Association of inhibin α gene promoter polymorphisms with risk of idiopathic primary ovarian insufficiency in Korean women

ObjectiveThe aim of this study was to investigate whether two polymorphisms in the promoter region of inhibin alpha (INHA) are associated with risk of idiopathic primary ovarian insufficiency (POI) in Korean women, which is a controversial topic.Study designWe genotyped the INHA polymorphisms c.-16C > T (rs35118453) and c.-124A > G (rs11893842) of 136 POI patients and 225 controls in Korean women by polymerase chain reaction and restriction fragment length polymorphism analysis. We then compared differences in genotype and allele frequencies (AF) of the polymorphisms between the two groups to determine odds ratios (OR) and 95% confidence intervals (CI) as measures of the strength of association between genotype and POI.ResultsThere were no significant differences in genotype or AF of the polymorphisms between the POI patients and controls. Haplotype analysis revealed that the T–G haplotype of the two variant alleles was more frequent in POI patients than in the controls (OR = 1.630, 95% CI = 1.081–2.457). Combination genotype analysis showed that the CT + TT/GG genotype frequency was higher in POI patients than in the controls (OR = 2.414, 95% CI = 1.190–4.895).ConclusionsWe provide evidence to suggest that when the two variant alleles are combined, the c.-16C > T and c.-124A > G polymorphisms are associated with increased POI risk in Korean women. We postulate that interactions between the INHA polymorphisms may affect POI risk.     

Serum anti-Müllerian hormone expression in women with premature ovarian failure

BACKGROUND: Premature ovarian failure (POF) is generally irreversible. However, developing follicles up to the antral stage are reported in POF and anti-Müllerian hormone (AMH) might be a good indicator of follicular presence. This study analysed serum AMH, ovarian histology and AMH immunoexpression in POF patients. METHODS: A cross-sectional study of 48 POF patients in an Endocrinology Department setting. Patients had an ovarian biopsy simultaneously with serum AMH sampling and/or ovarian AMH immunostaining. RESULTS: Mean serum AMH was 1.04 +/- 1.66 ng/ml. Serum AMH was significantly higher in women with 15 or more follicles at ovarian histology (P = 0.001). Comparison of ovarian AMH immunostaining from POF patients and 10 normal controls revealed a normal AMH expression in POF pre-antral follicles, but a decreased expression at the early antral stages. Serum AMH was undetectable in 77% of the patients with 0-5 AMH immunopositive follicles and detectable in 100% of the patients with more than 15 AMH immunopositive follicles. CONCLUSIONS: AMH levels in POF patients could identify women with persistent follicles. The decrease of AMH immunoexpression in POF antral follicles could suggest a defect of antral development.     

Transforming growth factor-β1 gene polymorphisms in Korean women with endometriosis

Citation Lee HJ, Kim H, Ku S‐Y, Kim SH, Kim JG. Transforming growth factor‐β1 gene polymorphisms in Korean women with endometriosis. Am J Reprod Immunol 2011; 66: 428–434 Problem To investigate the association between endometriosis, transforming growth factor‐β1 (TGFB1) gene polymorphisms, and serum TGF‐β1 levels in Korean women. Method of study The ?509C/T, 868T/C, 913G/C and 979G/A polymorphisms of the TGFB1 gene were analyzed in women with (n = 131) and without (n = 107) endometriosis using restriction fragment length polymorphism (RFLP) analysis. Serum TGF‐β1 levels were measured by enzyme‐linked immunosorbent assay (ELISA). Results The 913G/C and 979G/A polymorphisms were not observed in the study participants. The genotype and allele distribution of the ?509C/T and 868T/C polymorphisms in endometriosis were similar to those in controls. However, the ?509T/868C (TC) haplotype allele was observed 4.55 times more frequently in early‐stage endometriosis than in other haplotype alleles. Serum TGF‐β1 levels were significantly higher in endometriosis than in controls. The single and haplotype genotype of ?509C/T and 868T/C polymorphisms were not related with serum TGF‐β1 levels. Conclusion The TC haplotype allele of TGFB1?509C/T and 868T/C polymorphisms may be associated with early‐stage endometriosis in Korean women.     

