Increased mood symptoms in postmenopausal women related to the polymorphism rs743572 of the CYP17 A1 gene

Background: Menopausal and depressive symptoms are highly prevalent after the menopause; but may vary from one population to another and genetics play a key role.

Objective: To analyze the intensity of these symptoms in relation to the genetic variants of the rs743572 polymorphism of the CYP17 A1 gene in postmenopausal women.

Methods: DNA was extracted from the whole blood of 168 natural postmenopausal women (40–65 years) and tested for the rs743572 polymorphism of the CYP17 A1 gene. Intensity of menopausal (Menopause Rating Scale, MRS) and depressive symptoms (Hospital Anxiety and Depressive Scale, HADS) were correlated to polymorphism genotypes.

Results: Women with the GG genotype of the rs743572 polymorphism displayed significantly higher scores for the MRS (items 5 and 6 [irritability and anxiety] and the psychological subscale) and the HADS (total and subscales).

Conclusion: The intensity of menopausal symptoms related to mood was found higher among postmenopausal women presenting the GG genotype of the rs743572 polymorphism of the CYP17 A1 gene. There is a need for more research in this regard.     

CYP17 genetic polymorphism in patients with endometrial hyperplasia and cancer

Abstract.   Aban M, Arslan M, Tok E, Tekes S, Budak T, Altintas A. CYP17 genetic polymorphism in patients with endometrial hyperplasia and cancer. Int J Gynecol Cancer 2006; 16(Suppl. 1): 448–451.
We investigated the association of CYP17 gene polymorphism with the risk of having endometrial cancer and a well-known precursor of it, endometrial hyperplasia. Group A (control group) consisted of 35 patients who had histologically proven normal endometrium. Group B and C consisted of 18 and 30 patients who had endometrial hyperplasia with and without atypia, respectively. Group D consisted of 57 patients who had endometrial cancer. Venous blood samples were collected from patients in groups, and polymerase chain reaction was performed to determine the CYP17 gene polymorphism. Significant increase of A1/A1 and a decrease of A1/A2 genotype frequencies have been determined in patients with endometrial cancer and with atypical endometrial hyperplasia. No significant differences were found between groups in the frequency of A2/A2 genotype. There was no significant difference between the groups in the meaning of allele distributions. CYP17 polymorphism had correlation with endometrial atypia and cancer. Related effects of different types of CYP17 gene variants on the progression of hyperplastic endometrial cells into carcinoma should be evaluated in further studies. Progress in this area would help us modulate preventive treatments used in those actual high–risk group patients.     

Lack of association between endometriosis and the CYP17 MspA1 polymorphism in UK and Japanese populations

Endometriosis is a complex trait, which means that multiple susceptibility genes interact with one another and the environment to produce the phenotype. One of the genes previously implicated in the disease is CYP17; this encodes the enzyme P450c17α, which plays a vital role in steroid biosynthesis in the ovary. The presence of a single nucleotide polymorphism (T→C) in the 5′-promoter region of the gene creates a new recognition site for the restriction enzyme MspA1 producing a mutant allele (A₂), which affects circulating estrogen levels. In this study, we compared the frequency of the CYP17 MspA1 polymorphism in two different ethnic populations. DNA was obtained from (1) 94 women with revised American Fertility Society (rAFS) stage III–IV endometriosis and 97 male blood donors in the UK, and (2) 130 women with rAFS stage III–IV endometriosis and 179 female newborn infants in Japan. No significant differences in allele or genotype frequencies were seen in either population. The genotype distribution in the UK population was 33/94 [35.1%] (cases) and 39/97 [40.2%] (controls) for A₁A₁ (homozygous wild-type); 43/94 [45.7%] (cases) and 44/97 [45.4%] (controls) for A₁A₂; and 18/94 [19.1%] (cases) and 14/97 [14.4%] (controls) for A₂A₂. The genotype distribution in the Japanese population was 31/130 [23.9%] (cases) and 57/179 [31.8%] (controls) for A₁A₁; 73/130 [56.2%] (cases) and 89/179 [49.7%] (controls) for A₁A₂; and 26/130 [20.0%] (cases) and 33/179 [18.4%] (controls) for A₂A₂. The CYP17 MspA1 polymorphism is probably not associated with endometriosis in either the UK or the Japanese population.     

