The possible effects of the MTOR polymorphisms on preeclampsia susceptibility, severity, and onset: a case-control study and in silico analysis.

BACKGROUND: Preeclampsia (PE) is a gestational complication with developed hypertension and proteinuria. Evidence showed the role of mTOR in various cellular processes. Therefore, this study aimed to evaluate the effects of MTOR polymorphisms on susceptibility, severity, and onset of Preeclampsia (PE). METHODS AND RESULTS: A total of 250 PE pregnant women and 258 age-matched control subjects were recruited in this study. To genotype MTOR polymorphisms, the PCR-RFLP method was used. The SpliceAid 2 and PROMO tools were used for in silico analysis. The maternal MTOR rs17036508T/C polymorphism was associated with PE risk in various genetic models. There was no relationship between rs2536T/C and rs2295080T/G polymorphisms and PE. The TTC and TGC haplotypes of rs2536/ rs2295080/ rs17036508 polymorphisms were significantly higher in PE women. Subgroup analysis revealed the association between the MTOR rs2295080 variant and an increased risk of Early-onset PE (EOPE). However, the MTOR rs17036508 was associated with a higher risk of EOPE and Late- Onset PE. In addition, the MTOR rs2295080 could increase the risk of severe PE. The results of the in silico analysis showed that rs17036508 disrupted several binding motifs in the mutant sequence. The PROMO database revealed that the T to C substitution leads to the loss of the TFII-I binding site in the mutant allele. CONCLUSION: The MTOR rs17036508T/C polymorphism was associated with PE risk. There was an association between the MTOR rs2295080 variant and an increased risk of EOPE. The MTOR rs17036508T/C and rs2295080T/C variants could disrupt several binding motifs and TFII-I binding respectively.

The effects of ANRIL polymorphisms on colorectal cancer, tumor stage, and tumor grade among Iranian population.

BACKGROUND: Colorectal cancer (CRC) is a type of neoplasm, developing in the colon or rectum. The exact etiology of CRC is not well known, but the role of genetic, epigenetic, and environmental factors are established in its pathogenesis. Therefore, the aim of this research was to explore the effects of ANRIL polymorphisms on the CRC and its clinical findings. METHODS AND RESULTS: The peripheral blood specimens were collected from 142 CRC patients and 225 controls referred to Milad Hospital, Tehran, Iran. PCR- RFLP method was used to analyze ANRIL rs1333040, rs10757274 rs4977574, and rs1333048 polymorphisms. The ANRIL rs1333040 polymorphism was related to a higher risk of CRC in the co-dominant, dominant, and log-additive models. ANRIL rs10757274, rs4977574, and rs1333048 polymorphisms showed no effect on CRC susceptibility. The CGAA and TGGA haplotypes of ANRIL rs1333040/ rs10757274/ rs4977574/rs1333048 polymorphisms were associated with the higher and the lower risk of CRC respectively. The rs1333040 polymorphism was associated with higher TNM stages (III and IV). The frequency of ANRIL rs10757274 polymorphism was lower in CRC patients over 50 years of age only in the dominant model. In addition, the rs10757274 was associated with well differentiation in CRC patients. CONCLUSION: The ANRIL rs1333040 polymorphism was associated with a higher risk of CRC and higher TNM stages. ANRIL rs10757274 polymorphism was associated with the well-differentiated tumor in CRC.

Association of AXIN1 rs12921862 C/A and rs1805105 G/A and CTSB rs12898 G/A polymorphisms with papillary thyroid carcinoma: A case-control study.

BACKGROUND: Papillary thyroid cancer (PTC) is the most common type of thyroid cancer which its precise etiology remains unknown. However, environmental and genetic factors contribute to the etiology of PTC. Axis inhibition protein 1 (Axin1) is a scaffold protein that exerts its role as a tumor suppressor. In addition, Cathepsin B (Ctsb) is a cysteine protease with higher expression in several types of tumors. Therefore, the aim of this study was to investigate the possible association of AXIN1 rs12921862 C/A and rs1805105 G/A and CTSB rs12898 G/A polymorphisms with PTC susceptibility. MATERIALS & METHODS: In total, 156 PTC patients and 158 sex-, age-, and BMI-matched control subjects were enrolled in the study. AXIN1 rs12921862 C/A and rs1805105 G/A and CTSB rs12898 G/A polymorphisms were genotyped using the PCR-RFLP method. RESULTS: There was a relationship between AXIN1 rs12921862 C/A polymorphism and an increased risk of PTC in all genetic models except the overdominant model. The AXIN1 rs1805105 G/A polymorphism was associated with an increased PTC risk only in codominant and overdominant models. The frequency of AXIN1 Ars12921862 Ars1805105 haplotype was higher in the PTC group and also this haplotype was associated with an increased risk of PTC. Moreover, the AXIN1 rs12921862 C/A polymorphism was not associated with PTC clinical and pathological findings, but AXIN1 rs1805105 G/A polymorphism was associated with almost three folds of larger tumor size (≥1 cm). There was no association between CTSB rs12898 G/A polymorphism and PTC and its findings. CONCLUSION: The AXIN1 rs12921862 C/A and rs1805105 G/A polymorphisms were associated with PTC. AXIN1 rs1805105 G/A polymorphism was associated with higher tumor size.

