Biomedical subjects

Clemens B Tempfer

Publications and source records attributed to Clemens B Tempfer.

At least 19 recordsLinked to original sources

PubMed2007

An estrogen metabolism-related polymorphism of the 17-alpha HSD gene is associated with perimenopausal body mass index.

In a cross-sectional study of 2,802 perimenopausal caucasian women, carriage of at least one mutated allele of the 17-alpha-hydroxysteroid dehydrogenase type 1 (17-alpha HSD) vlV A-->C single nucleotide polymorphism (SNP) was associated with a significantly increased body mass index (mean 24.3 +/- 4.4 kg/m(2) vs. 23.5 +/- 4.2 kg/m(2); 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-alpha HSD as a candidate gene of perimenopausal obesity.

Body Mass Index↗

PubMed2006

Preoperative serum vascular endothelial growth factor as a prognostic parameter in ovarian cancer.

OBJECTIVE: Serum vascular endothelial growth factor (VEGF) levels have been shown to be associated with an adverse outcome in patients with ovarian cancer. We studied the clinical value of serum VEGF as an independent prognostic parameter. METHODS: In the present study, we ascertained preoperative serum VEGF in a series of 314 patients with ovarian cancer: 45 new cases and 269 from four previously published studies. Serum VEGF was evaluated prior to primary surgery, results were correlated with clinical data. RESULTS: Median serum VEGF was 407 (238-746) pg/mL. In a univariate Kaplan-Meier analysis, FIGO stage, residual tumor mass, tumor grade, patients' age, serum CA 125, and preoperative serum VEGF were associated with overall survival. In a multivariate Cox regression model, higher FIGO stage, presence of residual tumor mass after primary surgery, and higher serum VEGF were independently associated with a shortened overall survival. Planned subgroup analysis was performed for patients with ovarian cancer FIGO stage I. In a multivariate Cox regression model, higher tumor grade and higher serum VEGF were the only independent prognosticators for overall survival. Patients with FIGO stage I ovarian cancer and a serum VEGF > or = 380 pg/mL had an 8-fold increased risk for experiencing cancer-related death. CONCLUSION: Serum VEGF is an independent prognostic parameter in patients with all stages of ovarian cancer.

CA-125 Antigen↗

PubMed2006

A combination treatment of prednisone, aspirin, folate, and progesterone in women with idiopathic recurrent miscarriage: a matched-pair study.

OBJECTIVE: To compare a combination treatment of prednisone, aspirin, folate, and progesterone with no treatment in women with idiopathic recurrent miscarriage (IRM). DESIGN: Matched-pair study. SETTING: Academic research institution. SUBJECT(S): Women with a history of IRM, defined as three or more consecutive miscarriages before 20 weeks' gestation without associated anatomic, cytogenetic, hormonal, and infectious pathologies or antiphospholipid syndrome. INTERVENTION(S): Eighty of 210 eligible women consented to participate and were treated with prednisone (20 mg/d) and progesterone (20 mg/d) for the first 12 weeks of gestation, aspirin (100 mg/d) for 38 weeks of gestation, and folate (5 mg every second day) throughout their pregnancies. Fifty of 80 women became pregnant; they were compared with 52 women with IRM (matched for age and number of miscarriages), who became pregnant without treatment during the same observation period. MAIN OUTCOME MEASURE(S): Live birth rate, complications of pregnancy, such as preeclampsia, premature birth, and intrauterine growth restriction, and therapy-related side effects. RESULT(S): The overall live birth rates of the treatment and control groups were 77% (40 of 52) and 35% (18 of 52) (P=.04). The rates of first and second trimester miscarriage among the treatment and control groups were 19% (10 of 52) and 0 (0 of 52), and 63% (33 of 52) and 2% (1 of 52), respectively (P=.09 and P=1.0, respectively). The median gestational age at birth and median birth weight did not differ between the groups. We observed two and three cases of premature birth among the treatment and control groups, respectively (P=.3) and no cases of intrauterine growth restriction and Cushing's disease. Of 80 women who started treatment, one woman had an ectopic pregnancy and one woman terminated her pregnancy due to fetal chromosome aberration (trisomy 18). Three women stopped treatment due to nausea, depression, and tachycardia. CONCLUSION(S): A combination treatment of prednisone, aspirin, folate, and progesterone is associated with a higher live birth rate compared with no treatment in women with IRM.