Estrogen receptor alpha dinucleotide repeat and cytochrome P450c17alpha gene polymorphisms are associated with susceptibility to endometriosis

OBJECTIVE: To investigate the association of endometriosis with estrogen receptor alpha (ER alpha) and cytochrome P450c17alpha (CYP17) gene polymorphisms in light of the fact that estrogen plays a role in the pathogenesis of endometriosis and the CYP17 enzyme is involved with estrogen biosynthesis. DESIGN: Prospective study. SETTING: Genetics and gynecology units. PATIENT(S): All patients were divided into two groups: group 1, women with endometriosis (n = 119); group 2, normal controls (n = 108). INTERVENTION(S): A dinucleotide (thymine-adenine [TA]) repeat polymorphism lying upstream of the ER alpha gene and A1/A2 polymorphism of the CYP17 gene were amplified by polymerase chain reaction, enzyme restriction, and electrophoresis. MAIN OUTCOME MEASURE(S): The ER genotypes were classified into A through T (TA repeats, 10-29). The CYP17 genotypes included indigestible (A1 homozygote), heterozygote, and digestible (A2 homozygote). We compared these polymorphism distributions in both groups. RESULT(S): The percentage of genotypes D-G (TA, 13-16) in both groups were 10.5%, 29.4%, 13.0%, and 11.3% in group 1 and 7.9%, 16.7%, 19.9%, and 17.6% in group 2. The genotype E (14 TA repeats) is associated with a higher risk of endometriosis. Proportions of A1 homozygote/heterozygote/A2 homozygote for CYP17 were 26.1%/46.2%/27.7% for group 1 and 14.8%/44.5%/40.7% for group 2, respectively. The A1 homozygote and allele were associated with a higher susceptibility of endometriosis. CONCLUSION(S): ER alpha* 14 TA repeats and the CYP17* A1 allele are associated with an increased risk of endometriosis. Both polymorphisms are useful markers for predicting endometriosis susceptibility.     

人CYP17基因启动子5'上游-34碱基处T→C突变与复发性流产

目的:探讨人类CYP17基因启动子5'上游-34碱基处T→C突变与复发性流产的关系,以期为预防和治疗该病易感人群提供新思路。方法:采用聚合酶链式反应-限制性片段长度多态性(PCR-RFLP)方法,针对CYP17基因启动子5'上游-34碱基处的多态性,检测96例患有原因不明复发性流产患者(病例组)和102例有生育史的健康女性(对照组),并用非变性聚丙烯酰胺凝胶电泳和银染法进一步验证,且采用测序方法证实实验结果。结果:病例组和对照组CYP17基因启动子5'上游-34碱基处T和C的分布差异有统计学意义(χ2=8.188,P0.05),CYP17基因各基因型分布差异有统计学意义(χ2=10.096,P0.05)。杂合突变(T/C)基因型和纯合突变(C/C)基因型患复发性流产的危险度较野生(T/T)基因型分别提高了0.424和0.271倍。结论:人CYP17基因启动子5'上游-34碱基处T→C突变与中国东北地区人群复发性流产有关,C等位基因可能是复发性流产的遗传易感因素之一。     

CYP1A1 gene polymorphism and risk of endometrial hyperplasia and endometrial carcinoma

The cytochrome P4501A1 (CYP1A1) is involved in the metabolism of environmental carcinogens and estrogen. We hypothesized that CYP1A1 genetic polymorphism may be a susceptibility factor for endometrial hyperplasia (EH) and endometrial carcinoma (ECa). We therefore evaluated this hypothesis in patients with EH and ECa and control subjects using allele-specific polymerase chain reaction-based method in a Turkish population. The patients with CYP1A1 Ile/Val genotype had a fivefold higher risk of having EH than those with Ile/Ile. In contrast, a higher frequency of any Val genotype (Ile/Val and Val/Val) was found in patients with EH, indicating that persons carrying any Val allele are at increased risk for developing EH. In the ECa group, patients were also more likely to have CYP1A1 Ile/Val allele, with an adjusted odds ratio of 3.0. Moreover, there was a statistically significant increase in relative risk association with any Val genotype between patients and controls, suggesting that individuals carrying any Val genotype are at increased risk for developing ECa. We concluded that variant alleles of the CYP1A1 gene might be associated with EH and ECa susceptibility. Further studies with a large sample size should be considered to address issues of interactions between CYP1A1 and other risk factors.     

