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1.  Association of progesterone receptor polymorphisms with recurrent implantation failure after in vitro fertilization and embryo transfer 
Progesterone is the hormone of pregnancy and is required for its initiation. The actions of progesterone are mediated by the progesterone receptor. Polymorphic variants of human progesterone receptor genes have been implicated in implantation failure.
Materials and methods
We, therefore, investigated the prevalence of H770H(C/T genotype), V660L polymorphism and a 306 bp Alu insertion in exon 7 of the progesterone receptor among women with history of recurrent implantation failure to determine whether any of these polymorphisms may serve as a risk factor for implantation failure. DNA was extracted from the buccal swabs obtained from 66 women experiencing implantation failure and 75 fertile control women. PCR amplification of fragments was purified and the DNA sequenced to identify the polymorphism. The frequencies for the three variants were 27% for H770H, 21% for V660L and 0% for the 306 bp Alu insertion in exon 7 among women with implantation failure compared with control women of 25% for H770H and 24%for V660L and 0% for the 306 bp Alu insertion in exon 7.
No significant differences in the overall allelic frequency of progesterone receptor variants was seen when women experiencing recurrent implantation failure were compared with control women.
We conclude that the H770H and V660L and PROGINS progesterone receptor polymorphisms are not markers that can identify women at risk for recurrent implantation after IVF/ET.
PMCID: PMC2582074  PMID: 18392676
Progesterone; Receptor polymorphisms; Recurrent implantation failure; RIF
2.  Association of progesterone receptor polymorphism with idiopathic recurrent pregnancy loss in Taiwanese Han population 
Recurrent pregnancy loss (RPL) could be caused by insufficient progesterone in the luteal phase of menstruation and early pregnancy. Progesterone plays a critical role in oocyte maturation, embryo implantation and placenta maintenance in early gestation. This study was set out to investigate the association between polymorphisms of the progesterone receptor (PGR) gene and idiopathic RPL.
One hundred twenty-one women with a history of idiopathic recurrent pregnancy loss (RPL) and 179 control subjects were enrolled into the study. Six tag SNPs and two functional SNPs [PROGINS (rs1042838), +331 C/T (rs10895068)] of the progesterone receptor gene were genotyped.
We found that the allele and genotype frequencies of the functional SNP [PROGINS (rs1042838)] were both significantly higher in patients with idiopathic RPL than in the control subjects (both P values = 0.006). In addition, the C-C haplotype, which consists of rs590688C > G and rs11224592T > C, is associated with a decreased risk of RPL (p = 0.004).
PROGINS polymorphism confers susceptibility to idiopathic recurrent pregnancy loss in Taiwanese Han women.
PMCID: PMC3082658  PMID: 21086036
Progesterone receptor; PROGINS; Recurrent pregnancy loss; Tag SNP; Polymorphism
3.  MTHFR (C677T) polymorphism and PR (PROGINS) mutation as genetic factors for preterm delivery, fetal death and low birth weight: A Northeast Indian population based study 
Meta Gene  2015;3:31-42.
Preterm delivery (PTD) is one of the most significant contributors to neonatal mortality, morbidity, and long-term adverse consequences for health; with highest prevalence reported from India. The incidence of PTD is alarmingly very high in Northeast India. The objective of the present study is to evaluate the associative role of MTHFR gene polymorphism and progesterone receptor (PR) gene mutation (PROGINS) in susceptibility to PTD, negative pregnancy outcome and low birth weights (LBW) in Northeast Indian population.
A total of 209 PTD cases {extreme preterm (< 28 weeks of gestation, n = 22), very preterm (28–32 weeks of gestation, n = 43) and moderate preterm (32–37 weeks of gestation, n = 144) and 194 term delivery cases were studied for MTHFR C677T polymorphism and PR (PROGINS) gene mutation. Statistical analysis was performed using SPSS software.
Distribution of MTHFR and PR mutation was higher in PTD cases. Presence of MTHFR C677T polymorphism was significantly associated and resulted in the increased risk of PTD (p < 0.001), negative pregnancy outcome (p < 0.001) and LBW (p = 0.001); more significantly in extreme and very preterm cases. Presence of PR mutation (PROGINS) also resulted in increased risk of PTD and negative pregnancy outcome; but importantly was found to increase the risk of LBW significantly in case of very preterm (p < 0.001) and moderately preterm (p < 0.001) delivery cases.
Both MTHFR C677T polymorphism and PR (PROGINS) mutation are evident genetic risk factors associated with the susceptibility of PTD, negative pregnancy outcome and LBW. MTHFR C677T may be used as a prognostic marker to stratify subpopulation of pregnancy cases predisposed to PTD; thereby controlling the risks associated with PTD.
•This is the first study involving the analysis of genetic risk factors associated with preterm delivery in Northeast India.•MTHFR C677T polymorphism and PR (PROGINS) mutation in predisposition to preterm delivery, negative pregnancy outcome and low birth weight.•MTHFR C677T polymorphism may be used as a prognostic marker to stratify subpopulation of pregnancy cases predisposed to PTD; thereby controlling the risks associated with PTD.