Abortion, Habitual↗

PubMed2006

A model for predicting age at menopause in white women.

OBJECTIVE: To develop a model to predict the age at natural menopause and the risk for premenopausal hysterectomy. DESIGN: Cross-sectional study. SETTING: Multicenter study. PATIENT(S): A total of 1,345 white women. INTERVENTION(S): Ten single nucleotide polymorphisms (SNPs) of seven estrogen (E)-metabolizing genes (i.e., catechol-O-methyltransferase, 17-beta-hydroxysteroid dehydrogenase type 1, cytochrome P-450 [CYP] 17, CYP1A1, CYP1B1, CYP19, and E receptor [ER] alpha) were analyzed by sequencing-on-chip-technology. MAIN OUTCOME MEASURE(S): Patients' reproductive and medical histories were ascertained and correlated to genotypes. RESULT(S): The model incorporates the number of full term pregnancies, the body mass index (BMI), a history of breast surgery, and the presence of CYP17 and CYP1B1-4 polymorphisms as well as the BMI to predict age at natural menopause and the risk for undergoing premenopausal hysterectomy. CONCLUSION(S): We present the first model to date, which can predict age at natural menopause and the risk for undergoing premenopausal hysterectomy based on genotype information and personal history.

Aging↗

PubMed2006

How valid is single nucleotide polymorphism (SNP) diagnosis for the individual risk assessment of breast cancer?

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 MspI, 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.

Breast Neoplasms↗

PubMed2005

A common polymorphism within the steroid 5-alpha-reductase type 2 gene and timing of menopause in Caucasian women.

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.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗

PubMed2005

The influence of a Vitamin D receptor gene polymorphism on the timing of female reproductive functions in humans.

OBJECTIVE: To evaluate the association between a common polymorphism of the Vitamin D receptor gene (VDR) and the timing of female reproductive functions in humans. METHODS: One thousand fifty-eight consecutive women were included in this cross-sectional study. We analyzed the intron 8 Bsm I restriction fragment length polymorphism (RFLP) of VDR on chromosome 12q using a microarray-based system. RESULTS: The presence of the VDR polymorphism did not influence the timing of menarche and natural menopause and was not associated with the number of spontaneous abortions, full term pregnancies (FTP) as well as the total number of pregnancies. Of note, women with at least one mutant allele of VDR were at a significantly decreased risk for experiencing surgical menopause (odds ratio [OR] 0.65, 95% confidence interval [CI], 0.46-0.92, P = 0.02). Smoking and a body mass index (BMI) > 25 were associated with an earlier natural menopause and an increased risk for surgical menopause, respectively. CONCLUSIONS: While no association of a common polymorphism of VDR with the timing of menarche and menopause was ascertained, we found the presence of at least one mutant allele of VDR to be associated with a decreased risk of experiencing surgical menopause, i.e., premenopausal hysterectomy, in a large series of Caucasian women.

Adult↗

PubMed2005

Ultrasound criteria for ductal invasive breast cancer are modified by age, tumor size, and axillary lymph node status.

PURPOSE: To evaluate the influence of distinct clinicopathological parameters on ultrasound criteria for ductal invasive breast cancer. PATIENTS AND METHODS: The hardcopy prints of 337 ductal invasive breast cancers were analyzed. Ten ultrasound criteria (shape, orientation, echogenicity, echo pattern, calcifications, margin, margin contour, lesion boundary, surrounding tissue, and posterior acoustic features) were defined and correlated to age, tumor size, axillary lymph node status, and histological grading in a multivariate analysis. RESULTS: Tumors in women < or = 50 years displayed more often an indistinct margin (p = 0.003) and an enhanced/indifferent posterior ultrasound transmission (p = 0.008). Tumors in an advanced T-stage showed more frequently an irregular shape ( p = 0.006), an orientation parallel to the skin ( p = 0.01), hypoechogenicity ( p < 0.0001), and less often calcifications ( p = 0.002). A positive axillary lymph node status was significantly correlated to oval/round shape ( p = 0.004), hyper-/isoechogenicity ( p = 0.001), and a homogeneous echo pattern ( p = 0.002). Grading showed no correlation to the examined ultrasound criteria. CONCLUSION: Breast ultrasound criteria, which are used to differentiate benign from malignant breast lesions, are influenced by age, size and lymph node status. These clinical conditions should be considered in the ultrasound diagnosis of breast lesions.

