Single nucleotide polymorphisms in gynecological endocrinology

Polymorphisms are defined as mutations with an allele frequency of at least 1% in a given population. Humans are believed to carry over 1 million of these polymorphisms with around 30,000 of them exerting clinically visible phenotypic effects [1]. The determination of genetic polymorphisms is a new means to study the etiology of polygenetic disorders with complex inheritance patterns such as cancer, diabetes and hypertension. The last 10 years have seen a dramatic increase in reports investigating disease susceptibility based on the carriage of low-penetrance, high-frequency single nucleotide polymorphisms (SNPs). Evidence is accumulating defining specific individual variations in susceptibility for gynecological disorders such as breast cancer, thrombosis, recurrent miscarriage and endometriosis. Also, risks and benefits of postmenopausal hormone replacement therapy vary significantly according to the carriage of SNPs. Lastly, a series of reports assessed the contribution of SNPs to physiological phenomena, such as the timing of natural menopause and obesity.

Genetic variations of the estradiol and xenobiotic metabolisms, as well as genes involved in cell cycle control, have been described as significant contributors to breast cancer susceptibility with variations depending on ethnic background and cofactors such as smoking and family history of breast cancer. In summary, the highest level of evidence to date linking SNPs and breast cancer comes from nested case-control studies within the prospective Nurses’ Health Study. These data establish seven SNPs (human progesterone receptor (hPR)B +331 G/A, AR CAG repeat, cytochrome (CYP)19 TTA [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 spontaneous, nonhereditary breast cancer. In addition, meta-analyses of association studies established the transforming growth factor-β receptor TGFBR1*6A, the HRAS1, glutathione S-transferase (GST)P Ile105Val and the GSTM1 SNPs as low-penetrance genetic risk factors of sporadic breast cancer.

The clinical consequences of such a risk elevation may be a detailed instruction of the patient as to general measurements of breast cancer prevention such as a low-fat diet, optimization of the body mass index (BMI), physical exercise, avoidance of alcohol, long-term estrogen replacement therapy (ERT) and hormone replacement therapy (HRT), and participation in a breast cancer screening program between the ages of 50 and 70 years. Specific surgical or drug interventions, such as prophylactic mastectomy and oophorectomy or prophylactic intake of tamoxifen, are not indicated based on SNP analysis at this time.

SNPs hold promise for the individualization of ERT/HRT. For example, in a series of 2507 consecutive peri- and postmenopausal women, 66% had at least two homozygous mutant SNPs of interest [2]. Of those women seeking counseling on risks and benefits of ERT/HRT, 2.7% carried the F2 G20210A SNP, putting them at a substantially elevated risk for myocardial infarction during the first year of ERT/HRT. Another 6.8% of women had a substantially increased risk of ERT/HRT-associated thrombosis due to the thrombophilic F5 Leiden SNP. These women may be counseled not to use estrogen-containing regimens and to opt instead for progestogen/progesterone therapy or alternative regimens such as tibolone, phytoestrogens or black cohosh. Two or more homozygous alleles associated with an increased risk of breast cancer were observed in 23% of women. These women may be counseled to abstain from nontherapeutic, primary or secondary preventive use of ERT/HRT, as well as from use of ERT/HRT for more than 5 years. SNP analysis also identified women who may overproportionally derive benefit from ERT/HRT. For example, 18.4% of women were homozygous for estrogen receptor (ER)α IVS-401T>C, associated with early postmenopausal bone loss. In addition, women carrying the polymorphic ER-α allele have a 100% increase in ERT/HRT-induced high-density lipoprotein (HDL) elevation compared with women with the wild-type allele [3]. In summary, microarray-based analysis of 20 selected SNPs found 66% of the investigated women to carry at least two homozygous mutant alleles associated with risks and benefits of ERT/HRT. The quality of physicians’ counseling and of patients’ informed decisions on ERT/HRT could be improved in a large proportion of women.

A number of SNPs have been found to be associated with the clinical course of, and the susceptibility to, endometriosis. For example, our group found a 306-base pair insertion polymorphism in intron G of the progesterone receptor (PROGINS) to be associated with endometriosis, and the interleukin (IL)-6 promoter polymorphism -174 G/C to be associated with ovarian endometriosis cysts. Also, we demonstrated that the HSD17 vlV A→C SNP was associated with a significantly increased risk of endometriosis. Other groups described the vascular endothelial growth factor (VEGF) +405 C/G polymorphism, the IL-2 receptor (IL-2Rb)β-627*C polymorphism and the aryl hydrocarbon receptor (AhRR) codon 185 polymorphism to be associated with susceptibility to, and severity of, endometriosis. These data are of scientific interest in the understanding of endometriosis etiology, but have no clinical implications at this time.

Genotyping for the F5 Leiden G1691A and the F2 G20210A polymorphisms is clinically useful for individual risk assessment regarding pregnancy-associated thrombosis. Heterozygous and homozygous carriers of the F5 Leiden G1691A polymorphism will develop this condition in 6.4 and 8.9–16.7%, respectively. A total of 6.2% of women with the F2 G20210A polymorphism and 17.8% of women with simultaneous carriage of the F5 Leiden G1691A and F2 G20210A polymorphisms will develop pregnancy-associated thrombosis. The thrombophilic polymorphisms F5 Leiden G1691A and F2 G20210A are also risk factors of early recurrent, late recurrent and late spontaneous miscarriage based on a published meta-analysis of 31 studies [4]. Six case-control and cohort studies of 687 women with thrombophilic polymorphisms demonstrate live birth rates of 82% (181/221) using low-molecular-weight heparin or fractionated heparin 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 useful for determining the susceptibility to gynecological disorders such as breast cancer, thrombosis, recurrent miscarriage and endometriosis. Also, individual risks and benefits of postmenopausal ERT/HRT can be defined according to the carriage of SNPs. Thus, SNP analysis holds promise for individualized risk assessment, preventive medicine and counseling on risks and benefits of selected treatments.