Association of nitric oxide synthase gene polymorphisms (−786T>C, 4a4b, 894G>T) with primary ovarian insufficiency in Korean women

ObjectivesThe aim of our study was to investigate whether the endothelial nitric oxide synthase (eNOS) gene polymorphisms ?786T>C, 4a4b, and 894G>T that affect nitric oxide (NO) generation confer a risk for primary ovarian insufficiency (POI) in Korean women.Study designWe genotyped 136 POI patients and 236 controls among Korean women for the three single nucleotide polymorphism sites with PCR-RFLP analysis. Differences in the eNOS ?786T>C (rs2070744), 4a4b (rs61722009), and 894G>T (rs1799983) genotype frequencies between patients and controls were compared, and odds ratios and 95% confidence intervals were determined as a measure of the strength of the association between the genotypes and POI.ResultsThe POI patients had significantly decreased frequencies of the eNOS 894GT and ?786TT/894GT genotypes (P = 0.025 and 0.027, respectively). However, the significant association between these eNOS polymorphisms and POI disappeared after adjustment for multiple comparisons (adjusted P = 0.075 and 0.081, respectively). The eNOS ?786T/894G haplotype is more frequent in patients than controls (P = 0.030), whereas the ?786T/894T haplotype was less frequent in patients (P = 0.031). The associations between ?786/894 haplotypes and POI were confirmed by permutation tests. We did not find associations between the eNOS ?786T>C or 4a4b polymorphisms and POI.ConclusionsOur data suggest that the eNOS ?786T/894T haplotype is associated with a decreased POI risk, and we postulate that the eNOS ?786T/894T haplotype may confer less risk on POI occurrence by reducing pathologically increased NO generation by eNOS in POI. Further study is warranted to elucidate the effect of the eNOS 894G>T polymorphism and POI occurrence.     

Lack of association of polymorphisms of the lymphotoxin α gene with myocardial infarction in Japanese

Vascular inflammation plays an important role in the development of myocardial infarction (MI). Lymphotoxin (LTA) is a cytokine with multiple functions in regulation of the immune system and inflammatory reactions. The aim of this study was to examine whether polymorphisms of the LTA gene are associated with the risk of MI in Japanese men and women. A case-control association study was performed for the 252AG and 804CA polymorphisms of the LTA gene and the prevalence of MI. The study population comprised 3,689 unrelated Japanese individuals (2,486 men, 1,203 women), including 1891 patients with MI (1,493 men, 398 women) and 1798 control subjects (993 men, 805 women). Among the control subjects 257 individuals (108 men, 149 women) who had none of the conventional risk factors for coronary artery disease (CAD) were defined as low-risk controls. Genotypes for the two polymorphisms were determined with a fluorescence-based allele-specific DNA primer assay system. Among all study subjects the 252AG and 804CA polymorphisms exhibited linkage disequilibrium. No association of either polymorphism with MI was detected in men or in women in comparisons with total control or low-risk control subjects. However, each of the two polymorphisms was associated with the prevalence of type 2 diabetes mellitus both in men with MI and in those without MI in a recessive genetic model. No association was detected between the polymorphisms and other conventional risk factors for CAD. The LTA gene thus does not appear to be a susceptibility locus for MI in Japanese men or women, although it might affect susceptibility to type 2 diabetes in Japanese men.Abbreviations BMI Body mass index - CAD Coronary artery disease - HLA Human leukocyte antigen - LTA Lymphotoxin - MI Myocardial infarction - PCR Polymerase chain reaction - TNF Tumor necrosis factor     

Association of tumor necrosis factor-�� (TNF-��) promoter polymorphisms with overweight/obesity in a Korean population

Objective

Obesity is characterized by the activation of an inflammatory process leading to an increase in proinflammatory cytokines and adipokines. This study was designed to investigate the genetic association between tumor necrosis factor-?? (TNF-??) polymorphisms and the risk of obesity in the Korean population.

