Fas gene promoter –670 polymorphism in gynecological cancer

Abstract.   Ueda M, Terai Y, Kanda K, Kanemura M, Takehara M, Yamaguchi H, Nishiyama K, Yasuda M, Ueki M. Fas gene promoter −670 polymorphism in gynecological cancer. Int J Gynecol Cancer 2006; 16(Suppl. 1): 179–182.
Single-nucleotide polymorphism at −670 of Fas gene promoter (A/G) was examined in a total of 354 blood samples from normal healthy women and gynecological cancer patients. They consisted of 95 normal, 83 cervical, 108 endometrial, and 68 ovarian cancer cases. Eighty-three patients with cervical cancer had statistically higher frequency of GG genotype and G allele than 95 controls ( P = 0.0353 and 0.0278, respectively). There was no significant difference in the genotype or allele prevalence between control subjects and endometrial or ovarian cancer patients. The Fas −670 GG genotype was associated with an increased risk for the development of cervical cancer (OR = 2.56, 95% CI = 1.08–6.10) compared with the AA genotype. The G allele also increased the risk of cervical cancer (OR = 1.60, 95% CI = 1.05–2.43) compared with the A allele. Germ-line polymorphism of Fas gene promoter −670 may be associated with the risk of cervical cancer in a Japanese population.     

The relationship of the Fas 670 A/G gene polymorphism with cardiovascular risk factors in polycystic ovary syndrome (PCOS) patients

Aims.?Apoptosis has been shown in cardiac cells under divergent physiological and pathological conditions. Apoptosis plays a key role in the pathogenesis of cardiac diseases. We aimed to evaluate the relation between Fas 670 A/G gene polymorphism in polycystic ovary syndrome (PCOS) patients carrying a potential risk for developing cardiovascular disease (CVD).

Materials and methods.?Ninety-one patients with PCOS and 100 cases of healthy control people were included in this study. PCOS was defined by the Rotterdam PCOS consensus criteria. The evaluation of genotype for Fas 670 A/G gene polymorphism was performed by using PCR-RFLP method.

Results.?The evaluation of Fas genotype and gene allele frequency did not show statistically significant difference between patient and control groups. Both in PCOS patients and control groups, there were no statistically significant differences among A/A, A/G, and G/G.

Conclusions.?We found no relation between the cardiovascular risk factors and Fas 670 A/G gene polymorphism in women with PCOS and healthy subjects. Our results in risk factors of CVD can probably be explained by the fact that metabolic parameters and endothelial systems of the patients may not be affected yet in this short period of time.     

A single nucleotide A>G polymorphism at position -670 in the Fas gene promoter: relationship to preterm premature rupture of fetal membranes in multifetal pregnancies

OBJECTIVE: The relationship between a polymorphism at position -670 in the Fas gene (TNFRSF6) and preterm premature rupture of membranes (PPROM) in multifetal pregnancies was examined. METHODS: Buccal swabs from 119 mother-infant sets were analyzed for an adenine (A) to guanine (G) substitution at position -670 in the TNFRSF6 promoter. Pregnancy outcome data were subsequently obtained. Analysis was by Fisher exact test. RESULTS: Maternal allele G homozygosity (TNFRSF6*G) was observed in 42.4% of 33 PPROM pregnancies as opposed to 19.5% of 77 with no spontaneous preterm birth (P = .01). Similarly, TNFRSF6*G homozygosity was present in 37.5% of 32 first-born neonates from PPROM pregnancies as opposed to 18.7% of 75 uncomplicated pregnancies (P = .04). PPROM occurred in 8 of 14 (57.1%) pregnancies in which mother and all neonates were TNFRSF6*G homozygotes as opposed to 25 of 105 (23.8%) cases in which uniform TNFRSF6*G homozygosity was not observed (P = .02). CONCLUSIONS: A genetic variant in the Fas gene is associated with an increased rate of PPROM in multifetal pregnancies.     

