Editorial

10.1586/17446651.1.2.151 © 2006 Future Drugs Ltd ISSN 1744-6651 151

Single nucleotide polymorphisms in gynecological endocrinology‘Single nucleotide polymorphism analysis is useful for determining the susceptibility to gynecological disorders such as breast cancer, thrombosis, recurrent miscarriage and endometriosis.’

Johannes C Huber and Clemens B Tempfer†

†Author for correspondenceDepartment of Obstetrics and Gynecology, University of Vienna Medical School, Waehringer Guertel 18-20, A-1090 Vienna, AustriaTel.: +43 140 400 2813Fax: +43 140 400 2911clemens.tempfer@meduniwien.ac.at

Expert Rev. Endocrinol. Metab. 1(2), 151–152 (2006)

Polymorphisms are defined as mutations withan allele frequency of at least 1% in a givenpopulation. Humans are believed to carry over1 million of these polymorphisms with around30,000 of them exerting clinically visiblephenotypic effects [1]. The determination ofgenetic polymorphisms is a new means to studythe etiology of polygenetic disorders with com-plex inheritance patterns such as cancer, diabe-tes and hypertension. The last 10 years haveseen a dramatic increase in reports investigatingdisease susceptibility based on the carriage oflow-penetrance, high-frequency single nucle-otide polymorphisms (SNPs). Evidence is accu-mulating defining specific individual varia-tions in susceptibility for gynecologicaldisorders such as breast cancer, thrombosis,recurrent miscarriage and endometriosis. Also,risks and benefits of postmenopausal hormonereplacement therapy vary significantly accord-ing to the carriage of SNPs. Lastly, a series ofreports assessed the contribution of SNPs tophysiological phenomena, such as the timing ofnatural menopause and obesity.

Genetic variations of the estradiol and xenobi-otic metabolisms, as well as genes involved incell cycle control, have been described as signifi-cant contributors to breast cancer susceptibilitywith variations depending on ethnic back-ground and cofactors such as smoking andfamily history of breast cancer. In summary, thehighest level of evidence to date linking SNPsand breast cancer comes from nested case-control studies within the prospective Nurses’Health Study. These data establish seven SNPs(human progesterone receptor (hPR)B +331G/A, AR CAG repeat, cytochrome (CYP)19TTA [10], CYP1A1 Msp I, vitamin D receptor

(VDR)FOK1, x-ray repair cross-complementing(XRCC1) Arg194Trp and XRCC2 Arg188His)as small, but significant risk factors for spontane-ous, nonhereditary breast cancer. In addition,meta-analyses of association studies establishedthe transforming growth factor-β receptorTGFBR1*6A, the HRAS1, glutathione S-trans-ferase (GST)P Ile105Val and the GSTM1 SNPsas low-penetrance genetic risk factors of sporadicbreast cancer.

The clinical consequences of such a risk eleva-tion may be a detailed instruction of the patientas to general measurements of breast cancer pre-vention such as a low-fat diet, optimization of thebody mass index (BMI), physical exercise, avoid-ance of alcohol, long-term estrogen replacementtherapy (ERT) and hormone replacement ther-apy (HRT), and participation in a breast cancerscreening program between the ages of 50 and70 years. Specific surgical or drug interventions,such as prophylactic mastectomy and oophorec-tomy or prophylactic intake of tamoxifen, are notindicated based on SNP analysis at this time.

SNPs hold promise for the individualizationof ERT/HRT. For example, in a series of 2507consecutive peri- and postmenopausal women,66% had at least two homozygous mutantSNPs of interest [2]. Of those women seekingcounseling on risks and benefits of ERT/HRT,2.7% carried the F2 G20210A SNP, puttingthem at a substantially elevated risk for myo-cardial infarction during the first year ofERT/HRT. Another 6.8% of women had asubstantially increased risk of ERT/HRT-asso-ciated thrombosis due to the thrombophilic F5Leiden SNP. These women may be counselednot to use estrogen-containing regimens andto opt instead for progestogen/progesterone