The Glu331del mutation in the CYP17A1 gene causes atypical congenital adrenal hyperplasia in a 46,XX female

17α-Hydroxylase deficiency is an uncommon type of congenital adrenal hyperplasia (CAH) caused by mutations in the CYP17A1 gene encoding both 17α-hydroxylase and 17,20-lyase, essential for sex steroids production. Main clinical features include lack of pubertal development, hypertension, and hypokalemia. We report the first case of a 46,XX female homozygote for the p.Glu331del mutation in the CYP17A1 gene showing an atypical clinical presentation. She was evaluated the first time for primary amenorrhea and delayed puberty in the presence of low levels of androgens, 17β-estradiol, serum cortisol, and high levels of progesterone and gonadotropins. After puberty, the patient did not show hypocortisolism and/or hypertension. She started estrogen therapy for pubertal induction, followed by ethinylestradiol/gestodene with clinical and biochemical stability during the follow-up period. At the age of 40 years, she developed hypokalemia and clinical signs of hypocortisolism. Oral corticosteroid treatment was started showing a prompt clinical improvement. Modeling analysis predicted the main outcome of the E331 deletion to impair cytochrome b5 binding, according to a major effect on the enzyme’s lyase activity. These data broaden the molecular and clinical spectrum of CAH caused by 17α-hydroxylase deficiency and adds to current genotype–phenotype correlations.     

CYP1A1基因多态性与子宫内膜癌易感性关系的研究

目的:研究细胞色素P4501A1(CYP1A1)基因MspⅠ位点多态性与子宫内膜癌发生的关系。方法:用PCR-RFLP法检测174例子宫内膜腺癌患者和114例对照者CYP1A1基因MspI位点多态性。结果:合并杂合型T/C和突变型C/C后与野生型T/T比较,两组差异有统计学意义(P=0.047,OR=1.635)。在绝经年龄<50岁的病例组,T和C等位基因频率与对照组相比差异有统计学意义(P=0.032);初潮年龄≤14岁,等位基因频率在两组中差异有统计学意义(P=0.036);经BMI分层分析,未发现MspI多态性与子宫内膜癌有关。结论:CYP1A1基因MspI多态中突变等位基因C可显著增加子宫内膜癌的发病风险,且绝经年龄越早、初潮年龄越早携带等位基因C的个体越易感子宫内膜癌。     

Insertion-deletion polymorphism in the gene for angiotensin-converting enzyme is associated with obstetric cholestasis but not with preeclampsia

OBJECTIVE: Our purpose was to investigate the contribution of angiotensin-converting enzyme insertion-deletion polymorphism in the development of obstetric complications. STUDY DESIGN: In a retrospective case-control study, angiotensin-converting enzyme insertion-deletion polymorphism was investigated in a control group of healthy women (n = 115) and in a group of women diagnosed with preeclampsia (n = 133) and obstetric cholestasis (n = 57). Polymerase chain reaction detection of insertion-deletion polymorphism was used to determine the presence of the two angiotensin-converting enzyme alleles in the groups; the frequencies in the general population in our area are presented for comparison. RESULTS: The frequency of the D allele was 43.9% among women with obstetric cholestasis and 27% among healthy fertile women, which is close to the rate in the general population in our area (28%). The odds ratio for obstetric cholestasis associated with the DD genotype was 2.12 (95% CI, 1.08-4.12) compared with the pooled II and ID genotypes (P = .03). Neither the ID genotype distributions nor the allele frequencies differed significantly between preeclamptic and normotensive pregnancies (P = .36). CONCLUSION: The present data indicate that the DD genotype is a genetic marker associated with an elevated risk of obstetric cholestasis, but this polymorphism of the angiotensin-converting enzyme gene is unlikely to play any significant role in preeclampsia.     

Evidence for association of the rs605059 polymorphism of HSD17B1 gene with recurrent spontaneous abortions

Objective: To investigate whether the missense rs605059 polymorphism of HSD17B1 gene, which is expressed mainly in the placenta, is associated with recurrent spontaneous abortions (RSA).

Methods: This study group consisted of 138 women with three or more unexplained spontaneous abortions, before the 20th week of gestation, with the same partner, while 140 healthy women served as controls. To genotype the individuals, we used the polymerase chain reaction-restriction fragment length polymorphism method.

Results: The genotyping of the rs605059 polymorphism revealed the frequencies 0.22, 0.45 and 0.33, for AA, GA and GG genotypes, respectively, for the patient group and 0.37, 0.41 and 0.22, respectively, for the control group. The A allele frequencies were 0.44 and 0.57 for the patient and control group, respectively, and the G allele frequencies were 0.56 and 0.43 for the patient and control group, respectively. Statistical analysis of the results indicated the existence of significant differences in genotype and allele frequencies between the two groups.