G/A polymorphism at -258 of the hepatic glucokinase promoter is not associated with decreased birth weight in preterm neonates

BACKGROUND: A high percentage of preterm neonates are born small for gestational age (SGA). These children show a high morbidity and mortality after birth and often develop insulin resistance with ensuing impaired glucose metabolism in adulthood. Since insulin is important for intrauterine growth, fetal insulin resistance might also influence birth weight of preterm neonates. OBJECTIVES: A common polymorphism in the promoter region of the human hepatic glucokinase (-258) is associated with a decreased promoter activity, an enhanced insulin secretion, and hypertension and hepatic insulin resistance in adults. In this pilot study we wanted to investigate whether the G/A polymorphism at -258 of the hepatic glucokinase promoter has an effect on birth weight of preterm neonates and therefore might constitute a genotype leading to low birth weight and metabolic defects. METHODS: We enrolled 106 preterm neonates in our study. 44 of them were SGA and 62 AGA neonates. We extracted DNA from a buccal swab and identified the polymorphism by PCR-ARMS. RESULTS: We found no difference in the prevalence of the polymorphism in either groups. CONCLUSION: The polymorphism at -258 of the fetal hepatic glucokinase promoter is most probably not of a major relevance in the pathophysiology of low birth weight in preterm neonates.     

The (-2548G/A) polymorphism of leptin gene in women with gestational hypertension and preeclampsia

INTRODUCTION: Leptin is a polypeptide hormone (167 amino acids, molecular weight of about 16kDa), synthesized mainly in white adipose tissue. The hormone plays an important role in regulation of hunger and satiety processes, in metabolism of carbohydrates and fats, development of cardio-vascular diseases and obesity. The occurrence of the increased level of leptin in pregnant women with hypertension, especially in women with preeclampsia, has also been brought to our attention. In recent years it has been suggested that the presence of different variants of leptin and leptin receptor genes may modify the leptin level in serum, and, in this way, influence an increased risk of obstetric complications, such as preeclampsia or eclampsia. MATERIALS AND METHODS: We have analyzed a group of 103 hypertensive pregnant women--61 women with gestational hypertension (GH) and 42 women with preeclampsia (PE). The control group consisted of 113 healthy pregnant women who have been investigated. Gestational hypertension and preeclampsia were recognized with the help of and assessed according to the ACOG criteria. The (-2548G/A) polymorphism was determined using polymerase chain reaction/restriction fragment length polymorphism (PCR/RFLP). RESULTS: In our study, a higher frequency of mutated AA genotype in GH group and PE groups (21.31% and 21.43% respectively vs. 16.81% in the controls) and the overrepresentation of mutated A allele in both analyzed groups (47.54% and 45.24% respectively vs. 41.59% in the controls) have been observed, without statistically significant differences. CONCLUSIONS: The overrepresentation of AA genotypes and higher frequency of mutated A allele of (-2548G/A) polymorphism of leptin gene in GH and PE groups might indicate its possible contribution in gestational hypertension and preeclampsia.     

Serotonin receptor 1A C(-1019)G polymorphism associated with premenstrual dysphoric disorder

OBJECTIVE: To assess whether the G allele of the serotonin receptor 1A C(-1019)G polymorphism is associated with premenstrual dysphoric disorder. METHODS: The study sample comprised 53 women with clinically diagnosed premenstrual dysphoric disorder (age range 27-46 years, mean 37.7 years) and 51 healthy control subjects (age range 22-48 years, mean 36.2 years). The serotonin receptor 1A C(-1019)G polymorphism was genotyped and compared between the two groups. RESULTS: In contrast to the postulated "high-risk" G/G genotype, there was a marked overrepresentation of the C/C genotype in the premenstrual dysphoric disorder group (P=.034; odds ratio 3.63, 95% confidence interval 1.22-10.78). The presence of at least one C allele was associated with a 2.5-fold increased risk of premenstrual dysphoric disorder (P=.053; odds ratio 2.46, 95% confidence interval 1.03-5.88). CONCLUSION: Our hypothesis that the high-risk G allele is associated with the occurrence of premenstrual dysphoria was not proved in this study. However, due to the increased prevalence of the C variant, we suggest that the C(-1019) allele may contribute to the risk of premenstrual dysphoria. LEVEL OF EVIDENCE: II.     