PMCID: PMC4329826  PMID: 25709895
Preterm delivery; Negative pregnancy outcome; Low birth weight; MTHFR C677T polymorphism; PR (PROGINS) mutation; Northeast India
4.  Associations between androgen receptor CAG & GGN repeat polymorphism & recurrent spontaneous abortions in Chinese women 
Background & objectives:
Recurrent spontaneous abortion (RSA) is a reproductive problem that occurs in women in reproductive age with a frequency of 1-3 per cent. Previous studies have reported high levels of serum androgens to be associated with RSAs. At the molecular level, the effect of androgens is mediated through the activation of the androgen receptor (AR). The CAG and GGN repeat polymorphisms of the AR gene are associated with the AR activity. We hypothesize that the AR CAG/GGN repeat polymorphism may be associated with levels of serum androgens. Thus, this study as undertaken to evaluate the relationship between CAG/GGN repeats in exon 1 of the AR gene in women with RSAs.
This case-control study was performed in Ningxia, PR China, including 149 women with RSAs and 210 controls. The CAG and GGN repeats of the AR gene were genotyped using a PCR-based assay and were analyzed using Peak Scanner Software v1.0 to determine the CAG/GGN repeat length.
CAG repeats ranged from 15 to 29 in the RSA patients, compared to 14 to 35 in the control group. The median value of CAG repeats was 22 for the RSA group and 24 for control group. The total AR CAG alleles (≤22 repeats), shorter AR CAG alleles (≤22 repeats), and biallelic means (≤22.5 repeats) were significantly different in the RSA group in comparison to the control group (P<0.001, P<0.01). The median value of the GGN repeats was 23 for the cases and 22 for controls. The total number of AR GGN alleles (≤23 repeats) was significantly different in the RSA group compared to the control group (P<0.5). There was no difference between the RSA group and the control groups in regards to shorter alleles, longer alleles, and biallelic means.
Interpretation & conclusions:
Our observation suggests that the CAG and GGN repeat length is shorter in women with RSAs as compared with controls and that shorter CAG and GGN repeats may be pathogenic for RSAs in Chinese women. Further studies need to be done in different ethnic populations.
PMCID: PMC4140038  PMID: 25027083
Androgen; androgen receptor gene; CAG repeats; GGN repeats; recurrent spontaneous abortion
5.  Progesterone receptor variation and risk of ovarian cancer is limited to the invasive endometrioid subtype: results from the ovarian cancer association consortium pooled analysis 
British Journal of Cancer  2008;98(2):282-288.
There is evidence that progesterone plays a role in the aetiology of invasive epithelial ovarian cancer. Therefore, genes involved in pathways that regulate progesterone may be candidates for susceptibility to this disease. Previous studies have suggested that genetic variants in the progesterone receptor gene (PGR) may be associated with ovarian cancer risk, although results have been inconsistent. We have established an international consortium to pool resources and data from many ovarian cancer case–control studies in an effort to identify variants that influence risk. In this study, three PGR single nucleotide polymorphisms (SNPs), for which previous data have suggested they affect ovarian cancer risk, were examined. These were +331 C/T (rs10895068), PROGINS (rs1042838), and a 3′ variant (rs608995). A total of 4788 ovarian cancer cases and 7614 controls from 12 case–control studies were included in this analysis. Unconditional logistic regression was used to model the association between each SNP and ovarian cancer risk and two-sided P-values are reported. Overall, risk of ovarian cancer was not associated with any of the three variants studied. However, in histopathological subtype analyses, we found a statistically significant association between risk of endometrioid ovarian cancer and the PROGINS allele (n=651, OR=1.17, 95% CI=1.01–1.36, P=0.036). We also observed borderline evidence of an association between risk of endometrioid ovarian cancer and the +331C/T variant (n=725 cases; OR=0.80, 95% CI 0.62–1.04, P=0.100). These data suggest that while these three variants in the PGR are not associated with ovarian cancer overall, the PROGINS variant may play a modest role in risk of endometrioid ovarian cancer.
PMCID: PMC2361465  PMID: 18219286
ovarian cancer; progesterone receptor; SNPs; PROGINS; pooled analyses; endometrioid ovarian cancer
6.  Association of the IL4R single-nucleotide polymorphism I50V with recurrent spontaneous abortion (RSA) 
Recurrent spontaneous abortion (RSA) is defined as three or more consecutive abortions before the 20th week of gestation. There is increasing evidence to support an immunological mechanism for the occurrence of RSA. The purpose of our study was to examine whether single-nucleotide polymorphisms (SNPs) of the interleukin-4 receptor gene IL4R influence susceptibility to, recurrent spontaneous abortion.
Materials and methods
This is a case-control study. We recruited 200 patients with RSA (case group) using established diagnostic criteria and 200, normal individuals (control group) at the fertility and infertility center in Yazd city and Isfahan city during 2012 to 2013. We screened the I50V variant in IL-4R in patients and controls by PCR-RFLF method, and we performed an association analysis between I50V variant and RSA.the data was analyzed by spss 16 software using Chi-square test.
No differences in the genotype and allele frequencies of the I50V SNPs were identified between patients with RSA and healthy controls.
The frequency of SNP in IL-4 receptor (I50V) in patients with recurrent spontaneous abortion did not differ significantly compared with the control group. Analysis of IL4R SNP haplotypes or complex alleles suggested no dominant protection in patients with RSA.
PMCID: PMC4096890  PMID: 24803421
Recurrent spontaneous abortion; IL4R single-nucleotide polymorphism; I50V
7.  The progesterone receptor Val660→Leu polymorphism and breast cancer risk 
Breast Cancer Research  2004;6(6):R636-R639.
