AH, Wein AJ, Malkowicz SB . Modification of clinical presentation of prostate tumors by a novel genetic variant in CYP3A4. J Natl Cancer Inst 1998; 90: 1225–1229.

    Article  CAS  Google Scholar 

  19. Hesselink DA, van Schaik RH, van der Heiden IP, van der Werf M, Gregoor PJ, Lindemans J et al. Genetic polymorphisms of the CYP3A4, CYP3A5, and MDR-1 genes and pharmacokinetics of the calcineurin inhibitors cyclosporine and tacrolimus. Clin Pharmacol Ther 2003; 74: 245–254.

    Article  CAS  Google Scholar 

  20. Saito S, Iida A, Sekine A, Ogawa C, Kawauchi S, Higuchi S et al. 906 variations among 27 genes encoding cytochrome P450 (CYP) enzymes and aldehyde dehydrogenases (ALDHs) in the Japanese population. J Hum Genet 2002; 47: 419–444.

    Article  CAS  Google Scholar 

  21. Tenhunen J, Salminen M, Lundstrom K, Kiviluoto T, Savolainen R, Ulmanen I . Genomic organization of the human catechol O-methyltransferase gene and its expression from two distinct promoters. Eur J Biochem 1994; 223: 1049–1059.

    Article  CAS  Google Scholar 

  22. Grossman MH, Emanuel BS, Budarf ML . Chromosomal mapping of the human catechol-O-methyltransferase gene to 22q11.1–q11.2. Genomics 1992; 12: 822–825.

    Article  CAS  Google Scholar 

  23. Lotta T, Vidgren J, Tilgmann C, Ulmanen I, Melen K, Julkunen I et al. Kinetics of human soluble and membrane-bound catechol O-methyltransferase: a revised mechanism and description of the thermolabile variant of the enzyme. Biochemistry 1995; 34: 4202–4210.

    Article  CAS  Google Scholar 

  24. Berstein LM, Imyanitov EN, Kovalevskij AJ, Maximov SJ, Vasilyev DA, Buslov KG et al. CYP17 and CYP19 genetic polymorphisms in endometrial cancer: association with intratumoral aromatase activity. Cancer Lett 2004; 207: 191–196.

    Article  CAS  Google Scholar 

  25. http://snp500cancer.nci.nih.gov/snp.cfm?both_snp_id=CYP1A2-11.

  26. Palmatier MA, Kang AM, Kidd KK . Global variation in the frequencies of functionally different catechol-O-methyltransferase alleles. Biol Psychiatry 1999; 46: 557–567.

    Article  CAS  Google Scholar 

  27. Burim RV, Canalle R, Martinelli AL, Takahashi CS . Polymorphisms in glutathione S-transferases GSTM1, GSTT1 and GSTP1 and cytochromes P450 CYP2E1 and CYP1A1 and susceptibility to cirrhosis or pancreatitis in alcoholics. Mutagenesis 2004; 19: 291–298.

    Article  CAS  Google Scholar 

  28. Gaspar PA, Kvitko K, Papadopolis LG, Hutz MH, Weimer TA . High frequency of CYP1A1*2C allele in Brazilian populations. Hum Biol 2002; 74: 235–242.

    Article  Google Scholar 

  29. Esteller M, Garcia A, Martinez-Palones JM, Xercavins J, Reventos J . Susceptibility to endometrial cancer: influence of allelism at p53, glutathione S-transferase (GSTM1 and GSTT1) and cytochrome P-450 (CYP1A1) loci. Br J Cancer 1997; 75: 1385–1388.

    Article  CAS  Google Scholar 

  30. Wang XL, Greco M, Sim AS, Duarte N, Wang J, Wilcken DE . Effect of CYP1A1 MspI polymorphism on cigarette smoking related coronary artery disease and diabetes. Atherosclerosis 2002; 162: 391–397.

    Article  CAS  Google Scholar 

  31. Kvitko K, Nunes JCB, Hutz MH . (TTTA)n polymorphism of CYP19 (aromatase gene) in Euro- and Afro-Brazilians. Genet Mol Biol 2004; 27: 335–336.

    Article  CAS  Google Scholar 

  32. Almeida S, Franken N, Zandoná MR, Osório-Wender MC, Hutz MH . Estrogen receptor 2 and progesterone receptor gene polymorphisms and lipid levels in women with different hormonal status. Pharmacogenomics J 2005; 5: 30–34.

