Progesterone Receptor Gene Polymorphisms and Breast Cancer Risk.

The objective of this systematic review was to investigate the association between polymorphisms in the progesterone receptor gene (PGR) and breast cancer risk. A search of PubMed, Scopus, and Web of Science databases was performed in November 2021. Study characteristics, minor allele frequencies, genotype frequencies, and odds ratios were extracted. Forty studies met the eligibility criteria and included 75 032 cases and 89 425 controls. Of the 84 PGR polymorphisms reported, 7 variants were associated with breast cancer risk in at least 1 study. These polymorphisms included an Alu insertion (intron 7) and rs1042838 (Val660Leu), also known as PROGINS. Other variants found to be associated with breast cancer risk included rs3740753 (Ser344Thr), rs10895068 (+331G/A), rs590688 (intron 2), rs1824128 (intron 3), and rs10895054 (intron 6). Increased risk of breast cancer was associated with rs1042838 (Val660Leu) in 2 studies, rs1824128 (intron 3) in 1 study, and rs10895054 (intron 6) in 1 study. The variant rs3740753 (Ser344Thr) was associated with decreased risk of breast cancer in 1 study. Mixed results were reported for rs590688 (intron 2), rs10895068 (+331G/A), and the Alu insertion. In a pooled analysis, the Alu insertion, rs1042838 (Val660Leu), rs3740753 (Ser344Thr), and rs10895068 (+331G/A) were not associated with breast cancer risk. Factors reported to contribute to differences in breast cancer risk associated with PGR polymorphisms included age, ethnicity, obesity, and postmenopausal hormone therapy use. PGR polymorphisms may have a small contribution to breast cancer risk in certain populations, but this is not conclusive with studies finding no association in larger, mixed populations.

Association between a progesterone receptor mutation and hepatitis E sero-positivity in liver transplant recipients.

PROBLEM: We investigated if the PROGINS mutation increases the risk of hepatitis E virus (HEV) infection in liver transplant recipients. PROGINS was analyzed through KASP assay; HEV serologies assessed via enzyme-linked immunosorbent assay and multiplex cytokine assays were evaluated in plasma with the ProcartaPlex human immunoassay. Seventy liver transplant recipients were evaluated, of which 23 (33%) were HEV immunoglobuln G (IgG)-positive (HEV+). The frequency of PROGINS in the HEV+ group was 34%, compared with 14% in those that were HEV IgG negative (HEV-). Cytokine measurements in a sub-set of samples from HEV+/PROGINS+ individuals showed decreased plasma levels of monokine induced by gamma interferon, a proliferation-inducing ligand, and stem cell factor, as well as increased levels of eotaxin-3 and interleukin-31 compared with those HEV-/PROGINS- samples. Our findings suggest an association between the PROGINS mutation and seropositivity for HEV in liver transplant recipients with consequent distorted cytokine levels.

The Neandertal Progesterone Receptor.

The hormone progesterone is important for preparing the uterine lining for egg implantation and for maintaining the early stages of pregnancy. The gene encoding the progesterone receptor (PGR) carries introgressed Neandertal haplotypes with two missense substitutions and a mobile Alu element. These Neandertal gene variants have reached nearly 20% frequency in non-Africans and have been associated with preterm birth. Here, we show that one of the missense substitutions appears fixed in Neandertals, while the other substitution as well as the Alu insertion were polymorphic among Neandertals. We show that two Neandertal haplotypes carrying the PGR gene entered the modern human population and that present-day carriers of the Neandertal haplotypes express higher levels of the receptor. In a cohort of present-day Britons, these carriers have more siblings, fewer miscarriages, and less bleeding during early pregnancy suggesting that the Neandertal progesterone receptor alleles promote fertility. This may explain their high frequency in modern human populations.

Molecular Evaluation of PROGINS Mutation in Progesterone Receptor Gene and Determination of its Frequency, Distribution Pattern and Association with Breast Cancer Susceptibility in Saudi Arabia.