Recent evidence suggests a role for progesterone in breast cancer development and tumorigenesis. Progesterone exerts its effect on target cells by interacting with its receptor; thus, genetic variations, which might cause alterations in the biological function in the progesterone receptor (PGR), can potentially contribute to an individual's susceptibility to breast cancer. It has been reported that the PROGINS allele, which is in complete linkage disequilibrium with a missense substitution in exon 4 (G/T, valine→leucine, at codon 660), is associated with a decreased risk for breast cancer.
Using a nested case-control study design within the Nurses' Health Study cohort, we genotyped 1252 cases and 1660 matched controls with the use of the Taqman assay.
We did not observe any association of breast cancer risk with carrying the G/T (Val660→Leu) polymorphism (odds ratio 1.10, 95% confidence interval 0.93–1.30). In addition, we did not observe an interaction between this allele and menopausal status and family history of breast cancer as reported previously.
Overall, our study does not support an association between the Val660→Leu PROGINS polymorphism and breast cancer risk.
PMCID: PMC1064075  PMID: 15535845
breast cancer; linkage disequilibrium; polymorphism; progesterone receptor
8.  Association of kinase insert domain-containing receptor (KDR) gene polymorphism/ haplotypes with recurrent spontaneous abortion and genetic structure  
Recurrent spontaneous abortion is one of the diseases that can lead to physical, psychological, and, economical problems for both individuals and society. Recently a few numbers of genetic polymorphisms in kinase insert domain-containing receptor (KDR) gene are examined that can endanger the life of the fetus in pregnant women.
The risk of KDR gene polymorphisms was investigated in Iranian women with idiopathic recurrent spontaneous abortion (RSA).
Materials and Methods:
A case controlled study was performed. One hundred idiopathic recurrent spontaneous abortion patients with at least two consecutive pregnancy losses before 20 weeks of gestational age with normal karyotypes were included in the study. Also, 100 healthy women with at least one natural pregnancy were studied as control group. Two functional SNPs located in KDR gene; rs1870377 (Q472H), and rs2305948 (V297I) as well as one tag SNP in the intron region (rs6838752) were genotyped by using PCR based restriction fragment length polymorphism (PCR-RFLP) technique. Haplotype frequency was determined for these three SNPs’ genotypes. Analysis of genetic STRUCTURE and K means clustering were performed to study genetic variation.
Functional SNP (rs1870377) was highly linked to tag SNP (rs6838752) (D´ value=0. 214; χ2 = 16.44, p<0. 001). K means clustering showed that k = 8 as the best fit for the optimal number of genetic subgroups in our studied materials. This result was in agreement with Neighbor Joining cluster analysis.
In our study, the allele and genotype frequencies were not associated with RSA between patient and control individuals. Inconsistent results in different populations with different allele frequencies among RSA patients and controls may be due to ethnic variation and used sample size.
PMCID: PMC4827512  PMID: 27141535
Abortion; Genetic structures; Polymorphism; Restriction fragment length polymorphism; VEGF receptor 2
9.  Role of 14-bp deletion/insertion polymorphism in exon 8 of the HLA-G gene in recurrent spontaneous abortion patients 
Human leukocyte antigen (HLA)-G belongs to the nonclassical Class I major histocompatibility complex, and is predominantly and specifically found on the extravillous cytotrophoblast cells of the placenta. HLA-G has been postulated as an important immunotolerant molecule in maintaining successful pregnancy and maternal tolerance of the semiallogenic fetus. Recent reports indicate that the 14-bp deletion/insertion polymorphism in exon 8 of the 3’UTR region of the HLA-G gene influences the HLA-G mRNA stability and isoform splicing patterns, thus modulating the levels of HLA-G expression.
The aim was to study the 14-bp deletion/insertion polymorphism in exon 8 of the 3’UTR region of the HLA-G gene.
A total of 50 women with unexplained three or more recurrent spontaneous abortions (RSAs) and 41 normal healthy control women who have had normal pregnancies and were genotyped for the 14-bp deletion/insertion polymorphism were genotyped for the 14-bp deletion/insertion polymorphism by polymerase chain reaction for exon 8-specific primers
It was found that the 14-bp allele deletion frequency was lower in patients (67%) versus controls (73%), while 14-bp allele insertion was higher among patients (33%) versus controls (9%). Similarly, the homozygous deletion halotype was higher among the controls (80.48%); the heterozygous insertion deletion haplotype (34%) and homozygous insertion haplotype (16%) were higher in RSA patients. The HLA haplotype HLA A*02:11_B*40:06:01:01 was increased among RSA women compared to controls.
Our results suggest that 14-bp deletion/insertion polymorphisms might have importance in the outcome of pregnancy and the 14-bp deletion polymorphism in exon 8 of the HLA-G gene may be important from an evolutionary perspective of successful pregnancy.
PMCID: PMC3276949  PMID: 22346082
HLA-G 14-bp deletion/insertion gene; India; RSA
10.  Genetic variation in the progesterone receptor gene and risk of endometrial cancer: a haplotype-based approach 
Carcinogenesis  2010;31(8):1392-1399.