Methods

Three single nucleotide polymorphisms [G-238A (rs361525), C-857T (rs1799724), and C-863A (rs1800630)] in the promoter region of TNF-?? gene were analyzed in 123 control [body mass index (BMI) between 18 and 23] and 208 overweight/obese (BMI????23) subjects.

Results

The mean values of BMI in the control and overweight/obese groups were 21.1?±?1.4 and 25.4?±?1.8, respectively. Of the three SNPs, G-238A presented a significant association with overweight/obesity in the codominant model; the frequency of the G/G genotype in the overweight/obese group was 9.3% higher than that in the control group (P?=?0.0046). When control and overweight/obesity subjects were combined together and analyzed, the level of high-density lipoprotein (HDL) was significantly higher in the C-857T C/C type SNP (P?Conclusions The results of this study suggest that the G allele of G-238A in TNF-?? gene may be a risk factor for overweight/obesity in the Korean population and that the C allele of C-857T may be an protective factor in relation to the HDL level in the general Korean population.     

Interleukin-18 promoter polymorphisms in patients with Behçet's disease

Beh?et's disease (BD) is an idiopathic systemic inflammatory disease and is considered to be a T helper 1 (Th1) type cytokine driven disorder. Moreover, levels of interleukin-18 (IL-18), a pivotal mediator of Th1 cytokine response, have been reported to be upregulated in BD. Therefore, we investigated the distribution of IL-18 promoter -607 C/A and -137 G/C polymorphisms in 103 BD patients (mean age 41.0 years; 48 male, 55 female) using allele-specific-polymerase chain reaction. As compared with healthy control subjects, BD patients had a significantly higher frequency of the -607 CC genotype (42.7% vs 23.3%, odds ratio [OR] = 2.455, 95% confidence interval [CI] = 1.350-4.461, p(c) = 0.021) and a higher frequency of the -607 C allele (60.7% vs 48.1%, OR = 1.668, 95% CI = 1.129-2.464, p = 0.0101). Haplotype analysis showed that BD patients had significantly less -607A/-137G haplotype (27.3% vs 44.2%, OR = 0.469, 95% CI = 0.268-0.820, p(c) = 0.032) and -607A/-137G haplotype homozygote (5.8% vs 20.4%, OR = 0.242, 95% CI = 0.096-0.612, p(c) = 0.014) than control subjects. In addition, the frequency of -607C/-137G haplotype homozygote was significantly higher in BD patients than control subjects (48.5% vs 20.4%, OR = 3.684, 95% CI = 1.997-6.791, p(c) = 0.0014). Although there were no associations between the polymorphisms and clinical manifestations or severity, patients with the -607 CC genotype or -607C/-137G haplotype homozygote showed significantly earlier symptom development (p = 0.034 by ANOVA; p = 0.009 by t-test, respectively) than those with other genotypes or diplotypes. These results suggest that the IL-18 promoter gene is a candidate susceptibility gene in BD patients.     

IL-1β, IL-6 promoter,TNF-α promoter and IL-1RA gene polymorphisms and the risk of preterm delivery due to preterm premature rupture of membranes in a population of Polish women

Introduction

Our previous study revealed that anti-inflammatory cytokine gene polymorphisms increase the risk of spontaneous preterm delivery (PD) in a population of Polish women. Different genetic background of PD due to preterm premature rupture of membranes (pPROM) than PD without pPROM has been suggested. The aim of this study was to examine the relationship between the maternal carriage of polymorphic alleles of the following genes: interleukin 1β(IL-1β [+3953C>T]), interleukin 6 promoter (IL-6 [−174G>C]), tumour necrosis factor promoter (TNF-α [–308G>A]) and interleukin 1 receptor antagonist (IL-1RN) and the risk of PD caused exclusively by pPROM in a population of Polish women.

Material and methods

A case-control study. 95 Caucasian women were examined including 32 cases and 63 controls. Case subjects experienced a delivery at less than 36 weeks and 6 days of gestation due exclusively to pPROM while control subjects gave birth at term. Polymorphisms were determined by polymerase chain reaction-restriction fragment length polymorphism analysis (PCR-RFLP).

