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Background Ovarian hyperstimulation syndrome (OHSS) is the most serious complication of IVF/ICSI therapy. The pathophysiology and etiology of the disease is still not fully clarified. Methods To assess whether polymorphisms of the VEGF/VEGF-receptor system contribute to the occurrence of ovarian hyperstimulation syndrome (OHSS), we performed a retrospective analysis of 116 OHSS patients, and 124 female controls. The following SNPs were genotyped: Rs2071559 (VEGFR2-604); rs2305948 (VEGFR2-1192); rs1870377 (VEGFR2- 1719); rs2010963 (VEGF-405); and rs111458691 (VEGFR1-519). Odds ratios (ORs) were estimated with a 95% confidence interval (CI). Linkage disequilibrium (LD) analysis was performed in the three loci of the VEGFR2 gene. Result We found an overrepresentation of the T allele of the VEGFR1-519 polymorphism in OHSS patients (P = 0.02, OR: 3.62, CI: 1.16 – 11.27). By genotype modeling, we found that polymorphism of VEGFR1-519 and VEGF-405 showed significant differences in patients and controls (p = 0.02, OR: 3.79 CI: 1.98 – 11.97 and p = 0.000005, OR: 0.29, CI: 0.17 – 0.50). LD analysis revealed significant linkage disequilibrium in VEGFR2. Conclusion Polymorphisms in the VEGFR2 gene and in the VEGF gene are associated with the occurrence of OHSS. This strengthens the evidence for an important role of the VEGF/VEGF- receptor system in the occurrence of OHSS. [ABSTRACT FROM AUTHOR]

The CYP19 gene encodes aromatase, an enzyme catalyzing the conversion of androgens to estrogens. Studies analyzing associations between single nucleotide polymorphisms in CYP19 and breast cancer risk have shown inconsistent results. The rs10046 polymorphism is located in the 3' untranslated region of the CYP19 gene, but the influence of this polymorphism on breast cancer risk is unclear. In this study, we investigated the impact of rs10046 SNP on breast cancer risk, age at onset and association with clinical characteristics in an Austrian population of 274 breast cancer patients and 253 controls. The results show that a significantly increased fraction of patients with the TT genotype of rs10046 develop breast cancer under the age of 50 (41.8% of TT patients, compared to 26.6% of C carriers; p = 0.018, Chi-square test). No rs10046 genotypes were significantly associated with increased breast cancer risk or patient characteristics other than age at onset. These results suggest that the rs10046 polymorphism in the CYP19 gene may have an effect on breast cancer susceptibility at an age under 50 in the investigated population. [ABSTRACT FROM AUTHOR]

The relation between genetic variation of the androgen metabolism and transsexualism is unknown. In a case-control study of 100 male-to-female (MtF) transsexuals, 47 female-to-male (FtM) transsexuals, and 1670 controls, the authors assess allele and genotype frequencies of the steroid 5-α reductase (SRD5A2) Val89Leu polymorphism using polymerase chain reaction. Allele and genotype frequencies are not significantly different between MtF transsexuals and male controls (SRD5A2 V: 137/200 [69%] and SRD5A2 L: 63/200 [31%] vs 1065/1510 [71%] and 445/1510 [29%], respectively; P = .6; odds ration [OR], 1.10; 95% confidence interval [CI], 0.76-1.58; SRD5A2 V/V+V/L: 92/100 [92%] and L/L 8/100 [8%] vs SRD5A2 683/755 [91%] and 72/755 [9%]respectively, P = .7; OR, 0.82; 95% CI, 0.24-2.84). Allele and genotype frequencies are also not significantly different between FtM transsexuals and female controls (SRD5A2 V: 70/94 [74%] and SRD5A2 L: 24/94 [26%] vs 1253/1830 [69%] and 573/1830 [31%], respectively; P = .3; OR, 0.75; 95% CI, 0.45-1.26; SRD5A2 V/V+V/L: 44/47 [93%] and L/L 3/47 [7%] vs 823/915 [90%] and 92/915 [10%], respectively, P = .6; OR, 0.61; 95% CI, 0.11-3.323 Of note, there is no gender-specific genotype distribution among controls. The SRD5A2 Val89Leu SNP is not associated with transsexualism, refuting SRD5A2 as a candidate gene of transsexualism. [ABSTRACT FROM AUTHOR]