Adult↗

PubMed2005

Ten estrogen-related polymorphisms and endometriosis: a study of multiple gene-gene interactions.

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-beta-hydroxysteroid dehydrogenase type 1 (HSD17), vlV A->C, cytochrome P450 (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 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. LEVEL OF EVIDENCE: II-2.

Adult↗

PubMed2005

The C46T polymorphism of the coagulation factor XII gene and idiopathic recurrent miscarriage.

Thrombophilia has been described to be involved in the pathogenesis of idiopathic recurrent miscarriage (IRM). We investigated the association between IRM and a C-->T polymorphism at nucleotide 46 in the 5'-untranslated region of the coagulation factor XII (FXII) gene. Two hundred and twelve women with a history of IRM and 149 healthy controls were tested by a mutagenically separated polymerase chain reaction assay (MS PCR). Allele and genotype frequencies were not significantly different between the study and the control groups. Our data suggest that the FXII gene is not a candidate gene for this condition.

Abortion, Habitual↗

PubMed2004

The influence of Nos3 polymorphisms on age at menarche and natural menopause.

OBJECTIVE: Deficiency of the gene encoding endothelial nitric oxide synthase, i.e. Nos3, has been reported to be associated with late menarche, reduced ovulation rates, fewer deliveries, and earlier onset of menopause in a mouse model. METHODS: We assessed the Glu298Asp and the T-786C polymorphisms of Nos3 in 87 consecutive healthy postmenopausal women by pyro- and capillary-sequencing, respectively. Results were correlated with age at menarche and natural menopause, number of miscarriages and live births, as well as body mass index (BMI) and smoking habits. RESULTS: Allelic frequencies of the Glu298Asp polymorphism of Nos3 were 121 (69.5%) and 53 (30.5%) for the wild-type G allele and the mutant T allele, respectively. Forty-one women (47.1%) were homozygote wild-type (G/G), 39 (44.9%) were heterozygote (G/T), and 7 (8.0%) were homozygote mutant (T/T). Allelic frequencies of the T-786C polymorphism of Nos3 were 105 (60.6%) and 69 (39.4%) for the wild-type T allele and the mutant C allele, respectively. Thirty-three women (38.0%) were homozygote wild-type (T/T), 39 (45.1%) were heterozygote (T/C), and 15 (16.9%) were homozygote mutant (C/C). Presence of at least one mutant allele of the Glu298Asp or the T-786C polymorphisms of Nos3 were not associated with age at menarche, natural menopause, and number of miscarriages and deliveries. BMI above 27 kg/m2 and smoking were associated with earlier onset of natural menopause (47.8 years versus 50.2 years (P = 0.01) and 46.8 years versus 49.8 years (p = 0.02)). CONCLUSIONS: Our data show that smoking and increased BMI, but not Glu298Asp or the T-786C polymorphisms of Nos3, are associated with an early onset of natural menopause.

Age Factors↗

PubMed2004

Estrogen-metabolizing gene polymorphisms in the assessment of breast carcinoma risk and fibroadenoma risk in Caucasian women.

BACKGROUND: Genes encoding enzymes involved in estrogen metabolism are held to be candidate genes for associations with breast disease. In these candidate genes, no critical combination of single-nucleotide polymorphisms (SNPs) for assessing breast carcinoma risk has been reported to date. METHODS: In a large case-control study, the authors investigated 10 estrogen-metabolizing SNPs in 396 patients with breast carcinoma, 154 patients with fibroadenoma, and 1936 healthy control patients without breast carcinoma in their personal history. The following 10 SNPs were analyzed using sequencing-on-chip technology via a solid-phase polymerase chain reaction assay performed on oligonucleotide microarrays: catechol-O-methyltransferase Val158Met G-->A, 17-beta-hydroxysteroid dehydrogenase type 1 vIV A-->C, cytochrome P-450 (CYP) family 17 A2 allele T-->C, CYP1A1-1 MspI restriction fragment length polymorphism (RFLP) T-->C, CYP1A1-2 Ile462Val A-->G, CYP19-1 Trp39Arg T-->C, CYP19-2 Arg264Cys C-->T, CYP19-3 Cys1558Thr C-->T, steroid-5-alpha reductase type 2 Val89Leu G-->C, and vitamin D receptor BsmI RFLP. A total of 21,350 genotypes were evaluated. Associations and two-way interaction models were calculated using stepwise logistic regression. RESULTS: In a multiple model, CYP1A1-1 (P = 0.004) and CYP1A1-2 (P = 0.03) were found to be associated with significantly decreased and increased risks of breast carcinoma, respectively. When two-way interactions involving investigated SNPs were ascertained, no significant interactions among polymorphisms were noted. Comparison of patients with fibroadenoma with control patients revealed significantly increased and decreased risks of fibroadenoma when the mutant alleles of CYP17 (P = 0.02) and CYP1A1-1 (P = 0.04), respectively, were present. CONCLUSIONS: The authors obtained the first SNP data indicating that CYP17 and CYP1A1-1 play a role in the pathogenesis of fibroadenoma. Although the authors were not able to develop interaction models involving SNPs, they did provide evidence that CYP1A1 is a low-penetrance susceptibility gene with respect to breast carcinoma in a large series of Caucasian women.