Background: It is well established that estrogen increases endometrial cancer risk, whereas progesterone opposes the estrogen effects. The PROGINS allele of the progesterone receptor (PGR) gene reduces the function of PGR and has been associated with increased risk of the endometrioid type ovarian cancer. We investigated whether genetic variation in PGR is also associated with endometrial cancer risk using a haplotype-based approach. Methods: We pooled data from two endometrial cancer case–control studies that were nested within two prospective cohorts, the Multiethnic Cohort Study and the California Teachers Study. Seventeen haplotype-tagging single nucleotide polymorphisms (SNPs) across four linkage disequilibrium (LD) blocks spanning the PGR locus were genotyped in 583 incident cases and 1936 control women. Odds ratios (ORs) and 95% confidence intervals (CIs) associated with each haplotype were estimated using conditional logistic regression, stratified by age and ethnicity. Results: Genetic variation in LD block 3 of the PGR locus was associated with endometrial cancer risk (Pglobal test = 0.002), with haplotypes 3C, 3D and 3F associated with 31–34% increased risk. Among whites (383 cases/840 controls), genetic variation in all four blocks was associated with increased endometrial cancer risk (Pglobal test = 0.010, 0.013, 0.005 and 0.020). Haplotypes containing the PROGINS allele and several haplotypes in blocks 1, 3 and 4 were associated with 34–77% increased risk among whites. SNP analyses for whites suggested that rs608995, partially linked to the PROGINS allele (r2 = 0.6), was associated with increased risk (OR = 1.30, 95% CI = 1.06–1.59). Conclusions: Our results suggest that genetic variation in the PGR region is associated with endometrial cancer risk.
PMCID: PMC2915632  PMID: 20547493
11.  Association of progesterone receptor gene polymorphism with male infertility and clinical outcome of ICSI 
To investigate the association of Progesterone Receptor (PR) gene variations and male infertility
DNA extraction, PCR and sequencing of PR gene, PROGINS insertion by PCR. Association of the variations with seminal parameters and outcomes of ICSI.
Four known SNPs in the PR gene were identified in the study of which three (rs3740753, rs1042838, rs104283) were co-inherited and in complete linkage disequilibrium with the PROGINS Alu insertion. There were no differences in their frequencies between fertile and infertile males. The rs2020880 was found at a very low frequency only in the controls but not in the infertile subjects. The sperm counts, fertilization rate, embryo quality or pregnancy rates were not different in individuals with or without PROGINS allele.
PR gene alterations are not associated with male infertility or ICSI outcome.
Electronic supplementary material
The online version of this article (doi:10.1007/s10815-013-0074-2) contains supplementary material, which is available to authorized users.
PMCID: PMC3800537  PMID: 23934021
Progesterone receptor; Polymorphism; PROGINS; Male infertility; ICSI; Azoospermia; Sperm counts
12.  Progesterone Receptor Gene Polymorphisms and Risk of Endometriosis: Results from an International Collaborative Effort 
Fertility and sterility  2010;95(1):40-45.
To investigate the association between self-reported endometriosis and the putative functional promoter +331C/T single nucleotide polymorphism (SNP) and the PROGINS allele.
Control subjects from ovarian cancer case-control studies participating in the international Ovarian Cancer Association Consortium. The majority of controls are drawn from population-based studies.
An international ovarian cancer consortium including studies from the Australia, Europe and the United States,
5,812 White female controls, of whom 348 had endometriosis, from eight ovarian cancer case-control studies.
Main Outcome Measures
Genotypes for the +331C/T SNP and PROGINS allele and a history of endometriosis.
The occurrence of endometriosis was reduced in women carrying one or more copies of the +331 T allele (OR=0.65; 95% CI: 0.43–0.98, p=0.042), whereas there was no association between the PROGINS allele and endometriosis (OR=0.94, 95% CI 0.76, 1.16).
Additional studies of the +331C/T variant are warranted given the current finding and the equivocal results of previous studies. The +331 T allele has been shown to result in a reduced PR-A to PR-B ratio and if the observed association with endometriosis is confirmed it would suggest that this ratio is important for this disease.
PMCID: PMC3176720  PMID: 20719308
Endometriosis; progesterone receptor; ovarian cancer; PROGINS
13.  Association between HLA-E gene polymorphism and unexplained recurrent spontaneous abortion (RSA) in Iranian women 
Human leukocyte antigen-E (HLA-E)is a non-classical major histocompatibility complex (MHC) class I antigens which expressed on extra villous cytotrophoblast, which interacts with NKG2A, is an inhibitory receptor on natural killer (NK) cells and leading to down regulation of immune response in the maternal-fetal interface and provides maternal immune tolerance of the fetus.
This study was designated to investigate the gene frequencies of E0101 and E0103 in HLA-E gene in Iranian women with recurrent spontaneous abortion (RSA).
Materials and Methods:
Amplification Refractory Mutation System (ARMS-PCR) technique was carried out to detect polymorphism in exon 3 of the HLA-E gene in women with RSA and controls (n=200). Differences between groups were analyzed by SPSS19 software using 2 test.
There was no significant difference in the allele frequencies of the HLA-E polymorphism between RSA and fertile controls but HLA-E 0101/0103 heterozygous genotype was found to be significantly higher in RSA group (p=0.006, OR=1.73), so this genotype might confer susceptibility to RSA.
Our results suggest that HLA-E 0101/0103 heterozygous genotype leads to increase of RSA risk. It seems that by genotyping of HLA-E polymorphism, we can predict the risk of RSA in infertile women.