AIMS: Experimental and clinical evidence demonstrate that progesterone hormone and its nuclear receptor, the Progesterone Receptor (PR), play critical role in controlling mammary gland tumorigenesis and breast cancer development. Hormonal therapy (Tomaxifen) is the frontline treatment for hormone-dependent breast cancers. Progesterone hormone induces its action on the target cells by binding with its Progesterone receptor (PgR) therefore any genetic variations, which might induce alienation in the progesterone receptor, can result in an increased susceptibility of gynecological cancers. Alu insertion (PROGINS) mutation in PgR gene is reported to be associated with an increased risk of ovarian cancer and a decreased risk of breast cancer. However, its association with breast cancer risk remains inconclusive. Therefore, we investigated the association of PROGINS allele and its link with breast cancer risk. METHODS: This case control study was performed on 200 subjects in which 100 were breast cancer cases and 100 gender matched healthy controls.The mutation was detected by using mutation specific PCR and results were confirmed by direct Sanger sequencing. RESULTS: A clinically significant difference was reported in genotype distribution of PROGINs allele among the cases and gender-matched healthy controls (P<0. 032). Genotype frequencies of A1/A1, A1/A2, A2/A2 reported in cases was 81%, 19% (18% & 1%) and in matched healthy controls were 93%, 7% (6% & 1%). The higher frequency of PROGINs allele (19%) was observed in cases than the healthy controls (7%). The findings indicated that PgR variants (CC vs CT) increased the risk of Breast cancer in codominant inheritance model with OR= 3.44, 95% CI =1. 30-9.09, P<0.021) whereas nonsignificant association was found for CC vs TT genotypes with OR=1.14, 95% CI=0.07-18.658, P=0. 92. However, subgroup analysis revealed that CT + TT vs CC genotype increased the risk of breast cancer in dominant inheritance model tested OR = 3. 11, 95% CI = (1.24-7.79), P = 0.015). A nonsignificant association for PgR (CC+CT) vs TT) genotypes were reported in breast cancer OR = 1. 0, 95% CI= (0. 061-16.21), P=1) in recessive inheritance model tested. However, analysis with clinicalpathological variables revealed that the PROGINs allele is significantly associated with the distant metastasis and advanced stage of the disease. CONCLUSION: The mutation specific PCR was successfully developed as an alternative to Sanger sequencing for the cost-effective detection for PROGINS allele of progesterone receptor gene. A clinically significant correlation of PROGINs allele was reported with the distant metastasis and advanced stage of the disease. Taken together, these results demonstrated that PROGINS variant is associated with an increased susceptibility to Breast cancer, providing novel insights into the genetic etiology and underlying biology of Breast carcinogenesis. Further studies with large sample sizes are required to validate our findings.

Mutations in the Progesterone Receptor (PROGINS) May Reduce the Symptoms of Acute Hepatitis E and Protect Against Infection.

BACKGROUND: Mutations in the progesterone receptor (PR) gene, PROGINS, have been studied in relation to hepatitis E virus (HEV) infection. Patients with the PROGINS gene may develop a worse clinical course of hepatitis E. The aim of our study was to evaluate the influence of PROGINS on the susceptibility to and the clinical course of HEV infection in HIV patients. METHODS: This study included patients with HIV who were evaluated in previous prospective studies for the prevalence and incidence of HEV. The following three groups of patients were studied: (i) never infected, (ii) past infections, and (iii) recently infected. We determined the PR genotype to evaluate the proportion of patients who were homozygous for PROGINS according to HEV infection. We also compared the proportion of PROGINS carriers with a recent HEV infection according to their symptomatology. RESULTS: In this study, 311 patients infected with HIV were included. Of those patients, 198 were homozygous wild type (63.7%), 91 were heterozygous (29.3%), and 22 were homozygous PROGINS (7.1%). We found that the homozygous PROGINS genotype in women was associated with a lower HEV seroprevalence. In addition, in patients with a recent HEV infection, none of those homozygous for PROGINS presented symptoms. CONCLUSION: The PROGINS mutation plays a protective role against HEV infection and is associated with subclinical infection in HIV-infected patients, particularly women.