The V109G polymorphism in the p27 gene is associated with endometriosis

Objective

To investigate the prevalence of the p27 gene polymorphism in women with endometriosis.

Study design

Transversal case–control study. Genomic DNA was extracted from cells collected from buccal swabs. The p27 V109G polymorphism was investigated using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method in a hospital-based Brazilian population.

Results

We analysed the 104 patients and 109 control subjects. The distribution of genotype and allele frequencies of p27 V109G polymorphism was significantly different between the endometriosis cases and healthy women (p = 0.016 and 0.002). Women who had at least one mutated allele presented twofold chances for endometriosis development (OR = 1.9; 95% CI, 1.120–3.343).

Conclusion

The polymorphic variant at codon 109 of the p27 gene seems to be associated with higher risk of endometriosis development.     

A polymorphism in the matrix metalloproteinase-1 gene promoter is associated with the prognosis of patients with ovarian cancer

OBJECTIVE: The enzyme matrix metalloproteinase (MMP)-1 is involved in ovarian carcinogenesis. A common guanine insertion-deletion promoter polymorphism within the gene encoding MMP-1 (MMP1) has been suggested to be a candidate gene for ovarian cancer. We investigated whether this common polymorphism can also serve as independent prognostic parameter in a large series of affected women. METHODS: The MMP1 promoter polymorphism was examined in 151 Caucasian patients with epithelial ovarian cancer using polymerase chain reaction. Results were correlated with clinical data. RESULTS: No associations were ascertained between the MMP1 polymorphism and tumor stage (P = 1.0, odds ratio [OR] 1.08), lymph node involvement (P = 1.0, OR 0.8), tumor grading (P = 0.2, OR 0.5), and patient's age at diagnosis (P = 1.0, OR 1.04). Besides the clinically established prognosticators, tumor stage and histological grade, presence of the MMP1 polymorphism was associated with a shortened disease-free and overall survival in a univariate Kaplan-Meier analysis (P = 0.01) and a multivariate Cox regression model (P = 0.04). CONCLUSION: Presence of the MMP1 gene promoter polymorphisms was found to be a negative prognostic parameter in patients with ovarian cancer.     

A polymorphism in the resistin gene promoter is associated with body mass index in women with polycystic ovary syndrome

Resistin does not appear to be a major gene predisposing to polycystic ovary syndrome (PCOS). However, an association of a resistin variant with body mass index was found in women with PCOS, suggesting that resistin may be related to adiposity in PCOS.     

Association of Fas-670 gene polymorphism with risk of cervical cancer in North Indian population

OBJECTIVES: Cervical cancer is the second most common cancer among women in the world, with approximately 470,000 new cases and 231,000 deaths occurring each year. Incidence is greater in developing countries such as India, where this is the most common female malignancy with almost 100,000 new cases each year. Apoptosis must be considered as a safe mechanism that controls the integrity of the cell erasing abnormal clones and it is likely that failure of apoptosis constitutes a key factor responsible for tumor formation, progression and resistance to drugs. The Fas gene plays a key role in regulation of apoptotic cell death and corruption of this signaling pathway has been shown to participate in immune escape and tumorgenesis. STUDY DESIGN: A single-nucleotide polymorphism at -670 of Fas gene promoter (A/G) was examined in a total of 400 blood samples from normal healthy women and cervical cancer patients, using polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) technique. RESULTS: Significant association was observed for AG (OR = 3.0, 95% CI = (1.68-5.09, p < 0.001) and combined AG+GG (OR = 2.54, 95% CI = 1.47-4.40, p < 0.001) genotype with risk of cervical cancer. Heterozygous genotype (AG) in SCC showed a highly significant association with risk of cervical cancer (OR = 2.57, 95% CI = 1.47-4.50 p <0.001). Similarly, combined AG+GG genotype had a 2.25-fold risk for SCC patients (OR = 2.25, 95% CI = 1.30-3.90, p < 0.001). There was high increase risk of cervical cancer in passive smokers with AG and combined (AG+GG) genotypes (OR = 4.6, 95% CI = 2.07-10.32, p < 0.001 - OR = 4.9, 95% CI = 2.20-10.32, p < 0.001), respectively. CONCLUSION: This is the first study to provide evidence for the association of a Fas -670 (A/G) gene polymorphism with the risk of cervical cancer in a North Indian population.     