PMCID: PMC4971558  PMID: 27525333
Spontaneous Abortions; HLA-E antigen; Polymorphism
14.  The progins progesterone receptor gene polymorphism is not related to endometriosis‐associated infertility or to idiopathic infertility 
Clinics  2010;65(11):1073-1076.
This study aimed to determine the frequency of the PROGINS polymorphism in women with endometriosis‐associated infertility, in infertile women without endometriosis and in controls.
The human progesterone receptor gene has two isoforms that modulate the biological action of progesterone: isoform A, which is capable of inhibiting the activation of the estrogen receptors, and isoform B, which has the capacity to activate the estrogen receptors. Several polymorphisms have been described for this gene, among which one stands out: a polymorphism named PROGINS, which has been speculated to be related to the genesis of endometriosis by several studies with conflicting results.
This was a prospective study that included 148 patients with endometriosis‐associated infertility, 50 idiopathic infertile patients and 179 fertile women as controls. The PROGINS polymorphism was studied by PCR.
Genotypes P1P1, P1P2 and P2P2 (P2 representing the PROGINS polymorphism) of the progesterone receptor gene presented frequencies of 93.9%, 5.4% and 0.7%, respectively, in the women with endometriosis‐associated infertility (p = 0.2101, OR = 0.51, 95% CI = 0.24‐1.09); 94.4%, 4.2% and 1.4%, respectively, in the patients with minimal/mild endometriosis (p = 0.2725, OR = 0.53, 95% CI = 0.20‐1.43); 93.5%, 6.5% and 0%, respectively, among the patients with moderate/severe endometriosis (p = 0.3679, OR = 0.49, 95% CI = 0.18‐1.31); 86.0%, 14.0% and 0%, respectively, in idiopathic infertile women (p = 0.8146, OR = 1.10, 95% CI = 0.46‐2.63); and 88.3%, 10.6% and 1.1%, respectively, in the control group.
The data suggest that PROGINS is not related either to endometriosis‐associated infertility or to idiopathic infertility in the population studied.
PMCID: PMC2999697  PMID: 21243274
endometriosis; polymorphism; PROGINS; progesterone receptor gene; infertility
15.  Idiopathic Recurrent Pregnancy Loss: Role of Paternal Factors; A Pilot Study 
This case-control study was designed with the aim of evaluating the role of sperm, oxidative stress and DNA damage in idiopathic recurrent pregnancy loss (iRPL). This pilot study is the first study done on the Indian population which reports the association between DFI, TAC and ROS in couples experiencing iRSA.
Twenty infertile men with a history of iRPL and 20 fertile controls (having fathered a child a year earlier) were included in the study which was performed in Laboratory for Molecular Reproduction and Genetics, India, from March 2010 to July 2011. The female partners of the participants were normal on gynaecological examination and had normal endocrine and blood profiles. Conventional semen analysis was performed (concentration, motility, morphology; WHO criteria, 2010) within 1 hour of sample collection. Levels of reactive oxygen species (ROS) were assessed by luminol-dependant chemiluminescence. The total antioxidant capacity (TAC) was quantified by ELISA. The Sperm chromatin structure assay (SCSA) was performed by flow cytometry to determine DNA fragmentation Index (DFI). Statistical analysis was performed using SPSS version 15 and parameters were compared by Mann-Whitney test. Pearson correlation test was used to find the correlation between parameters and a p-value <0.05 was considered significant. Receiver operating characteristics (ROC) curve analysis was applied to find out the cut-off value of DNA fragmentation index.
No significant differences in age, seminal volume, liquefaction time, pH and sperm concentration were observed between the male partner of iRPL cases and the controls, but sperm morphology and motility were significantly (p <0.05) lower in the male partner of cases with idiopathic recurrent spontaneous abortion (RSA). The mean ROS levels observed were 47427.00 relative light unit (RLU)/min/20 million sperm in the male partners as compared to 13644.57 RLU/ min/20 million sperm in the controls (normal <15000 RLU/min/20 million). The mean TAC levels in the controls (6.95 mM trolox) were significantly (p <0.05) higher as compared to the male partners of women with IRPL (2.98 mM trolox). The average mean DFI of male partners were found to be 23.37±9.9 and the mean DFI of controls was 13.89±5.40. The mean DFI was significantly (p <0.05) higher when compared to the controls. The range of DFI in male partners was 8.50–44.07. However, in the controls the range was 7.70–23.50.
Sperm DNA integrity is critical for normal embryonic development and birth of healthy offspring. Oxidative stress due to the imbalance between raised free radical levels and low total antioxidant capacity is one of the critical causes of DNA damage. Thus assay of oxidative stress and sperm genomic integrity is essential in couples with iRSA following natural and spontaneous conception.