Results

No statistically significant relationship between polymorphisms of examined genes and risk of PD due to pPROM in a population of Polish women was found: OR = 0.84 (95% CI: 0.34-2.01) for IL-1β, OR = 0.77 (95% CI: 0.27-2.13) for IL-6, OR = 0.72 (95% CI: 0.26-1.90) for TNF-α and OR = 1.74 (95% CI: 0.66-4.64) for IL-1RN.

Conclusions

Maternal carriage of polymorphic alleles of IL-1β, IL-6 promoter, TNF-α promoter and IL-1RA seems to have no impact on the risk of PD due to pPROM in the population of Polish women.The genetic contribution and pathomechanism of PD related to pPROM seems to differ from those of spontaneous PD without pPROM.     

45-Year-old female with propionic acidemia, renal failure, and premature ovarian failure; late complications of propionic acidemia?

We describe a 45-year-old patient who was diagnosed with propionic acidemia in infancy, who experienced an unstable first two years of life but who eventually had a good developmental outcome. She developed severe renal failure requiring renal transplantation in her forties and premature ovarian failure. Renal failure and premature ovarian failure have not previously been associated with propionic acidemia. We hypothesize that propionic acidemia may have contributed to these complications, and discuss several possible mechanisms for this, emphasizing mainly the electron transport chain/mitochondrial energy deficiency hypothesis.     

Interleukin-1 β gene polymorphisms in Egyptian patients with rheumatoid arthritis

The present study aimed at evaluating the role of IL-1β ?511 promoter and IL-1β +3953 exon 5 gene polymorphisms in the risk of developing rheumatoid arthritis (RA) and its correlation to disease activity in Egyptian patients. Thirty-two patients having RA as defined by American College of Rheumatology and 20 healthy control subjects were included. All were subjected to DNA analysis for IL-1β ?511and IL-1β +3953 gene polymorphisms using PCR-RFLP technique with restriction enzymes AvaI and TaqI, respectively. No special pattern of association could be detected either between IL-1β ?511 and +3953 gene polymorphisms and disease susceptibility or between the polymorphisms and the disease activity parameters represented by disease activity score 28 (DAS 28), ESR, and number of swollen and tender joints. Allele distribution failed as well to detect any association with either disease susceptibility or activity; however, a trend towards positive association involving IL-1β ?511 C allele was observed (P?=?0.054). Our results suggest that IL-1β ?511 and IL-1β +3953 gene polymorphisms do not influence the susceptibility to acquire RA in our population with no relation to disease activity. The complex role of the genetic factors in RA and the magnitude of the effects will require further thorough confirmations in other populations and on larger samples to acknowledge this issue.     

FCεRI gene promoter polymorphisms and total IgE levels in susceptibility to atopic dermatitis in Korea

IgE-dependent activation of mast cells and basophils through the high-affinity IgE receptor (FcεRI) is involved in the pathogenesis of allergen-induced immune responsiveness in atopic diseases like atopic dermatitis (AD). We sought to determine FcεRI gene polymorphisms are associated with AD in Korean patients, and analyzed the relevance of FcεRI gene polymorphisms and serum IgE levels. We conducted a case-control association analysis (175 patients and 56 controls) of Korean subjects. Genotyping was performed using the TaqMan fluorogenic 5' nuclease assay, and serum levels of IgE were measured using a fluorescence enzyme immunoassay. We found that there were no significant relationships between FcεRI and AD, although there were trends towards an association between the 66T>C (rs2251746) polymorphism and total serum IgE levels in the Korean AD patients. In conclusion, while the 66T>C (rs2251746) of the FcεRIα polymorphism may be linked to AD and higher serum IgE levels, polymorphisms in the FcεRIβ gene did not confer susceptibility to AD in our patient sample.     