ESR1 promoter polymorphism is not associated with nonsyndromic cryptorchidism

The ESR1 promoter microsatellite (TA)n was reported as a potential functional polymorphism. In a case-control study, we were unable to demonstrate any association between (TA)n and nonsyndromic cryptorchidism in Italian and Spanish study populations.     

The IL-10 -1082G polymorphism is associated with clearance of HPV infection

The role of cytokines in protecting against human papillomavirus (HPV) and HPV-associated disease is not fully understood. We compared the frequency of the interleukin (IL)-10 polymorphism (G allele) at position --1082 and the distribution of GG/GA/AA genotypes among 116 HPV-positive women, grouped according to their cervical cytological profiles, with 119 HPV-negative controls with normal smears. No difference was observed in genotype frequency between the groups. Among women in the HPV-positive, smear-normal group, who were re-tested for HPV after 12 months, there was a significant inverse association between presence of at least one variant G allele (high activity) and HPV persistence (OR per G allele = 0.082 [95% CI 0.009-0.73], P= 0.001; after controlling for ethnicity). This association remained significant after controlling for age, smoking and hormonal contraception (OR = 0.028 [95% CI 0.001-0.66], P= 0.001). This preliminary study suggests that higher levels of IL-10 may prevent cervical neoplasia through their role in eliminating HPV.     

PROGINS receptor gene polymorphism is associated with endometriosis

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.     

The MDM2 promoter T309G polymorphism was associated with preeclampsia susceptibility

Purpose

Preeclampsia (PE) is a hypertensive disorder of pregnancy in which abnormal proliferation and apoptosis of placenta trophoblast has a pivotal role in its pathophysiology. The aim of the current study was to examine the association between Mouse Double Minute 2 (MDM2) T309G and 40 bp insertion/deletion (I/D) polymorphisms and PE risk.

Methods

A case-control study was conducted on 208 PE women and 164 healthy pregnant women matching age, sex, and ethnicity. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and PCR methods were used for genotyping.

Results

The MDM2 309GG genotype was associated with PE, and this genotype was found to be a risk factor for PE. There was no association between the MDM2 I/D polymorphism and PE. The haplotype-based association analysis revealed no association between MDM2 T309G and 40 bp I/D polymorphisms and PE. The frequency of TT-DD and GG-DD combined genotypes were significantly higher in PE women with marginal P values (P = 0.046).

Conclusions

The MDM2 309GG genotype was associated with higher risk of PE. The TT-DD and GG-DD combined genotypes were higher in PE women.

     

A fetal cyclooxygenase-2 gene polymorphism is associated with placental malperfusion.

Prostaglandin levels vary during pregnancy, mostly under the control of the inducible enzyme cyclooxygenase-2 (COX-2). The expression of COX-2 has been associated with ischemic events in the heart and brain, but its direct effect on human placental perfusion has not been previously examined. The purpose of this study was to investigate whether a functional polymorphism in the COX-2 gene that controls enzyme expression levels is associated with placental histopathologic lesions. Maternal and neonatal DNA from twin gestations were analyzed by a polymerase chain reaction-based assay for a single G to C nucleotide polymorphism at position -765 in the COX-2 gene promoter. Placental histopathology was evaluated in 6 major categories: meconium, malperfusion, inflammation, umbilical cord problems, villitis, and thrombosis. There was no significant association between placental histopathologic findings and polymorphisms of the COX-2 gene in the mother. In the fetus, carriage of the COX-2 C allele, which is correlated with decreased COX-2 gene expression, was negatively associated with lesions of placental ischemia/malperfusion (P = 0.02). Placental ischemic lesions were positively associated with intrauterine growth restriction (IUGR; P < 0.001). No other group of histopathologic lesions was associated with fetal polymorphisms in the COX-2 gene or with IUGR. Thus, a fetal polymorphism in the COX-2 gene influences the occurrence of placental malperfusion and ischemia, which may be of sufficient severity to promote or allow the development of IUGR.