PMCID: PMC3719307  PMID: 23926513
Oxidative stress; Reactive oxygen species; Recurrent spontaneous abortion; Sperm DNA damage; Sperm chromatin structure assay
16.  Relationship between cytokine gene polymorphisms and recurrent spontaneous abortion 
Recurrent spontaneous abortion (RSA), defined as three or more sequential abortions before the twentieth week of gestation. Some studies have led to the awareness that immunological factors play an important role in establishing a successful pregnancy. The aim of present study was to investigate the relationship between RSA and polymorphisms of cytokine genes coding for TNF-α (-308 G→A, -238 G→A), TNF-β (+252 G→A) as Th1 or pro-inflammatory factors as well as IL-6 (-634 G→C, -174 G→C), IL-10 (-1082 A→G, -819 C→T, -592C→A) as Th2 cytokines in women with RSA compared with healthy women. A total of 284 women with RSA and 284 control women with at least two successful pregnancies and no history of abortion were included in the study. The polymerase chain reaction (PCR), allele-specific oligonucleotide polymerase chain reaction (ASO-PCR) or PCR-RFLP (restriction fragment length polymorphism) methods were used for genotyping. In addition, the ELISA was conducted to investigate four cytokine serum levels in women with RSA and healthy women. Results showed that: TNF-α -308G/A, IL-6 -174 G/C and IL-10 -819 G/C polymorphisms showed statistically significant differences between the RSA patients and controls (P=0.008, P=0.0005 and P=0.03 separately). Levels of four cytokines in the serum showed that there were no significant differences in TNF-α and TNF-β between patients and control (P>0.05), while the level of IL-6 and IL-10 were lower than control group and the differences were statically significant (P<0.05). This study demonstrated a possible association between TNF-α -308, IL-6 -174 and IL-10 -819 promoter polymorphism and RSA.
PMCID: PMC4538128  PMID: 26309657
Recurrent spontaneous abortion; cytokine gene polymorphisms; tumor necrosis factor-α; tumor necrosis factor-β; interleukin-6; Interleukin-10
17.  Progesterone Receptor Gene (PROGINS) Polymorphism Correlates with Late Onset of Migraine 
DNA and Cell Biology  2015;34(3):208-212.
Progesterone influences central neuronal excitability, a key event in migraine pathophysiology. Progesterone receptor gene (PGR) rs1042838 (G/T - Val660Leu) variant is indicative of PROGINS haplotype and associated to a reduced PGR activity. With the aim of investigating whether any type of association existed between this genetic variant and migraine pathophysiology, genotyping was performed in 380 consecutive migraine patients and 185 age-, sex-, and race-ethnicity-matched healthy controls from Interinstitutional Multidisciplinary BioBank (BioBIM) of IRCCS San Raffaele Pisana, Rome, Italy. rs1042838 genotypes did not correlate with demographics or clinical migraine features. However, TT (Leu) genotype was significantly associated with a later age of migraine onset: Patients affected by migraine with aura showed a linear relationship between copy number of the T allele carried by the individual and the age of migraine onset. Our data suggest that the PROGINS PGR polymorphism does not directly predispose to migraine but significantly delays migraine onset probably via a reduction in brain neuronal excitability.
PMCID: PMC4337459  PMID: 25494303
18.  Association of VEGF Genetic Polymorphisms with Recurrent Spontaneous Abortion Risk: A Systematic Review and Meta-Analysis 
PLoS ONE  2015;10(4):e0123696.
Studies of the associations between the genetic polymorphisms of the vascular endothelial growth factor (VEGF) gene and recurrent spontaneous abortion (RSA) have revealed conflicting results. The present meta-analysis was performed to provide a more precise estimation of these relationships and to explore potential sources of heterogeneity that may have influenced the reported disparities.
An extensive literature search for relevant studies was conducted on PubMed, Embase, and The Cochrane Library through June 6, 2014. Crude odds ratio (OR) with 95% confidence intervals were calculated.
10 case-control studies including 1,832 RSA patients and 2,271 healthy controls were identified. Meta-analysis indicated that rs1570360, rs3025039, rs2010963, and rs3025020 polymorphisms in the VEGF gene correlated with elevated RSA risk. The rs1570360 variant was statistically significantly relevant to RSA risk among non-Asian populations. Interestingly, the rs3025039 variant was statistically significantly relevant to RSA risk among Asian populations.
The current meta-analysis indicates that rs1570360, rs3025039, rs2010963, and rs3025020 polymorphisms increase RSA susceptibility. Moreover, rs1570360 and rs3025039 polymorphisms may play various roles in RSA susceptibility in various geographic groups.
PMCID: PMC4404341  PMID: 25894555
19.  Molecular Detection and Genotypic Characterization of Toxoplasma gondii in Paraffin-Embedded Fetoplacental Tissues of Women with Recurrent Spontaneous Abortion  
Congenital toxoplasmosis is an important cause of spontaneous abortion worldwide. However, there is limited information on detection and genotypic characterization of Toxoplasma gondii (T. gondii) in women with recurrent spontaneous abortion (RSA). The aim of this study is the molecular detection and genotypic characterization of T. gondii in formalin-fixed, paraffin-embedded fetoplacental tissues (FFPTs) of women with RSA that have referred to the Avicenna Research Institute in Tehran, Iran.
Materials and Methods
This experimental research was undertaken on 210 FFPTs of women with RSA. The information of the patients was collected from the archives of Avicenna Research Institute in Tehran, Iran. After DNA extraction, the presence of T. gondii was examined by nested polymerase chain reaction targeting the GRA6 gene. Genotyping was performed on positive samples using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) that targeted the GRA6 and SAG3 genes. Sequencing was conducted on two GRA6 positive samples.
T. gondii DNA was detected in 3.8% (8/210) of the samples. Genotyping showed that all positive samples belonged to type III of the T. gondii genotype. Sequencing two genomic DNAs of the GRA6 gene revealed 99% similarity with each other and 99-100% similarity with T. gondii sequences deposited in GenBank. There were six patients with histories of more than three abortions; one patient had a healthy girl and another patient had two previous abortions. Abortions occurred in the first trimester of pregnancy in seven patients and in the second trimester of pregnancy in one patient.
