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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.  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
3.  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
4.  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
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.  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
9.  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
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.  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
12.  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
13.  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
14.  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
15.  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
16.  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
17.  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
18.  An immunohistochemical study of CD83- and CD1a-positive dendritic cells in the decidua of women with recurrent spontaneous abortion 
There are more and more women with recurrent spontaneous abortion (RSA). The mechanism of RSA is still unclear. Immunological factors have been postulated to play a role in the etiology of RSA. Dendritic cells (DCs) are the most potent antigen-presenting cells in the immune system, and the decidual DCs may take part in the occurrence of RSA. The difference in maturity status of decidual DCs among women with RSA and women with normal pregnancies is worthy of studying for its application to prevention and therapy.
The EnVision two-step immunohistochemical staining technique was used to detect the expression of CD83 and CD1a in the decidua of women with RSA (30 cases) and normal pregnancies (30 cases). The maturity status, distribution and quantity of DCs in the two groups were observed. Observation of the staining and cell counting were done using microscope within 30 randomly selected high-power fields (HPF, 40 × 10). All data analyses were conducted with SPSS 17.0 and the statistical significance was set at P <0.05.
The decidua from the two groups contained DCs that stained with the anti-CD83 and anti-CD1a antibody. Most of the decidual CD83+DCs from two groups were located in the stroma. There were more CD83+DCs clustered with other DCs in the stroma from women with RSA than normal pregnancies. Most of the CD1a+DCs in the decidua from the two groups are located close to maternal glandular epithelium. No difference in the location of CD1a+DCs was found in the decidua between two groups. The number of decidual CD83+DCs was statistically significantly higher in RSA women than in normal early pregnant women (14.20 ± 13.34/30 HPF versus 4.77 ± 2.64/30 HPF; t = 3.800, P = 0.001). The number of CD1a+DCs in the decidua was statistically significantly lower in RSA women compared with normal early pregnant women (3.97 ± 3.75/30 HPF versus 7.60 ± 6.08/30 HPF; t = 2.786, P = 0.008).
These findings suggest that the increase in the number of mature DCs and the decrease in the quantity of immature DCs in the decidua may be related to RSA. The maturation of decidual DCs may play an important role in the pathogenesis of RSA.
PMCID: PMC4301856  PMID: 25563385
recurrent spontaneous abortion; decidua; dendritic cells; CD83; CD1a; immunohistochemistry
19.  HLA allele associations in idiopathic recurrent spontaneous abortion patients from India 
Rejection of semiallogenic foetus in recurrent spontaneous abortion (RSA) has been postulated to be a consequence of genetic and immunological phenomena.
To evaluate the role of human leukocyte antigen (HLA) alleles in RSA in Indian couples.
A case-control study.
Eighty-one randomly selected couples with unexplained three or more RSAs and a control group of 97 couples with live birth belonging to the same ethnic background, referred to the Gynaecology Department, KEM Hospital were included in the case-control study. Serological HLA A and B typing was done followed by molecular subtypes, defined using PCR-SSOP technique for HLA A, B, and C in 40 couples and DRB1* and DQB1* in 28 couples which were then compared with appropriate case 46 and 88 controls.
Serologically A3 (15.43% vs. 4.43%; odds ratio (OR) = 4.34; P = 0.0002) and B17 (25.3% vs. 11.34%; OR = 3.49; P = 0.0001) were increased. Haplotype A1-B17 was significantly increased. Molecular subtyping revealed that A*030102 (11.25% vs. 4.34%; OR = 3.00; P = 0.07), B*5701 (11.25% vs. 1.08%; OR = 13.10; P = 0.003), Cw*120201 (25% vs. 4.34%; OR = 10.50; P = 2.05E-05), HLA DRB1*030101 (17.85% vs. 3.40%; OR = 7.6; P = 0.0001), DRB1*150101 (32.14% vs. 13.63%; OR = 4.8; P = 0.0003), and DQB1*060101 (35.71% vs. 29.34%; OR = 2.3; P = 0.004) were significantly increased in patients. A differential association was noticed when compared with reported world RSA patients.
The HLA alleles A*030101, B*5701, Cw*120201, DRB1*030101, and DRB1*150101 as well as their associated ancestral haplotype may play a significant role in development of RSA in India.