    Article  CAS  Google Scholar 

  33. Herrington DM, Howard TD, Hawkins GA, Reboussin DM, Xu J, Zheng SL et al. Estrogen-receptor polymorphisms and effects of estrogen replacement on high-density lipoprotein cholesterol in women with coronary disease. N Engl J Med 2002; 346: 967–974.

    Article  CAS  Google Scholar 

  34. Koivu TA, Fan YM, Mattila KM, Dastidar P, Jokela H, Nikkari ST et al. The effect of hormone replacement therapy on atherosclerotic severity in relation to ESR1 genotype in postmenopausal women. Maturitas 2003; 44: 29–38.

    Article  CAS  Google Scholar 

  35. Zhu BT, Conney AH . Functional role of estrogen metabolism in target cells: review and perspectives. Carcinogenesis 1998; 19: 1–27.

    Article  Google Scholar 

  36. Bennink HJTC . Are all estrogen the same? Maturitas 2004; 47: 269–275.

    Article  Google Scholar 

  37. Hong CC, Tang BK, Hammond GL, Tritchler D, Yaffe M, Boyd NF . Cytochrome P450 1A2 (CYP1A2) activity and risk factors for breast cancer: a cross-sectional study. Breast Cancer Res 2004; 6: R352–R365.

    Article  Google Scholar 

  38. Pernerger TV . What's wrong with Bonferroni adjustments. BMJ 1998; 316: 1236–1238.

    Article  Google Scholar 

  39. American Diabetes Association. Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care 1997; 17: 1183–1201.

  40. Friedwald WT, Levy RI, Fredrickson DS . Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 1972; 18: 499–502.

    Google Scholar 

  41. Lahiri DK, Nurnberger Jr JI . A rapid non-enzymatic method for the preparation of HMW DNA from blood for RFLP studies. Nucleic Acids Res 1991; 19: 5444.

    Article  CAS  Google Scholar 

  42. Kunugi H, Nanko S, Ueki A, Otsuka E, Hattori M, Hoda F et al. High and low activity alleles of catechol-O-methyltransferase gene: ethnic difference and possible association with Parkinson's disease. Neurosci Lett 1997; 221: 202–204.

    Article  CAS  Google Scholar 

  43. Tsuchiya Y, Sato T, Kiyohara C, Yoshida K, Ogoshi K, Nakamura K et al. Genetic polymorphisms of cytochrome P450 1A1 and risk of gallbladder cancer. J Exp Clin Cancer Res 2002; 21: 119–124.

    CAS  PubMed  Google Scholar 

  44. van Schaik RH, de Wildt SN, van Iperen NM, Uitterlinden AG, van den Anker JN, Lindemans J . CYP3A4-V polymorphism detection by PCR-restriction fragment length polymorphism analysis and its allelic frequency among 199 Dutch Caucasians. Clin Chem 2000; 46: 1834–1836.

    CAS  PubMed  Google Scholar 

  45. Arvanitis DA, Koumantakis GE, Goumenou AG, Matalliotakis IM, Koumantakis EE, Spandidos DA . CYP1A1, CYP19, and GSTM1 polymorphisms increase the risk of endometriosis. Fertil Steril 2003; 79: 702–709.

    Article  Google Scholar 

  46. Benjamini Y, Hochberg Y . Controlling the false discovery rate: a practical and powerful approach to multiple testing. JR Stat Soc 1995; 57: 289–300.

    Google Scholar 

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Acknowledgements

The financial support was provided by Programa de Apoio a Núcleos de Excelência (PRONEX, Brazil) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, Brazil).

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Authors and Affiliations

  1. Departamento de Genética, Instituto de Biociências, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil

    S Almeida, M R Zandoná, N Franken & M H Hutz

  2. Departamento de Estatística, Instituto de Matemática, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil

    S M Callegari-Jacques

  3. Departamento de Ginecologia e Obstetrícia, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil

    M C Osório-Wender

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  1. S Almeida
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Correspondence to M H Hutz.

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DUALITY OF INTEREST: None declared.

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Almeida, S., Zandoná, M., Franken, N. et al. Estrogen-metabolizing gene polymorphisms and lipid levels in women with different hormonal status. Pharmacogenomics J 5, 346–351 (2005). https://doi.org/10.1038/sj.tpj.6500329

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