The results of this study have indicated that genotype III is the predominant type of T. gondii in women with RSA in Tehran, Iran. Also, our findings suggest that toxoplasmosis may play a role in the pathogenesis of RSA. However, further studies are needed to elucidate a clear relationship between T. gondii infection and RSA.
PMCID: PMC5135736  PMID: 28042412
Toxoplasma gondii; Abortion; Molecular Detection; Genotype; Iran
20.  Role of Androgen Receptor CAG Repeat Polymorphism and X-Inactivation in the Manifestation of Recurrent Spontaneous Abortions in Indian Women 
PLoS ONE  2011;6(3):e17718.
The aim of the present study was to investigate the role of CAG repeat polymorphism and X-chromosome Inactivation (XCI) pattern in Recurrent Spontaneous Abortions among Indian women which has not been hitherto explored. 117 RSA cases and 224 Controls were included in the study. Cases were recruited from two different hospitals - Lakshmi Fertility Clinic, Nellore and Fernandez Maternity Hospital, Hyderabad. Controls were roughly matched for age, ethnicity and socioeconomic status. The CAG repeats of the Androgen Receptor gene were genotyped using a PCR-based assay and were analysed using the GeneMapper software to determine the CAG repeat length. XCI analysis was also carried out to assess the inactivation percentages. RSA cases had a significantly greater frequency of allele sizes in the polymorphic range above 19 repeats (p = 0.006), which is the median value of the controls, and in the biallelic mean range above 21 repeats (p = 0.002). We found no evidence of abnormal incidence of skewed X-inactivation. We conclude that longer CAG repeat lengths are associated with increased odds for RSA with statistical power estimated to be ∼90%.
PMCID: PMC3056719  PMID: 21423805
21.  Association of the +49 A/G Polymorphism of CTLA4 Gene with Idiopathic Recurrent Spontaneous Abortion in Women in Southwest of Iran 
Survival of the semi-allograft fetus during pregnancy opens a new area for the immunological based causes of recurrent spontaneous abortion (RSA). Cytotoxic T lymphocyte-associated antigen 4 (CTLA4) is a negative regulator of the T-cell activation, which may modulate peripheral self-tolerance of the allogeneic fetus. The present study aimed to investigate the +49 A/G CTLA4 genetic polymorphism and predisposition to RSA.
The total participants were 120 women with at least two miscarriages and 120 healthy post-menopausal women as the control group. The +49 A/G polymorphism was genotyped using PCR-RFLP method. Required demographic information was collected through filling out a questionnaire. The obtained data were fed into SPSS software version 16.
The results showed a significant association between the minor alleles (G) with the decreased risk of the RSA. The frequency of the G allele in controls and patients was 25% and 12%, respectively. A GG genotype in the co-dominance model (OR: 0.25, 95%CI: 0.09–0.66) and in the dominant model for allele G (GG+AG vs. AA) (OR: 0.84, 95%CI: 0.8–0.87) showed significant association with RSA by imposing the protective role. The frequency of miscarriage is significantly (p=0.04) higher among the relatives of RSA women (33.3%) in comparison with the women in the control group (21.7%).
It can be concluded that +49G allele may act as a dominant allele and reduce the risk of RSA. Family history of miscarriage increased the risk of RSA among women.
PMCID: PMC4947202  PMID: 27478768
CTLA4; PCR-RFLP; Polymorphism; Recurrent spontaneous abortion
22.  Evidence of Paternal N5, N10 - Methylenetetrahydrofolate Reductase (MTHFR) C677T Gene Polymorphism in Couples with Recurrent Spontaneous Abortions (RSAs) in Kolar District- A South West of India 
Introduction: Recurrent spontaneous abortion (RSA) is a multifactorial clinical obstetrics complication commonly occurring in pregnancy. Many research studies have noted the mutations such as C677T in N5, N10 - Methylenetetrahydrofolate reductase (MTHFR)gene which is regarded as RSA risk factor. This study was carried out to determine the occurrence of frequency of C677T of the MTHFR gene mutations with RSA. Aim: The purpose of present study is to determine the frequency of MTHFR C677T polymorphisms in couples with recurrent pregnancy loss and the impact of paternal polymorphisms of MTHFR C677T in recurrent pregnancy loss in population of couples living in Kolar district of Karnataka with RSA.
Design: A total of 15 couples with a history of two or more unexplained RSA were enrolled as subjects in the study and a total of 15 couples with normal reproductive history, having two or more children and no history of miscarriages were enrolled as controls.
Materials and Methods: DNA extraction from samples case and control group couples and its quantification by Agarose gel electrophoresis, assessment of DNA purity, MTHFR C 677T gene mutation detection by PCR-RFLP method.
Statistical analysis: Carried out by web based online SPSS tool.
Results: The frequency of C677T genotype showed homozygous wild type CC (80%), heterozygous CT type (13.3%) and homozygous mutation TT type (6.67%) observed in males. Similarly from female’s homozygous wild type CC (86.6%), heterozygous type (13.3%), and homozygous type mutations TT (0%) was recorded. In couple control groups, we observed homozygous wild type CC (86.6%), heterozygous CT type (13.3%) and homozygous type mutations TT type (0%).
Conclusion: We noticed a high frequency of MTHFR specifically T allele associated with paternal side.Therefore, the present study indicated the impact of paternal gene polymorphism of MTHFR C677T on screening in couples with recurrent pregnancy loss.