Breast Neoplasms↗

PubMed2004

Body mass index but not a polymorphism of the interleukin-1 receptor antagonist (IL-1 RA) gene is associated with age at natural menopause.

BACKGROUND: A genetic component of the onset of menopause has been described and several candidate genes have been identified. We hypothesized that carriage of a polymorphism of the interleukin-1 receptor antagonist gene (IL-1 RA) is associated with an early age at menopause. METHODS: In a prospective cohort study, 90 consecutive postmenopausal Caucasian women were genotyped by PCR for the presence of an 86-base pair tandem repeat polymorphism in intron 2 of IL-1 RA. RESULTS: We found that 36/90 (40%) women were homozygous for the wild-type allele 1 and 49/90 (54%) women were heterozygous for any of the variant alleles (1/2 [n = 44], 1/3 [n = 3], 2/3 [n = 2]). Two women (2%) were homozygous carriers of the variant allele 2. The wild-type allele 1 was identified on 119 of 180 chromosomes for an allele frequency of 0.66. The polymorphic alleles 2 and 3 were present on 56 and 5 chromosomes, respectively (allele frequencies 0.31 and 0.03, respectively). No correlation between the IL-1 RA genotype and the age at menarche and menopause, the length of the reproductive period, and the number of deliveries and miscarriages was ascertained. As to allele frequencies, homozygous and heterozygous carriers of the variant allele 2 had a median age at menopause of 50 (range 40-48) years, compared to 49.5 (range 39-56) years for women with no allele 2 (p value 0.41). Women with at least one allele 2 had a median age at menarche of 13 (range 10-16) years, compared to 13 (range 10-17) years for women with no allele 2 (p value 0.1). Decreasing body mass index, but not smoking, was correlated with an increasing age at natural menopause (r = -0.23, p = 0.04). CONCLUSIONS: Our preliminary data suggest that an 86-base pair tandem repeat polymorphism in intron 2 of IL-1 RA does not modulate the onset and cessation of menses in this cohort of Caucasian women.

Adult↗

PubMed2004

DNA microarray-based analysis of single nucleotide polymorphisms may be useful for assessing the risks and benefits of hormone therapy.

OBJECTIVE: To determine what percentage of women can be given individualized counseling based on genetic information, as single nucleotide polymorphisms (SNPs) are associated with risks and benefits of estrogen therapy and hormone therapy such as thrombosis, myocardial infarction, breast cancer, and bone protection. DESIGN: Cross-sectional study. SETTING: Academic research institution. PATIENT(S): A consecutive series of 2,507 perimenopausal and postmenopausal women. INTERVENTION(S): Peripheral venous puncture and multiplex polymerase chain reaction on a microarray system. MAIN OUTCOME MEASURE(S): Analysis of 22 SNPs of 17 genes: AGTMet235Thr, APOECys112Arg, APOEArg158Cys, COMTVal158Met, CYP17-34T>C, CYP191558C>T, CYP19Arg264Cys, CYP1A16235T>C, CYP1A1Ile462Val, CYP1B1Leu432Val, CYP1B1Asn453Ser, HSD17B1-27A>C, ER-alphaIVS-401T>C, prothrombin20210G>A, factor V Leiden, eNOS-786T>C, eNOSGlu298Asp, MRSer810Leu, MTHFR677C>T, PAI 15G>4G, SRD5A2Val89Leu, and VDRb>B. RESULT(S): Among the women in the study, 66% had at least two homozygous mutant SNPs of interest. A thrombophilic disposition was found in 9.9% of women, and 23% of women had at least two SNPs associated with an increased risk of breast cancer (COMT, CYP17, CYP19, CYP1A1, and CYP1B1). The SNPs predisposing women to cardiovascular pathologies (e.g., APOE, AGT, eNOS, and PAI 1) were found in 12.3% of women. Carriage of SNPs predisposing to early postmenopausal bone loss and osteoporosis (ER-alpha and VDR) were found in 26.7% of women. CONCLUSION(S): These data suggest that the assessment of SNPs associated with risks and benefits of estrogen/hormone therapy may be a new means to individualize counseling about and prescription of estrogen/hormone therapy in up to 66% of women.