PROGINS Polymorphism of the Progesterone Receptor Gene and the Susceptibility to Uterine Leiomyomas: A Systematic Review and Meta-Analysis.

AIMS: Steroid hormones play a central role in modulating the growth of uterine leiomyoma, and several studies have suggested that polymorphisms in genes encoding these hormones and their receptors may be risk factors for developing the disease. Progesterone is a potent antagonist of estrogen-induced proliferation in the endometrium, and the PROGINS polymorphisms have been associated with leiomyoma, but the results are inconsistent. In this study, we aimed to investigate the possible associations between the PROGINS polymorphisms and uterine leiomyoma. MATERIALS AND METHODS: MEDLINE using PubMed, Science Direct, and Google Scholar databases was searched using the terms "PROGINS," "progesterone receptor," "polymorphism," and "leiomyoma." We estimated risk with odds ratios [ORs] and 95% confidence intervals using standard genetic models (homozygous, recessive, dominant, and codominant). RESULTS: Six studies were included in this meta-analysis based on 837 cases and 1011 controls. Subjects in three studies were Asian (365 cases/391 controls), and five were non-Asian (472 cases/620 controls). Our findings showed no association between PROGINS and leiomyoma in the overall analysis (OR 0.91-1.07, p = 0.15-0.57) nor in either of the subgroups (Asian: OR 0.84-1.04, p = 0.68-0.98; or non-Asian: OR 0.77-1.34, p = 0.33-0.93), in all genetic models. CONCLUSION: The PROGINS polymorphisms cannot be considered a risk factor for developing uterine leiomyoma.

Association of the Alu insertion polymorphism in the progesterone receptor gene with breast cancer in a Mexican population.

INTRODUCTION: The progesterone receptor (PR) gene plays an important role in reproduction-related events. Data on polymorphisms in the PR gene have revealed associations with cancer, particularly for the Alu insertion polymorphism, which has been suggested to affect progesterone receptor function and contribute to tumor promotion in the mammary gland. MATERIAL AND METHODS: We examined the role of the Alu insertion polymorphism in the PR gene by comparing the genotypes of 209 healthy Mexican women with those of 481 Mexican women with breast cancer (BC). RESULTS: The genotype frequencies observed in the controls and BC patients were 0% and 4% for T2/T2 (Alu insertion), 16% and 21% for T1/T2, and 84% and 75% for T1/T1 (Alu deletion), respectively. The obtained odds ratio (OR) was 1.7, with a 95% confidence interval (95% CI) of 1.1-2.6, p = 0.009, for the T1/T2-T2/T2 genotypes. The association was also evident when the distributions of the T1/T2-T2/T2 genotypes in patients in the following categories were compared: obesity grade II (OR = 1.81, 95% CI: 1.03-3.18, p = 0.039) and the chemotherapy response (OR = 1.91, 95% CI: 1.27-3.067, p = 0.002). CONCLUSIONS: The T1/T2-T2/T2 genotypes of the Alu insertion polymorphism in the PR gene are associated with BC susceptibility in the analyzed Mexican population.

Association between male infertility and either the +331G/A or the progins polymorphism of the progesterone receptor gene in a Chinese population.

BACKGROUND: 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. OBJECTIVE: 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. RESULTS: 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). CONCLUSION: 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.

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.

