(TTTTA)n polymorphism in the promoter of the CYP11A1 gene in the pathogenesis of polycystic ovary syndrome
Authors:
Silvie Pražáková; Markéta Vaňková; Olga Bradnová; Petra Lukášová; Josef Včelák; Kateřina Dvořáková; Karel Vondra; Jana Vrbíková; Běla Bendlová
Authors‘ workplace:
Endokrinologický ústav Praha
Published in:
Čas. Lék. čes. 2010; 149: 520-525
Category:
Original Article
Overview
Background.
Polycystic ovary syndrome (PCOS) is a common endocrinopathy which is characterized by ovarian androgen excess. PCOS has a strong genetic component but the pathogenetic mechanisms responsible for hyperandrogenemia are still unknown. The CYP11A1 encodes the cholesterol side-chain cleavage enzyme that catalyzes the first and rate-limiting step of steroidogenesis. A promoter polymorphism (TTTTA)n CYP11A1 has been reported to be related to the risk of PCOS but the results were controversial.
Methods and Results.
We determined this polymorphism in a cohort of 256 PCOS and 109 healthy control women. Using two models (dominant model for allele with 4 repeats and dominant model for long alleles, i.e. 7 and more repeats) we did not find either the difference in allele and genotype distribution between PCOS and controls or the influence of polymorphism on serum testosterone and androstendione levels. However, the PCOS carriers of long alleles had lower FSH, total- and LDL-cholesterol compared to the carriers of short alleles (p = 0.007; p = 0.02; p = 0.02, ANOVA). In controls, the non-carriers of allele with 4 repeats had significantly higher DHEA-S (p = 0.02, ANOVA) levels than the carriers of allele with 4 repeats.
Conclusions.
Despite of some associations found, it seems that the promoter variability of CYP11A1 does not play a key role in the pathogenesis of PCOS.
Key words:
polycystic ovary syndrome, genetics, CYP11A1, promoter polymorphism
Sources
1. Diamanti-Kandarakis E, Kouli C R, Bergiele AT, et al. A survey of the polycystic ovary syndrome in the Greek island of Lesbos: hormonal and metabolic profile. J Clin Endocrinol Metab 1999; 84: 4006–4011.
2. Azziz R, Woods KS, Reyna R, et al. The prevalence and features of the polycystic ovary syndrome in an unselected population. J Clin Endocrinol Metab 2004; 89: 2745–2749.
3. Asuncion M, Calvo RM, San Millan JL, et al. A prospective study of the prevalence of the polycystic ovary syndrome in unselected Caucasian women from Spain. J Clin Endocrinol Metab 2000; 85: 2434–2438.
4. Azziz R, Carmina E, Dewailly D, et al. Positions statement: criteria for defining polycystic ovary syndrome as a predominantly hyperandrogenic syndrome: an Androgen Excess Society guideline. J Clin Endocrinol Metab 2006; 91: 4237–4425.
5. Ehrmann DA. Polycystic ovary syndrome. N Engl J Med 2005; 352: 1223–1236.
6. Vrbíková J, Bendlová B. Polycystic ovary syndrome in 2006. Čas Lék čes 2007; 146(3): 218–222.
7. Franks S. Polycystic ovary syndrome: a changing perspective. Clin Endocrinol (Oxf) 1989; 31: 87–120.
8. Ferriman D, Purdie AW. The inheritance of polycystic ovarian disease and a possible relationship to premature balding. Clin Endocrinol (Oxf) 1979; 11: 291–300.
9. Bendlová B, Vaňková M, Lukášová P, et al. Study of the genetic causes of polygeneticallv determined endocrinopathies-patience can bring success. Čas Lék čes 2007; 146: 198–204.
10. Jakimiuk AJ, Weitsman SR, Navab A, Magoffin DA. Luteinizing hormone receptor, steroidogenesis acute regulatory protein, and steroidogenic enzyme messenger ribonucleic acids are overexpressed in thecal and granulosa cells from polycystic ovaries. J Clin Endocrinol Metab 2001; 86: 1318–1323.
11. Moore CC, Brentano ST, Miller WL. Human P450scc gene transcription is induced by cyclic AMP and repressed by 12-O-tetradecanoylphorbol-13-acetate and A23187 through independent cis elements. Mol Cell Biol 1990; 10: 6013–6023.