The number of reports investigating disease susceptibility based on the carriage of low-penetrance, high-frequency single nucleotide polymorphisms (SNPs) has increased in recent years. Evidence is accumulating defining specific individual variations in breast cancer susceptibility. Genetic variations of estradiol and xenobiotics 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 co-factors such as smoking and family history of breast cancer. In sum, 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 – hPRB +331G/A, AR CAG repeat, CYP19 (TTTA) 10 , CYP1A1 Msp I, VDR FOK1, XRCC1 Arg194Trp and XRCC2 Arg188His – as small but significant risk factors for spontaneous, non-hereditary breast cancer. In addition, meta-analysis of data in the literature establishes the TGFBR1*6A , HRAS1 , GSTP Ile105Val and GSTM1 SNPs as low-penetrance genetic risk factors of sporadic breast cancer. The clinical consequences of such a risk elevation may be detailed instruction of the patient as to general measures of breast cancer prevention such as a low-fat diet, optimization of body mass index, physical exercise, avoidance of alcohol and long-term hormone replacement therapy, 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. [ABSTRACT FROM AUTHOR]

Objective: To investigate the association between the 306-base pair insertion polymorphism in intron G of the progesterone receptor (PROGINS) and endometriosis.Design: Case-control study.Setting: Tertiary care center.Patient(s): Ninety-five white women with surgically diagnosed and histologically confirmed endometriosis and 107 white women without endometriosis (controls).Intervention(s): Determination of PROGINS was performed by polymerase chain reaction and gel electrophoresis. MAIN OUTCOIME MEASURE(S): Frequency and distribution of the PROGINS allele.Result(s): Frequencies of the mutant allele T2 was 0.17 among women with endometriosis and 0.08 among controls (odds ratio, 2.41 [CI, 1.31-4.53]). Homozygosity for allele T2 was present in 3.2% of women with endometriosis and 0.9% of controls.Conclusion(s): PROGINS appears to be associated with endometriosis in white persons. [ABSTRACT FROM AUTHOR]

Interleukin (IL)-1 has been shown to induce peritoneal adhesions. We determined the IL-1 receptor antagonist (IL-1RN) genotype with respect to the two most common variant alleles IL-1RN*2 and IL-1RN*3 in Caucasian women with peritoneal adhesions. One hundred seven women with surgically verified peritoneal adhesions and 79 controls without peritoneal adhesions served as controls. Univariate analysis showed an increased risk for peritoneal adhesions for Caucasian women carrying the mutant IL-1RN*2 allele (OR: 2.1; 95% CI: 1.3–3.4; P = 0.004). Multiple logistic regression analysis demonstrated an increased risk for peritoneal adhesions, which is independent of previous abdominal surgery and endometriosis. Our data suggest that IL-1RN*2 allele carriers have an increased risk for adhesion formation. [ABSTRACT FROM AUTHOR]