PMCID: PMC2700679  PMID: 19562059
Cw*120201; DQB1*050301 association; HLA B*5701; India; RSA
20.  Autoantibody profile and other immunological parameters in recurrent spontaneous abortion patients 
An autoimmune cause and related immunological alterations resulting in recurrent spontaneous abortion (RSA) have been suggested in patients with unknown etiology.
Materials and Methods:
This study evaluated the autoantibody profile and other immunological parameters among RSA patients and normal pregnant women from Mumbai western India. Fifty RSA patients with unknown cause and greater than three consecutive abortions along with 50 normal pregnant women were studied for various auto antibodies such as ANA, anti-dsDNA, ANCA, AECA, 2 micro globulin, anti-HLA antibodies and ACLA using immunofluorescence microlymphocytotoxicity and ELISA. Immunological parameters such as HLA class I monoclonal antibody expression, CD3 (T cell), CD19 (B cell), and CD56 (NK cell) were estimated by flow cytometry.
The results revealed 34% positivity of all auto antibodies tested among patients. ANA(12%), ANCA (20%), AECA (24%), ACLA (8%), anti-dsDNA(0%), β2 microglobulin (14%), and anti-HLA antibodies(10%) among RSA patients were identified. An increased expression of HLA class I specific monoclonal antibody (10%) with HLA A3 (16%) specificity were found to correlate with shared HLA alleles among the RSA couples. Among normal pregnant (control) group ANA (2%), ANCA (2%), AECA (3%), ACLA (4%) and increased expression of CD56 with reduced HLA class I monoclonal were observed.
Our findings suggest a possible role of various autoantibodies along with the related immunological parameters underlying RSA.
PMCID: PMC3213746  PMID: 22082909
Autoantibody; Human leukocyte antigen; India; Recurrent spontanous abortion
21.  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
22.  Glutathione S-transferase A1 polymorphism and the risk of recurrent spontaneous abortion in Chinese Han population 
Recurrent spontaneous abortion (RSA) is a multifactor and distressing disease. There are still approximately half of the RSA patients with cause not being identified to date. Accumulating studies have confirmed that genetic polymorphisms in glutathione S-transferases (GSTs) were associated with the risk of recurrent spontaneous abortion. In this study, we aimed to investigate the relationship between the polymorphism of GSTA1, which is GSTA1 -69C/T (rs3957357), and the development of recurrent spontaneous abortion.
A case–control study of 127 cases with RSA and 112 ethnic and age matched women as controls was conducted. And measurement of Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) was performed to genotype all of samples in order to analyze the association between GSTA1 -69C/T (rs3957357) and the risk of RSA.
We found that the frequencies of genotypes between cases and controls have no significant difference (P = 0.908) and GSTA1 mutant allele GSTA1 −69 T was present at a frequency of 0.122 in case group, while in controls the frequency was 0.125 (P = 0.922).
The polymorphism of GSTA1 (rs3957357) may not be associated with the risk of recurrent spontaneous abortion in Chinese Han population.
PMCID: PMC3947069  PMID: 24390679
GSTA1; Recurrent spontaneous abortion; Variant; Genetics
23.  RsaI but not DraI polymorphism in CYP2E1 gene increases the risk of gastrointestinal cancer in Malaysians: a case–control study 
BMJ Open  2014;4(1):e004109.
Our study aimed to investigate the association of CYP2E1 C-1019T RsaI and T7678A DraI polymorphisms and factors such as age, gender and ethnicity to the risk of gastrointestinal cancer (GIC) in Malaysians.
Case–control study.
520 consented healthy blood donors with no previous GIC record and 175 patients with GIC.
C-1019T RsaI and T7678A DraI genotyping of CYP2E1 gene; direct sequencing.
This study reveals that the variant c2 allele and carrier with at least one c2 allele of C-1019T single nucleotide polymorphism (SNP) significantly increased the risk of GIC but no significant association was found between T7678A SNP and combined analysis of C-1019T and T7678A SNPs to risk of GIC. The Malaysian Chinese had greater risk of GIC compared with the Malays, Indians and KadazanDusun. An increased risk of GIC was observed in individuals aged >40 years and women had a 2.22-fold and 1.58-fold increased risk of stomach and colorectal cancers, respectively, when compared with men.