PMCID: PMC4378727  PMID: 25859445
MTHFR C677T; MTHFR A1298C; Paternal polymorphism; RSA couples; T-allele
23.  Genetic association between FXIII and β-fibrinogen genes and women with recurrent spontaneous abortion: a meta- analysis 
FXIII Val34Leu (rs5985) and β-fibrinogen -455G/A (rs1800790) genotypes have been reported to be associated with recurrent spontaneous abortion (RSA). However, this topic is controversial. This study aimed to explore whether FXIII Val34Leu or β-fibrinogen -455G/A gene polymorphisms are related to RSA.
In this analysis, PubMed, HuGENet and Chinese National Knowledge Infrastructure (CNKI) databases were reviewed. Four models including the dominant model (Val/Val+Val/Leu vs. Leu/Leu), recessive model (Val/Val vs Val/Leu+Leu/Leu), co-dominant model (Val/Val vs. Val/Leu, Val/Val vs. Leu/Leu) and per-allele analysis (Val vs. Leu) were applied. The odds ratio (OR) with 95 % confidence interval (CI) was used to assess the association between RSA and FXIII Val34Leu and β-fibrinogen -455G/A polymorphisms.
Nine studies with 10 sets of data were included according to the inclusion criterion. A positive association was detected in the pooled results for the dominant model (Val/Val+Val/Leu vs. Leu/Leu; OR = 0.417, 95 % CI: 0.180–0.965, I2 = 45.60 %) and co-dominant model (Val/Val vs. Val/Leu; OR = 0.638, 95 % CI: 0.452–0.899, I2 = 36.40 %) for FXIII Val34Leu polymorphisms. However, no statistically significant association between β-fibrinogen -455G/A polymorphisms and RSA was detected in the four different models, including the Asian and Caucasian subgroup analyses.
Our meta-analysis demonstrates that the FXIII Val34Leu polymorphism has a close association with RSA and women who carry the Val allele for the FXIII Val34Leu polymorphism could have a protective effect against RSA. However, no association is detected between β-fibrinogen -455G/A polymorphisms and the risk of RSA. Future well-designed studies are needed to confirm these results.
PMCID: PMC4429447  PMID: 25862345
FXIII Val34Leu; β-fibrinogen -455G/A; Recurrent spontaneous abortion; Polymorphism; Gene
24.  Tumor Necrosis Factor-α Gene Polymorphisms in Korean Patients With Recurrent Spontaneous Abortion 
Reproductive Sciences  2013;20(4):408-413.
The objective of this study was to investigate the contribution of the tumor necrosis factor-α (TNF-α) gene polymorphisms to recurrent spontaneous abortion (RSA). The study participants consisted of 357 Korean women with RSA and 236 fertile women controls. Four TNF-α gene variants of all participants were analyzed by polymerase chain reaction–restriction fragment length polymorphism assay. The TNF-α -1031T>C and TNF-α -238G>A variants increased the risk of RSA TNF-α -1031TC+CC; adjusted odds ratio [AOR], 2.292; 95% confidence interval [CI], 1.547-3.395; P < .001; TNF-α -238GA+AA; AOR, 2.327; 95% CI, 1.038-5.217; P = .040), and these data were not different in a stratified analysis according to the number of consecutive spontaneous abortions. Also, the mutant genotypes of TNF-α -1031 and TNF-α -238 showed synergistic effects on increased RSA risk (-1031TC+CC/-238GA+AA; AOR, 4.054; 95% CI, 1.520-10.812; P = .005). In haplotype analysis, there were similar trends of data for combination analysis. In conclusion, the TNF-α -1031T>C and TNF-α -238G>A variants are possible genetic risk factors for RSA.
PMCID: PMC4077515  PMID: 23202728
tumor necrosis factor-α; recurrent spontaneous abortion; polymorphism; risk factor
25.  Association between male infertility and either the +331G/A or the progins polymorphism of the progesterone receptor gene in a Chinese population 
Progesterone has been suggested to contribute to the regulation of spermatogenesis and to facilitate the production of viable sperm. Investigations have showed that polymorphism of progesterone receptor (PGR) is associated with some diseases.
To analyze the potential relationship between male infertility and the +331G/A and progins polymorphisms of PGR gene.
Materials and Methods:
The cross-sectional study was carried out at the Department of Male Reproduction, Reproductive Medical Center, the Second Hospital of Jilin University. The restriction fragment length polymorphism (RFLP) technique was used to detect gene point mutations. Of the 145 semen samples analyzed, 35 were asthenozoospermic, 50 were oligoasthenozoospermic, 21 were azoospermic, 11 were teratozoospermic and 28 were from fertile male subjects.
Statistical analyses revealed that the genotypes of the +331G/A polymorphisms were in Hardy-Weinberg equilibrium in both the fertile (2=0, p=0.534) and oligospermic groups (2=0.021, p=0.537). Similarly, the genotypes of the progins polymorphisms were also in Hardy–Weinberg equilibrium in both the fertile (2=0, p=1) and oligospermic groups (2=0.005, p=1).
Our results indicated that polymorphisms of the +331G/A and progins of the PGR gene are unrelated to male infertility, at least in a Chinese population.
PMCID: PMC4306983  PMID: 25653674
Progesterone receptor; +331G/A polymorphism; Progins polymorphism; Male infertility

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