Estrogen replacement therapy is associated with a reduced risk of colon cancer. Therefore, we evaluated the following ten estrogen metabolism-associated single-nucleotide polymorphisms (SNPs) by sequencing-on-chip technology using solid-phase polymerase chain reaction (PCR) on oligonucleotide microarrays: catechol-O-methyltransferase (COMT) Val158Met G→A, 17-beta-hydroxysteroid dehydrogenase type 1 (HSD17) vlV A→C, cytochrome P-450 (CYP) 17 A2 allele T→C, CYP1A1 MspI RFLP T→C, CYP1A1 Ile462Val A→G, CYP19 Arg264Cys C→T, CYP19 C1558T C→T, CYP 1B1 Leu432Val, CYP1B1 Asn453Ser, and estrogen receptor (ER) alpha IVS1 −401→C in 76 patients with a family history of colon cancer and 722 healthy controls. Using stepwise logistic regression models, we found that none of the investigated SNPs is associated with a family history of colon cancer in a univariate and multivariate logistic regression model. In addition, when all two-way interactions of the investigated SNPs were ascertained, no significant interactions between SNPs were observed. In conclusion, we found no association between the carriage of one or multiple SNPs of the estrogen metabolism and a family history of colon cancer. [Copyright &y& Elsevier]

Abstract: Objective: TNF-alpha G308A, IL-6 G174C and IL-10 G1082A polymorphisms have recently been associated with preeclampsia (PE). The aim of this study was to clarify whether the occurrence of TNF-alpha, IL-6 and IL-10 polymorphisms is increased in women of our population with PE in a previous pregnancy. Methods: A retrospective, controlled, open, multicenter study was carried out in 107 women with a history of PE and 107 women with uncomplicated pregnancies. Smears from buccal gingival cells were analyzed for the polymorphisms of TNF-alpha, IL-6 and IL-10 by hybridization on microarrays. Statistical significance was calculated by the chi-quadrant test. Results: Heterozygocity for the gene polymorphisms did not occur more often in preeclamptic women compared with controls (TNF-alpha: 29.0% versus 24.3%, p >0.05; IL-6: 46.7% versus 51.4%, p >0.05; or IL-10: 49.5% in each). Moreover, there was no significant difference between preeclamptics and controls with regard to homozygocity for TNF alpha (1.9% versus 3.7%, p >0.05); IL-6 (17.8% versus 13.1%, p >0.05); and IL-10 (30.8% versus 32.7%, p >0.05). Conclusion: In contrast to the findings of some other investigators, gene polymorphisms do not seem to be important in our population for development of PE. [Copyright &y& Elsevier]

Abstract: Objective: Androgens are thought to play an important role in various reproductive functions. We evaluated the association between a common polymorphism of the steroid 5-alpha-reductase type 2 gene (SRD5A2) involved in androgen metabolism and the timing of menopause. Study design: Three hundred and twenty-three consecutive women were included in this cross-sectional study. The common exon 1 Valine/Leucin polymorphism of the SRD5A2 gene was analyzed using a microarray-based system. Results: No significant association between the SRD5A2 polymorphism and age (years) at natural menopause was ascertained. There were no significant differences in the background characteristics of the subjects among SDR5A2 genotypes including the number of full term pregnancies, age at first delivery, BMI, personal or family history of breast cancer, smoking status and personal history of recurrent abortion. A multivariate regression analysis showed that the number of full term pregnancies, but not smoking, an increased body mass index, or a history of breast cancer significantly influenced timing of natural menopause. Conclusion: In the present study the number of full term pregnancies, but not the common V89L SRD5A2 polymorphism, is the only significant predictor for the timing of natural menopause in Caucasian women. [Copyright &y& Elsevier]