Conclusion: The rs605059 polymorphism of the HSD17B1 gene is associated with increased risk of RSA in our Caucasian Greek population. Thus it could be used as a prognostic genetic marker for RSA.     

Epistasis between FSHR and CYP19A1 polymorphisms is associated with premature ovarian failure

Follicle-stimulating hormone secreted from the pituitary gland plays a key role in human reproduction and regulates estrogen production by acting on the regulatory region of CYP19A1. We observed a significant association between premature ovarian failure and the combined genetic effect of single nucleotide polymorphism (SNP) rs4646 (CA+AA) in the 3' untranslated region of CYP19A1 and the missense FSHR SNP rs6166 (AG+GG) genotype (odds ratio 5.42, 95% confidence interval 1.96-14.98), and we identified a significant association between premature ovarian failure and the combined genetic effect of the FSHR missense SNP rs6166 (AA) and the rs4646-rs10046 haplotype (C-T)+(C-C) (odds ratio 5.47, 95% confidence interval 2.03-14.75), suggesting that two biochemical pathways may be involved in the regulation of folliculogenesis.     

Insulin gene variable number of tandem repeats regulatory polymorphism is not associated with hyperandrogenism in Spanish women

OBJECTIVE: To determine if the insulin gene variable number of tandem repeats (VNTR) regulatory polymorphism is associated with hyperandrogenism in a population of Spanish women. DESIGN: Controlled clinical study. SETTING: Tertiary institutional hospital. PATIENT(S): Ninety-six hyperandrogenic patients and 38 healthy control women. INTERVENTION(S): Whole blood and serum samples were collected during the follicular phase of the menstrual cycle. MAIN OUTCOME MEASURE(S): Insulin gene VNTR regulatory polymorphism genotypes (classes I/I, I/III, and III/III alleles) and serum androgen levels. Insulin resistance was estimated from fasting glucose and insulin levels by using the homeostatic model assessment. RESULT(S): The frequencies of VNTR genotypes were 45.5%, 43.3%, and 11.2% for I/I, I/III, and III/III alleles considering patients and controls as a whole. These frequencies were not statistically different in controls (47.4%, 34.2%, and 18.4%) and in patients (44.8%, 46.9%, and 8.3%). CONCLUSION(S): Hyperandrogenism and the insulin gene VNTR regulatory polymorphism are not associated in Spanish women.     

17-hydroxysteroid dehydrogenase type 5 gene polymorphism (-71A/G HSD17B5 SNP) and treatment with oral contraceptive pills in PCOS women without metabolic comorbidities

We studied (1) the effects of oral contraceptive pills (OCPs) on hirsutism, hormonal and metabolic variables in 49 polycystic ovary syndrome patients without metabolic comorbidities and (2) the effect of 17-hydroxysteroid dehydrogenase type 5 gene polymorphism (-71A/G HSD17B5 SNP) on the response to OCP treatment. Mean age was 21.9 ± 6.5 years. Patients received monophasic OCP (20 μg ethinyl estradiol plus 75 μg gestodene), 21/28 days per cycle, during 6 months; 32 patients with severe hirsutism also received spironolactone 100 mg. The frequencies of HSD17B5 genotypes were: AA?=?0.49 (55.1%), AG?=?0.42 (30.6%) and GG?=?0.09 (14.3%). After 6 months, body mass index and waist circumference remained unchanged regardless of the presence of allele G. A slight reduction (p?<?0.05) was noted in systolic blood pressure (p?<?0.05) and luteinizing hormone levels, whereas a slight increase (p?<?0.05) was noted in lipids. Total testosterone and hirsutism score declined, while sex hormone binding globulin increased after OCP treatment (p?<?0.05). None of these changes were associated with genotype. Insulin and homeostasis model assessment remained unchanged after treatment and did not vary according to the presence of allele G. OCP seems to ameliorate androgenic symptoms without compromising metabolic parameters. The -71A/G SNP of HSD17B5 gene did not contribute to the improvements observed.     