IL-1 cluster gene polymorphisms in Turkish patients with Behçet's disease

Several cytokine genes may play crucial roles in host susceptibility to Behçet’s Disease (BD), since the cytokine production capacity varies among individuals and depends on the cytokine gene polymorphisms. The association of the IL‐1 cluster gene polymorphisms with the development of BD was investigated in this study. DNA samples were obtained from a Turkish population of 97 patients with BD, and 77 healthy control subjects. All genotyping (IL‐1α, IL‐1β, IL‐1R and IL‐1Ra) experiments were performed using sequence specific primers PCR (PCR‐SSP). When compared to the healthy controls, the frequencies of IL‐1Ra IL‐1α and IL‐1R gene polymorphisms were not significantly different in BD patients. The frequency of IL‐1β?511 TT genotype was higher in the BD group in comparison to the control group. Interestingly, we demonstrated that IL‐1 β +3962 gene polymorphism seems to be associated with the presence of Erythema nodosum in BD patients. Our data suggest that polymorphisms in IL‐1β gene may affect host susceptibility to BD. In order to confirm the biological significance of our results, further studies should be performed in a large‐scale study and/or in different ethnic groups.     

Apolipoprotein E gene promoter (–219G/T) polymorphism is associated with premature coronary heart disease

The relationship of two apolipoprotein (apo) E gene polymorphisms and coronary heart disease (CHD) was investigated in 118 Finnish families with premature CHD and in 110 healthy control subjects. Affected siblings and probands with premature CHD had higher frequencies of the T allele of the -219G/T promoter polymorphism and the epsilon 4 allele (genotypes epsilon 4/3 or epsilon 4/4) of the apo epsilon 2/epsilon 3/ epsilon 4 polymorphism than those of healthy control subjects. Additionally, when the two apo E gene polymorphisms were combined, affected siblings and probands had a higher frequency of the -219T allele and the epsilon 4 allele combinations than did healthy controls. The -219T and the epsilon 4 alleles both separately and together were associated with higher levels of 2-h glucose in an oral glucose tolerance test. These results indicate that the two polymorphisms of the apo E gene have similar effects on the risk of coronary atherosclerosis in families with premature CHD. This risk was not explained by the effect of apo E gene polymorphisms on cholesterol metabolism, but their effect on cardiovascular risk factor clustering with insulin resistance may be of importance. We conclude that in addition to the epsilon 4 allele, also the -219G/T promoter polymorphism of the apo E gene is associated with early onset CHD.     

CYP 17 and estrogen receptor α gene polymorphisms: association with breast cancer susceptibility and clinicopathological parameters in a cohort of Egyptian patients

The association between exposure to endogenous and exogenous steroid hormones and breast cancer (BC) risk is well established. The aim of this study was to examine whether Cytochrome P450 (CYP)17 -34T>C and estrogen receptor (ER)α XbaI gene polymorphisms might influence endogenous estrogen hormone level. Also, we aimed to examine the potential association between these polymorphisms and BC risk, as well as some clinicopathological parameters in BC patients. Eighty-one Egyptian female subjects were recruited; 41 pathologically confirmed BC patients and 40 apparently healthy, age-matched female control subjects. Serum estradiol level was assayed using radioimmunoassay. Polymerase chain reaction–restriction fragment length polymorphism technique was used for detection of CYP 17 -34T>C and ERα-XbaI polymorphisms. Serum estradiol level did not show statistically significant difference when compared between the different CYP17 and ERα genotypes in controls (p?=?0.088 and 0.241, respectively). No significant association between CYP17 and ER α gene polymorphisms and BC risk was encountered. There was a statistically significant association between ER α genotypes in overall BC cases with each of age at menarche, p?=?0.024, age at diagnosis, p?=?0.011, and nodal involvement, p?=?0.037, and between nodal number and ER α genotypes in the premenopausal BC group, p?=?0.038. In conclusion, CYP17 and ERα genotypes did not influence serum estradiol level. No statistically significant association was found between CYP17 -34T>C and ERα XbaI gene polymorphisms and breast cancer risk in Egyptian women. ER α gene may have an association with some clinicopathological parameters in breast cancer in Egyptian patients.     