OBJECTIVE: Genetic as well as hormonal factors are known to influence the development and clinical course of endometriosis. We aimed to investigate the association among 10 single nucleotide polymorphisms (SNPs) involved in the estrogen metabolism and endometriosis and to develop a multiple genetic model. METHODS: In a case-control study, we investigated the genotype frequencies of 10 estrogen metabolizing SNPs in 32 patients with endometriosis and 790 healthy controls using sequencing-on-chip-technology with solid-phase polymerase chain reaction on oligonucleotide microarrays: catechol-O-methyltransferase, Val158Met G-»A, 17-β-hydroxysteroid dehydrogenase type 1 (HSD17), vlV A-»C, cytochrome P450 (CYP), 17 A2 allele T-»C, CYP1A1 Mspl RFLP T-»C, CYPIA1 Ile462Val A-»G, CYP19 Arg264Cys C-»T, CYP19 C1558T C-»T, CYP 1B1 Leu432Val, CYPIB1 Asn453Ser, and estrogen receptor alpha IVS1 -401»C. Associations and 2-way interaction models between SNPs were calculated by stepwise logistic regression models. RESULTS: In a univariate model, HSD17 vlV A-»C was associated with a significantly increased risk of endometriosis (P = .004; odds ratio 3.9, 95% confidence interval 1.6–9.8). When all 2-way interactions of investigated SNPs were ascertained, no significant interactions among SNPs were observed. In a multivariate model, HSD17 vlV A-»C was also significantly associated with endometriosis (P = .002). CONCLUSION: We present data on multiple SNPs in patients with endometriosis indicating an association between HSD17 gene variation and the disease. Although not able to demonstrate interaction models of SNPs, we provide evidence of HSD17 vlV A-»C as a low penetrance genetic marker of endometriosis. [ABSTRACT FROM AUTHOR]

: Objective:To explore whether having the mutant tumor necrosis factor (TNF)2 (G−308*A) and TNFA-A (G−238*A) alleles in the TNF-α gene promotor region is higher in women with endometriosis, we determined the respective genotype and allele frequencies in a retrospective case-control study.: Methods:Polymerase chain reaction was performed to identify the G−308A and G−238A promotor polymorphisms in 92 women with surgically and histologically confirmed endometriosis. A series of 69 healthy women without a history of endometriosis served as clinical controls.: Results:The allele frequencies of the TNF2 polymorphism were 0.13 and 0.16 in women with endometriosis and in the control group, respectively, and the frequencies of the TNFA-A polymorphisms in women with endometriosis and in the control group were 0.04 and 0.05, respectively, with no significant difference between the study and control groups. The TNF2 polymorphism was present in the homozygous form (TNF2/2) in 4.3% of women with endometriosis and in 2.9% of controls (P= .7). No TNFA-A homozygotes (TNFAA/A) were detected.: Conclusion:We studied TNF-α promotor gene variants among women with endometriosis and found that having the G−308A TNF-α and the G−238A TNF-α polymorphism was not associated with endometriosis in a white population. [Copyright &y& Elsevier]

This study introduces a DNA microarray-based genotyping system for accessing single nucleotide polymorphisms (SNPs) directly from a genomic DNA sample. The described one-step approach combines multiplex amplification and allele-specific solid-phase PCR into an on-chip reaction platform. The multiplex amplification of genomic DNA and the genotyping reaction are both performed directly on the microarray in a single reaction. Oligonucleotides that interrogate single nucleotide positions within multiple genomic regions of interest are covalently tethered to a glass chip, allowing quick analysis of reaction products by fluorescence scanning. Due to a fourfold SNP detection approach employing simultaneous probing of sense and antisense strand information, genotypes can be automatically assigned and validated using a simple computer algorithm. We used the described procedure for parallel genotyping of 10 different polymorphisms in a single reaction and successfully analyzed more than 100 human DNA samples. More than 99% of genotype data were in agreement with data obtained in control experiments with allele-specific oligonucleotide hybridization and capillary sequencing. Our results suggest that this approach might constitute a powerful tool for the analysis of genetic variation. [Copyright &y& Elsevier]

In a cross-sectional study of 2,802 perimenopausal caucasian women, carriage of at least one mutated allele of the 17-α-hydroxysteroid dehydrogenase type 1 (17-α HSD) vlV A→C single nucleotide polymorphism (SNP) was associated with a significantly increased body mass index (mean 24.3 ± 4.4 kg/m2 vs. 23.5 ± 4.2 kg/m2; P<.001), and obesity was more frequent among mutant allele carriers (P=.06; odds ratio 1.38; 95% confidence interval 0.97–1.95), providing evidence of 17-α HSD as a candidate gene of perimenopausal obesity. [Copyright &y& Elsevier]