UNLABELLED: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

The progins progesterone receptor gene polymorphism is not related to endometriosis-associated infertility or to idiopathic infertility

OBJECTIVE: 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. INTRODUCTION: 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. METHODS: 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. RESULTS: Genotypes P1P1, P1P2 and P2P2 (P2 representing the PROGINS polymorphism) of the progesterone receptor gene presented frequencies of 93.9 percent, 5.4 percent and 0.7 percent, respectively, in the women with endometriosis-associated infertility (p=0.2101, OR=0.51, 95 percent CI=0.24-1.09); 94.4 percent, 4.2 percent and 1.4 percent, respectively, in the patients with minimal/mild endometriosis (p=0.2725, OR=0.53, 95 percent CI=0.20-1.43); 93.5 percent, 6.5 percent and 0 percent, respectively, among the patients with moderate/severe endometriosis (p=0.3679, OR=0.49, 95 percent CI=0.18-1.31); 86.0 percent, 14.0 percent and 0 percent, respectively, in idiopathic infertile women (p=0.8146, OR=1.10, 95 percent CI=0.46-2.63); and 88.3 percent, 10.6 percent and 1.1 percent, respectively, in the control group. CONCLUSION: The data suggest that PROGINS is not related either to endometriosis-associated infertility or to idiopathic infertility in the population studied.

A study on association of progesterone receptor gene polymorphism (PROGINS) with Endometriosis

PURPOSE: Endometriosis is a steroid dependent disease with a particular genetic background but the location of possible genomic aberrations are still poorly clarified. This study was designed to investigate the associations between the polymorphism of the progesterone receptor gene (PROGINS) and endometriosis. METHODS: 100 women with surgically diagnosed and histologically confirmed endometriosis were enrolled as a patient population and a total of 110 female control subjects undergoing health examination were enrolled as control population. DNA extraction and polymerase chain reaction (PCR) were used to genotype women for the presence of the PROGINS polymorphism in peripheral blood samples. The x2-test was used to compare genotype distributions between endometriosis and controls. RESULTS: T1/T2 heterozygote was found to be one patient in each group, and the rest of the subjects were all T1/T1 homozygotes. There was no difference in the genotype distribution between the endometriosis group and the control group. CONCLUSION: These results suggest that the progesterone receptor gene PROGINS is not associated with the risk for endometriosis.

Association of Progesterone Receptor Gene Polymorphism (PROGINS) and Estrogen Receptor Gene Polymorphism with Endometriosis in Korean Population / 대한산부인과학회지

OBJECTIVE: Endometriosis is defined as the presence of endometrial tissue outside the uterus, causing diverse progressive diseases such as infertility, pelvic pain, and dysmenorrhea. Although the mechanisms responsible for its pathogenesis and progression remain poorly understood, it is well established that endometriosis grows and regresses in an estrogen-dependent fashion and that administration of progestin can relieve the symptoms caused by endometriosis. Some genetic studies have demonstrated the association between the estrogen or progesterone receptor gene polymorphism and the susceptibility to endometriosis. This study was designed to investigate the associations of the polymorphism of the progesterone receptor gene (PROGINS), PvuII and XbaI polymorphism of estrogen alpha receptor gene with endometriosis in the Korean population. METHODS: A total of 100 women with surgically diagnosed and histologically confirmed endometriosis of stage III-IV were enrolled as a patient population and a total of 110 female control subjects undergoing health examination were enrolled as control population. Following isolation of genomic DNA from peripheral blood, polymerase chain reaction-sequence specific primer assays were performed for analyzing progesterone receptor gene polymorphism (PROGINS) and polymerase chain reaction-restriction fragment length polymorphism assays were performed for analyzing estrogen alpha receptor gene PvuII and XbaI polymorphism. The chi-square-test was used to compare genotype distributions between endometriosis and controls. RESULTS: Only one patient in each group was found to be T1/T2 heterozygote, and the rest of the subjects were all T1/T1 homozygotes. Analysis of PvuII has shown that the significantly lower number of patients had (pp) genotypes and (p) alleles in the endometriosis group compared with the control group (32 (32%) vs. 50 (45.5%), P<0.05; 109 (54.5%) vs. 142 (64.5%), P<0.05, respectively). There was no difference in the genotype distribution or allele frequency in XbaI polymorphism between the endometriosis group and the control group. CONCLUSION: These results suggest that the PvuII polymorphism of the estrogen receptor-alpha gene is associated with the risk for endometriosis in the Korean population.