Polymorphisms in tumor necrosis factor-alpha (−863C>A, −857C>T and +488G>A) are associated with idiopathic recurrent pregnancy loss in Korean women

Polymorphisms in TNF-a have been reported as genetic risk factors for recurrent spontaneous abortion and TNF-α may be immunologically important. We therefore examined the contribution of several TNF-a mutations to this phenomenon. The study participants consisted of 388 patients with idiopathic recurrent pregnancy loss (RPL), which was diagnosed on the basis of at least two consecutive spontaneous abortions; control subjects were 224 healthy women with a history of successful pregnancies. Polymerase chain reaction-restriction fragment length polymorphism analysis was performed to determine the TNF-α −863C>A, −857C>T, and +488G>A genotypes. The TNF-α −863C>A variants correlated with increased risk of RPL (CA + AA; adjusted odds ratio [AOR], 2.142; 95% confidence interval [CI], 1.493–3.074). These data did not differ in a stratified analysis according to number of consecutive spontaneous abortions. In haplotype analysis, there were similar trends of data for combination analysis, but in patients with 3+ pregnancy losses, a stratified analysis revealed that this correlation did not increase directly with the number of pregnancy losses. The TNF-α −863C>A variant is a possible genetic risk factor for idiopathic RPL in Korean women.     

Three TNF α single nucleotide polymorphisms in the Japanese population

Background : Tumour necrosis factor-alpha (TNF &#102 ) is an essential regulator of immune responses and is implicated to relate to several types of disease susceptibilities. Population information on polymorphisms is essential for the study of genetic diseases. Aim : To obtain accurate information about single nucleotide polymorphisms (SNPs) in the TNF &#102 gene in the Japanese population. Subjects and Methods : The entire TNF &#102 gene was screened for SNPs by directly sequencing 48 chromosomes derived from 24 unrelated Japanese individuals. Allele frequencies of each polymorphism were determined and compared with those previously reported in other populations. Results : Three SNPs, -308G/A at nt -308, IVS1 + 125G/A at nt 492 and IVS3 + 104G/A at nt 1359 were observed, of which one (IVS3 + 104G/A at nt 1359) was novel. In addition, allele frequencies of -308G/A were remarkably different from those presented in the NCBI dbSNP, indicating a significant ethnic difference. Conclusions : The polymorphisms and allele frequencies obtained in this study will be useful for genetic studies of common diseases such as osteoporosis and rheumatoid arthritis in the Japanese population.     

The –553 T/A polymorphism in the promoter region of the FGF2 gene is associated with increased breast cancer risk in Polish women

Introduction

Fibroblast growth factor-2 (FGF2) is an important signalling molecule contributing to angiogenesis, tumour growth and progression and its expression is implicated in breast cancer (BC) development. We investigated whether –553 T/A FGF2 gene polymorphism is associated with the risk and progression of BC in Polish women.

Material and methods

The –553 T/A polymorphism was genotyped in 230 breast cancer patients and 245 control subjects, using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) approach. Moreover, FastQuant human angiogenesis array was used to measure FGF2 levels in tumour (n = 127) and serum (n = 76) samples.

Results

The T/A genotypes (OR = 2.12, 95% CI: 1.20–3.74) (p = 0.08) and the combined heterozygotes T/A and homozygote A/A (OR = 2.18, 95% CI: 1.24–3.83) (p = 0.006) had an increased risk of BC. The median FGF2 levels in the tumours of A allele carriers were significantly increased compared to T/T patients, whereas in serum FGF2 levels were hardly altered among different genotype carriers. Significantly higher frequency of A allele was found in patients with lymph node metastases (OR = 2.53; 95% CI: 1.23–5.17) (p = 0.009) and human epidermal growth factor receptor 2 positive tumour (OR = 3.22, 95% CI: 1.49–6.99) (p = 0.002). Furthermore, Kaplan-Meier survival analysis showed that the A allele predicted worse disease-free survival (DFS) in BC patients.

Conclusions

Our study shows for the first time that the –553 T/A FGF2 gene polymorphism may be associated with a risk of BC developing and progression in Polish women and may have prognostic value for the assessment of BC high-risk groups.