Breast Neoplasms↗

PubMed2004

Polymorphisms of thrombophilic and vasoactive genes and severe preeclampsia: a pilot study.

OBJECTIVE: Carriage of thrombophilic and vasoactive polymorphic alleles has been associated with various pregnancy complications. The effect of carrying multiple polymorphisms is not known. We conducted a case-control study to determine the association between eight polymorphisms of thrombophilic and vasoactive genes and the risk of severe preeclampsia. METHODS: The following polymorphisms were analyzed by sequencing-on-chip-technology using solid-phase polymerase chain reaction on oligonucleotide microarrays: factor 5 (F5) Leiden, factor 2 (F2)-prothrombin G20210A, plasminogen activator inhibitor (PAI)-1 4G/5G, nitric oxide synthase (NOS) 3 T768C, NOS 3 Glu298Asp, angiotensinogen (AGT) Met235Thr, estrogen receptor (ER) alpha Pvu II, and mineralcorticoid receptor (MLR) Ser810Leu. The study comprised 24 patients with severe preeclampsia and 24 controls from a cohort of consecutive white women treated at the Obstetrics Department of the University of Vienna Medical School. Genotypes were correlated with clinical data. RESULTS: The investigated polymorphisms did not influence the risk of severe preeclampsia independently. When separately considering the simultaneous carriage of multiple thrombophilic or vasoactive polymorphisms, neither the combined carriage of thrombophilic polymorphisms (F5 Leiden, F2 G20210A, PAI-1 4G/5G), nor the combined carriage of vasoactive polymorphisms (NOS 3 T768C, NOS 3 Glu298Asp, AGT Met235Thr) conferred an increased risk of severe preeclampsia. Cumulative genotype frequencies for at least two homozygous mutant genotypes, however, were nine of 24 (38%) and two of 24 (8%) for the study and control groups, respectively (P <.05). All of these nine women with severe preeclampsia had at least two homozygous mutant genotypes of four polymorphisms, ie, F5 Leiden, NOS 3 T768C, NOS 3 Glu298Asp, or ER alpha Pvu II. CONCLUSION: Our data fail to document an independent significant influence of the investigated polymorphisms on the risk of severe preeclampsia. In an attempt to build a multigenetic model of severe preeclampsia, the combination of F5 Leiden, NOS 3 T768C, NOS 3 Glu298Asp, and ER alpha Pvu II was the most effective combination to predict the presence of severe preeclampsia in this small series of white women.

Adult↗

PubMed2004

A polymorphism of the interleukin-1 receptor antagonist plays a prominent role within the interleukin-1 gene cluster in vulvar carcinogenesis.

OBJECTIVE: The interleukin-1 (IL-1) family, that is, IL-1alpha and beta and the IL-1 receptor antagonist (IL-1RA), is known to modulate various tumorigenic and tumoricidal effects in humans. Its biological function in squamous cell carcinogenesis of various anatomical sites has been stressed. Although various studies showed a certain association between genes encoding the IL-1 family and human malignancies, no data with respect to vulvar cancer have been published to date. METHODS: We ascertained four polymorphisms of the IL-1alpha gene (IL1A C[-889]T), the IL-1beta gene (IL1B promoter C[-511]T and IL1B exon 5 position +3953), and the IL-1RA gene (IL1RN intron 2) in 68 patients with surgically treated squamous cell vulvar cancer and 228 healthy Caucasian controls. RESULTS: Presence of the minor allele of the IL1RN polymorphism was found to be protective for vulvar cancer [odds ratio (OR)=0.5, P=0.03], the other investigated polymorphisms showed no association with the disease and the investigated clinicopathological parameters. In a multivariate analysis, only the established prognosticators were associated with patients' survival. CONCLUSION: We are the first to report on polymorphisms in genes encoding cytokines in patients with vulvar cancer. Reflecting its biological role, the common IL1RN intron 2 polymorphism seems to play a prominent role within the IL-1 gene cluster with respect to vulvar carcinogenesis.