For reprint orders, please contact reprints@future-drugs.com

Huber & Tempfer

152 Expert Rev. Endocrinol. Metab. 1(2), (2006)

therapy or alternative regimens such as tibolone, phytoestro-gens or black cohosh. Two or more homozygous alleles associ-ated with an increased risk of breast cancer were observed in23% of women. These women may be counseled to abstainfrom nontherapeutic, primary or secondary preventive use ofERT/HRT, as well as from use of ERT/HRT for more than5 years. SNP analysis also identified women who may over-proportionally derive benefit from ERT/HRT. For example,18.4% of women were homo-zygous for estrogen receptor(ER)α IVS-401T>C, associatedwith early postmenopausal boneloss. In addition, women carryingthe polymorphic ER-α allele havea 100% increase in ERT/HRT-induced high-density lipopro-tein (HDL) elevation compared with women with the wild-type allele [3]. In summary, microarray-based analysis of 20selected SNPs found 66% of the investigated women to carry atleast two homozygous mutant alleles associated with risks andbenefits of ERT/HRT. The quality of physicians’ counselingand of patients’ informed decisions on ERT/HRT could beimproved in a large proportion of women.

A number of SNPs have been found to be associated with theclinical course of, and the susceptibility to, endometriosis. Forexample, our group found a 306-base pair insertion polymor-phism in intron G of the progesterone receptor (PROGINS) tobe associated with endometriosis, and the interleukin (IL)-6promoter polymorphism -174 G/C to be associated with ovar-ian endometriosis cysts. Also, we demonstrated that theHSD17 vlV A→C SNP was associated with a significantlyincreased risk of endometriosis. Other groups described thevascular endothelial growth factor (VEGF) +405 C/G poly-morphism, the IL-2 receptor (IL-2Rb)β-627*C polymorphism

and the aryl hydrocarbon receptor (AhRR) codon 185 poly-morphism to be associated with susceptibility to, and severityof, endometriosis. These data are of scientific interest in theunderstanding of endometriosis etiology, but have no clinicalimplications at this time.

Genotyping for the F5 Leiden G1691A and the F2 G20210Apolymorphisms is clinically useful for individual risk assessmentregarding pregnancy-associated thrombosis. Heterozygous and

homozygous carriers of the F5 Lei-den G1691A polymorphism willdevelop this condition in 6.4 and8.9–16.7%, respectively. A total of6.2% of women with the F2G20210A polymorphism and

17.8% of women with simultaneous carriage of the F5 LeidenG1691A and F2 G20210A polymorphisms will develop preg-nancy-associated thrombosis. The thrombophilic polymor-phisms F5 Leiden G1691A and F2 G20210A are also risk fac-tors of early recurrent, late recurrent and late spontaneousmiscarriage based on a published meta-analysis of 31 studies [4].Six case-control and cohort studies of 687 women with throm-bophilic polymorphisms demonstrate live birth rates of 82%(181/221) using low-molecular-weight heparin or fractionatedheparin compared with 20% (95/466) without therapy(p <0.001, odds ratio: 17.7; 95% CI: 12.2–25.5).

Based on these data, it can be stated that SNP analysis is use-ful for determining the susceptibility to gynecological disorderssuch as breast cancer, thrombosis, recurrent miscarriage andendometriosis. Also, individual risks and benefits of post-menopausal ERT/HRT can be defined according to the car-riage of SNPs. Thus, SNP analysis holds promise for individu-alized risk assessment, preventive medicine and counseling onrisks and benefits of selected treatments.

References

1 Shastry BS. SNP alleles in human disease and evolution. J. Hum. Genet. 47, 561–566 (2002).

2 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. 82(1), 132–137 (2004).

3 Herrington DM. Role of estrogen receptor-α in pharmacogenetics of estrogen action. Curr. Opin. Lipiodol. 14(2), 145–150 (2003).

4 Rey E, Kahn S, David M, Shrier I. Thrombophilic disorders and fetal loss: a meta-analysis. Lancet 361, 901–908 (2003).

Affiliations

• Johannes C Huber, MD, PhD

Department of Obstetrics and Gynecology,

Division of Gynecologic Endocrinology and Reproductive Medicine, Medical University of Vienna, Austria

• Clemens B Tempfer, MD

Department of Obstetrics and Gynecology, University of Vienna Medical School, Waehringer Guertel 18-20, A-1090, Vienna, AustriaTel.: +43 140 400 2813Fax: +43 140 400 2911clemens.tempfer@meduniwien.ac.at

‘Single nucleotide polymorphism analysis holds promise to individualize risk assessment, preventative medicine and counseling on risks and benefits of

selected treatments.’