The future research should be conducted with a larger sample population and including the gene–gene and gene–environmental interactions.
Our study suggests that the rare c2 allele and carrier with at least one c2 allele of CYP2E1 RsaI polymorphism significantly elevated the risk of GIC and may be used as a genetic biomarker for early screening of GIC in Malaysians. The risk age-group has been shifted to a younger age at 40s and women showed a significant greater risk of stomach and colorectal cancers than men.
PMCID: PMC3902529  PMID: 24394801
Gastroenterology; Molecular Biology
24.  Prevalence of ERα-397 PvuII C/T, ERα-351 XbaI A/G and PGR PROGINS polymorphisms in Brazilian breast cancer-unaffected women 
Polymorphisms of hormone receptor genes have been linked to modifications in reproductive factors and to an increased risk of breast cancer (BC). In the present study, we have determined the allelic and genotypic frequencies of the ERα-397 PvuII C/T, ERα-351 XbaI A/G and PGR PROGINS polymorphisms and investigated their relationship with mammographic density, body mass index (BMI) and other risk factors for BC. A consecutive and unselected sample of 750 Brazilian BC-unaffected women enrolled in a mammography screening program was recruited. The distribution of PGR PROGINS genotypic frequencies was 72.5, 25.5 and 2.0% for A1A1, A1A2 and A2A2, respectively, which was equivalent to that encountered in other studies with healthy women. The distribution of ERα genotypes was: ERα-397 PvuII C/T: 32.3% TT, 47.5% TC, and 20.2% CC; ERα-351 XbaI A/G: 46.3% AA, 41.7% AG and 12.0% GG. ERα haplotypes were 53.5% PX, 14.3% Px, 0.3% pX, and 32.0% px. These were significantly different from most previously published reports worldwide (P < 0.05). Overall, the PGR PROGINS genotypes A2A2 and A1A2 were associated with fatty and moderately fatty breast tissue. The same genotypes were also associated with a high BMI in postmenopausal women. In addition, the ERα-351 XbaI GG genotype was associated with menarche ≥12 years (P = 0.02). ERα and PGR polymorphisms have a phenotypic effect and may play an important role in BC risk determination. Finally, if confirmed in BC patients, these associations could have important implications for mammographic screening and strategies and may be helpful to identify women at higher risk for the disease.
PMCID: PMC3854186  PMID: 22584640
Genetic polymorphisms; Estrogen receptor gene; Progesterone receptor gene; Breast cancer susceptibility
25.  MYBPC3 gene variations in hypertrophic cardiomyopathy patients in India 
Hypertrophic cardiomyopathy (HCM) is a complex cardiac muscular disorder, inherited as an autosomal dominant disease with variable penetrance. Cardiac myosin-binding protein C (MyBPC) is the predominant myosin-binding protein isoform in the heart muscle. One hundred forty-seven mutations have been detected in MYBPC3, accounting for 15% of all HCM cases.
To screen exons 16, 18, 19, 22, 24, 28, 30, 31 and 34 in the MYBPC3 gene in Indian HCM patients.
Sixty control and 95 HCM samples were collected from cardiology units of the CARE Hospital (Nampally, Banjara Hills, Secunderabad, India) for genomic DNA isolation followed by polymerase chain reaction and single-stranded conformational polymorphism analysis.
Screening of the exons revealed two variations – one novel frame shift mutation in exon 19 at the nucleotide position 11577^11578 and one novel single nucleotide polymorphism (SNP) in codon 1093 of exon 31, coding for glycine with a C>T transition (GGC/GGT), in addition to the seven known SNPs mainly in the intronic region and one known missense mutation D770N in this population.
The novel frame shift mutation identified in exon 19, D570fs, with the insertion of an adenine residue in codon 570 coding for aspartate, results in a premature termination codon that produces a truncated protein lacking myosin- and titin-binding sites, explaining the role of the nonsense-mediated decay pathway. A novel SNP identified in codon 1093 of exon 31 was found to be a synonymous codon, which may have a regulatory effect at the translational level, attributing to affinity differences between codon-anticodon interactions. The screening of this gene may be relevant in the Indian context.
PMCID: PMC2644567  PMID: 18273486
Hypertrophic cardiomyopathy; MYBPC3; Nonsense-mediated decay pathway; Novel mutation

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