Adult↗

PubMed2004

Polymorphisms of the endothelial nitric oxide synthase gene in women with vulvar cancer.

OBJECTIVE: Nitric oxide (NO) is involved in angiogenesis and tumor growth. We attempted to establish an association between two polymorphisms of the endothelial nitric oxide synthase (NOS3) gene and vulvar cancer. METHODS: We used peripheral venous blood sampling, DNA extraction, and polymerase chain reaction (PCR) and pyrosequencing to genotype 68 women with vulvar cancer and 227 healthy Caucasian women for the presence of the intron 4 27-bp-repeat [NOS3*A] and exon 7 Glu298Asp polymorphisms. RESULTS: The presence of a polymorphic NOS3*A allele (26.2% vs. 24.6%; OR: 1.01; 95% CI: 0.6-2.0; P = 0.9) or a polymorphic NOS3 exon 7 Glu298Asp allele (41.2% vs. 53.7%; OR: 0.6; 95% CI: 0.3-1.0; P = 0.09) was not associated with vulvar cancer. Within the vulvar cancer group, the presence of a polymorphic NOS3*A or a polymorphic NOS3 exon 7 Glu298Asp allele was not associated with clinico-pathological parameters such as advanced tumor stage, groin lymph node involvement, tumor grading, and age at diagnosis. Survival analysis demonstrated that the presence of a polymorphic NOS3*A allele was associated with a significantly reduced disease-free survival time (P = 0.03), whereas the presence of the polymorphic NOS3 exon 7 Glu298Asp allele was not associated with disease-free survival (P = 0.5). CONCLUSIONS: We are the first to report on NOS3 polymorphisms in vulvar cancer. We found that allelic variation within intron 4, but not ithin exon 7 of NOS3, influences the length of disease-free survival, but not the biological phenotype of vulvar cancer.

Adult↗

PubMed2004

Applications of polymorphisms and pharmacogenomics in obstetrics and gynecology.

The number of reports investigating disease susceptibility based on the carriage of low-penetrance, high-frequency polymorphisms has steadily increased over the last years. Evidence based on meta-analyses of individual case-control studies is accumulating, defining specific individual variations in disease susceptibility. For example, genetic variations of the estradiol metabolism have been described as significant contributors to disease susceptibility with variations depending on ethnic background. In the field of obstetrics and gynecology, the genetic contribution of polymorphic markers to a series of disorders has been characterized. These disorders include recurrent pregnancy loss, pre-eclampsia, endometriosis, breast cancer, and hormone replacement therapy (HRT)-related complications such as thrombosis. Among other genetic markers, thrombophilic genetic variants, such as the Factor V Leiden and prothrombin G20210A polymorphisms, as well as genetic variants of cytochrome P450 (CYP) enzymes, for example, CYP19 and CYP1B1, have been established as genetic risk markers and disease modifiers of recurrent and sporadic pregnancy loss and HRT-independent and -dependent breast cancer, respectively. In addition, meta-analyses of data in the literature established the TGFBR1*6A, GSTP I105V, and TP53 R72P polymorphisms, as well as the GSTM1 gene deletion as low-penetrance genetic risk factors of sporadic breast cancer. With respect to genetic modulation of therapeutic effects, beneficial effects of estrogen replacement therapy and HRT are modulated by the carriage of single nucleotide polymorphisms, for example, osteoprotection and blood lipid changes by the estrogen receptor-alpha (ER-a) PvuII polymorphism. Polymorphisms of the catechol-O-methyltransferase (COMT), ER-alpha, IL-1 receptor antagonist, and Factor V genes have been demonstrated to modulate the timing of natural menopause. Lastly, a strong genetic contribution of polymorphisms to the development and the clinical course of endometriosis has been established with data pointing to polymorphisms of the COMT, GST, NAT-2, and ER-alpha genes as susceptibility markers. In summary, the available evidence points to a number of polymorphisms of a wide variety of genes as strong hereditary determinants of the susceptibility to benign and malignant gynecologic and obstetric conditions.

Female↗