The relationship between single nucleotide polymorphisms in estrogen-metabolizing genes CYP1A1,CYP17,COMT and estrogen receptor alpha and the risk of endometrial adenocarcinoma among the Chinese women

<正>Objective:To explore whether polymorphisms of the genes responsible for catechol estrogen(CE)formation via estrogen biosynthesis(CYP17)and hydroxylation (CYP1A1)and CE inactivation(COMT)and ERa are associated with an elevated risk for en- dometrial adenocarcinoma in Chinese women.Methods:A multigenic case-control study was conducted,eighty-seven endometrial adenocarcinoma patients and ninety controls were recrui- ted.PCR-RFLP assays were used to determine the genotypes of estrogen-metabolizing genes and ERa gene.Results:The endometrial adenocarcinoma risk associated with individual susceptibili- ty genotypes varied among the six polymorphic sites and was the highest for CYP17,followed by CYP1 A1 Ile-Val,CYP1A1 MspI,COMT,ERa XhaI and ERa PvuII.Multivariate logistic regres- sion showed the CYP1A1 MspI genotype was the most significant determinant for endometrial adenocarcinoma development and was associated with a 3.61 fold increase in risk(95% confi- dence interval,1.73～7.55).Furthermore,a trend of increasing risk for developing endometrial adenocarcinoma was found in women harboring higher numbers of high-risk genotypes.Conclu- sion:The CYP1A1,CYP17 and ERa XbaI genotypes are related to the susceptibility of endome- trial adenocarcinoma,they may be useful markers for predicting endometrial adenocarcinoma susceptibility.The allele encoding for low acticity COMT,ERa PvuII may not be a genetic risk factor for endometrial adenocarcinoma.     

The vitamin D receptor gene BsmI polymorphism is not associated with anthropometric and biochemical parameters describing metabolic syndrome in postmenopausal women

Aim. Vitamin D could have a direct effect on adipocyte differentiation and metabolism and might be involved in glucose regulation of insulin secretion. In recent years several polymorphisms in the gene encoding the vitamin D receptor (VDR), which are potent to alter the activity of VDR protein, have been described. The present study aimed to investigate the prevalence of the VDR BsmI polymorphism and its association with anthropometric and biochemical features of metabolic syndrome in postmenopausal women.

Materials and methods. We studied 351 randomly selected healthy postmenopausal women, with mean age of 55.43 ± 2.75 years and mean body mass index (BMI) of 27.5 ± 4.78 kg/m², to evaluate the frequency of BsmI polymorphism (by restriction fragment length polymorphism–polymerase chain reaction) in the VDR gene and to find out whether there is an association between this polymorphism and BMI, total fat volume and visceral fat (as determined by total body dual-energy X-ray absorptiometry), blood pressure, lipid profile (total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol, triglycerides) glucose and fasting insulin in the whole group, as well as subgroups of obese and non-obese women.

Results. The prevalence of BsmI genotypes in the study group was 51.0% Bb, 37.3% bb and 11.7% BB. Genotype distribution did not differ from that expected under Hardy–Weinberg equilibrium conditions (χ² = 2.95, p = 0.22). Apart from LDL-C levels (F = 3.46, p = 0.032), there were no significant differences in anthropometric or metabolic parameters between genotypes.

Conclusions. The BsmI polymorphism in the VDR gene does not seem to predispose to obesity and insulin resistance, but the BB genotype is connected with an unfavorable lipid profile.     

Risk of premature ovarian failure is associated to the PvuII polymorphism at estrogen receptor gene ESR1

Purpose

Estrogen plays an important role in the human reproductive system and it action is mediated mainly by two specific receptors: α (ERα) and β (ERβ). There were described polymorphic variants in ESR1 and ESR2 genes and studies showed controversial results regarding their association with premature ovarian failure. We aimed to determine the prevalence of ESR1 and ESR2 polymorphisms in Brazilian patients and controls. After associate the polymorphisms with premature ovarian failure (POF).

Methods

Genetic association study was performed with 70 women with POF and 73 normally menopaused controls. Detection of ESR1 (PvuII/and XbaI) and ESR2 (AluI and RsaI) gene polymorphisms were performed using TaqMan PCR. The single-nucleotide polymorphism (SNPs) and haplotype effects were analyzed by multivariate logistic regression and haplotype analysis and a p-value < 0.05 was considered significant.

Results

Individual SNP analysis revealed that PvuII polymorphism was statistically associated with POF (p = 0.034) under a recessive model. Regarding XbaI, AluI and RsaI SNPs, no statistical difference was observed between POF group and controls (p = 0.575, p = 0.258 and p = 0.483, respectively). Combined genotypes of ESR1 and ESR2 polymorphisms did not identify a risk haplotype associated with POF.

Conclusion

In Brazilian population evaluated results have demonstrated that the genetic variation in ESR1 gene (PvuII polymorphism) is associated to POF risk.