12. Diamanti-Kandarakis E, Bartzis MI, Bergiele AT, et al. Microsatellite polymorphism (tttta)(n) at -528 base pairs of gene CYP11alpha influences hyperandrogenemia in patients with polycystic ovary syndrome. Fertil Steril 2000; 73: 735–741.
13. Gharani N, Waterworth DM, Batty S, et al. Association of the steroid synthesis gene CYP11a with polycystic ovary syndrome and hyperandrogenism. Hum Mol Genet 1997; 6: 397–402.
14. Gaasenbeek M, Powell BL, Sovio U, et al. Large-scale analysis of the relationship between CYP11A promoter variation, polycystic ovarian syndrome, and serum testosterone. J Clin Endocrinol Metab 2004; 89: 2408–2413.
15. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Hum Reprod 2004; 19: 41–47.
16. Bláha, P. ANTROPO – ein Programm für automatische Beartbeitung anthropologischer Daten. Wiss. Zeitschrift der Humboldt-Universität zu Berlin 1991; 5: 153-156.
17. Wang Y, Wu X, Cao Y, et al. A microsatellite polymorphism (tttta)n in the promoter of the CYP11a gene in Chinese women with polycystic ovary syndrome. Fertil Steril 2006; 86: 223–226.
18. Pusalkar M, Meherji P, Gokral J, et al. CYP11A1 and CYP17 promoter polymorphisms associate with hyperandrogenemia in polycystic ovary syndrome. Fertil Steril 2009; 92: 653-659.
19. San Millan JL, Sancho J, Calvo RM, Escobar-Morreale HF. Role of the pentanucleotide (tttta)n polymorphism in the promoter of the CYP11a gene in the pathogenesis of hirsutism. Fertil Steril 2001; 75: 797–802.
20. Daneshmand S, Weitsman SR, Navab A, et al. Overexpression of theca-cell messenger RNA in polycystic ovary syndrome does not correlate with polymorphisms in the cholesterol side-chain cleavage and 17alpha-hydroxylase/C(17-20) lyase promoters. Fertil Steril 2002; 77: 274–280.
21. Piras I, Falchi A, Moral P, et al.: Frequencies of promoter pentanucleotide (TTTTA)n of CYP11A gene in European and North African populations. Genet Test. 2008; 12(1): 93–96.
22. Hao CF, Bao HC, Zhang N, et al. Evaluation of association between the CYP11alpha promoter pentanucleotide (TTTTA)n polymorphism and polycystic ovary syndrome among Han Chinese women, Neuro Endocrinol Lett 2009; 30(1): 56–60.
23. Nelson VL, Legro RS, Strauss JF 3rd, McAllister JM. Augmented androgen production is a stable steroidogenic phenotype of propagated theca cells from polycystic ovaries. Mol Endocrinol 1999; 13: 946–957.
24. Wood JR, Nelson VL, Ho C, et al. The molecular phenotype of polycystic ovary syndrome (PCOS) theca cells and new candidate PCOS genes defined by microarray analysis. J Biol Chem 2003; 278: 26380–26390.
25. Wood JR, Ho CK, Nelson-Degrave, VL, et al. The molecular signature of polycystic ovary syndrome (PCOS) theca cells defined by gene expression profiling. J Reprod Immunol 2004; 63(1): 51–60.
26. Hum, DW, Staels B, Black SM, Miller WL. Basal transcriptional activity and cyclic adenosine 3’, 5’-monophosphate responsiveness of the human cytochrome P450scc promoter transfection into MA-10 Leydig cells. Endocrinology 1993; 132: 546–552.
27. Zheng W, Gao YT, Shu XO, et al. Population-based case-control study of CYP11A gene polymorphism and breast cancer risk. ancer Epidemiol Biomarkers Prev 2004; 13(5): 709–714.
28. Kumazawa T, Tsuchiya N, Wang L, et al. Microsatellite polymorphism of steroid hormone synthesis gene CYP11A1 is associated with advanced prostate cancer. Int J Cancer 2004; 110(1): 140–144.
29. Olson SH, Bandera EV, Orlow I. Variants in estrogen biosynthesis genes, sex steroid hormone levels, and endometrial cancer: a HuGE review. Am J Epidemiol 2007; 165: 235–245.
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