Impact of Survivin rs9904341 and rs17878467 Polymorphisms On Risk of Preeclampsia in Iran.

Preeclampsia (PE) is a hypertensive disorder that affects pregnancy, mother, and fetus. Early diagnosis of PE remains a challenge. This study aimed to investigate the association between survivin two (rs9904341 and rs17878467) SNPs and PE risk in healthy pregnant women compared to women with preeclampsia. A sample of 166 healthy pregnant women and 160 cases with preeclampsia was included and genotyped for rs9904341 with polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and rs17878467 with amplification-refractory mutation system (ARMS) PCR. The genotypic and allelic assessments were performed using various statistical approaches. The frequency of rs9904341 and rs17878467 polymorphisms was not significantly different between PE and healthy pregnant women. rs9904341: codominant (p = 0.5), dominant (p = 0.24), recessive (p = 0.61), over-dominant model (p = 0.38), and log additive (p = 0.25). rs17878467: codominant (p = 0.41), dominant (p = 0.23), recessive (p = 0.4), over-dominant model (p = 0.42), and log additive (p = 0.24). The frequency of survivin rs9904341 CG and CC genotypes was higher in severe PE women compared to controls and this polymorphism was associated with PE severity only in the dominant model (OR = 1.84, CI 1.04-3.26, P = 0.034). There was a significant association between survivin rs9904341 polymorphism and PE severity. No relationship was found between survivin rs9904341 and rs17878467 polymorphisms and PE onset. The allelic and genotypic frequencies of survivin rs9904341 and rs17878467 polymorphisms are not significantly different between the preeclampsia and control groups in all genetic models. Haplotype analysis showed lower frequency G rs9904341 T rs17878467 haplotype in PE woman and this haplotype was associated with lower risk of PE (OR = 0.54, CI 0.33-0.91, P = 0.02).

Association of Genetic Polymorphisms in Long Noncoding RNA HOTTIP with Risk of Idiopathic Recurrent Spontaneous Abortion.

The clustered homeobox gene family known as the Hox family plays a fundamental role in the morphogenesis of the vertebrate's embryo. A long noncoding RNA (lncRNA), known as HOTTIP (HOXA transcript at the distal tip), has been functionally characterized and contributed to the pathogenesis of various conditions. The current case-control study was undertaken to examine the gene frequencies and shared alleles of the HOTTIP  gene in Iranian participants with or without idiopathic recurrent spontaneous abortion (RSA). Both ARMS-PCR reaction and RFLP-PCR techniques were employed to detect three HOTTIP polymorphisms (rs2023843C/T, rs78248039A/T, and rs1859168C/A) in a DNA sample of 161 women with RSA and 177 healthy women. We found that the TT genotype of the HOTTIP rs2023843 C/T polymorphism was associated with a lower risk for idiopathic RSA. In contrast, the TT genotype of the HOTTIP rs78248039 A/T polymorphism was correlated with an enhanced risk of RSA. The presence of the A-allele for HOTTIP rs1859168 C/A polymorphism was associated with an increased risk for idiopathic RSA. Haplotype analysis showed that the T/T/A, C/T/A, T/T/C, and T/A/A haplotypes of rs2023843/rs78248039/rs1859168 enhanced RSA susceptibility. Computational analysis predicted that this lncRNA might act as a potential sponge for some microRNAs; therefore, affecting the expression of genes being targeted by them. In addition, both rs2023843 and rs1859168 variants could alter the local secondary structure of HOTTIP. Our results showed that HOTTIP rs2023843C/T, rs78248039A/T, and rs1859168C/A polymorphisms may confer genetic susceptibility to idiopathic RSA in an Iranian population.

Genetic variants of HOTAIR are associated with susceptibility to recurrent spontaneous abortion: A preliminary case-control study.

AIM: To investigate the association between Hox transcript antisenses RNA (HOTAIR) polymorphisms, rs12826786 C/T, rs920778 T/C, rs4759314 A/G, and rs1899663 G/T, with recurrent spontaneous abortion (RSA) susceptibility in the Iranian women. METHODS: We enrolled 161 patients diagnosed with RSA and 177 healthy women with at least one live birth without a history of abortion. Genotyping of HOTAIR polymorphisms was carried out using both restriction fragment length polymorphism-polymerase chain reaction and amplification refractory mutation system-polymerase chain reaction methods. Odds ratios (ORs) with 95% confidence intervals (CIs) were assessed to estimate the strength of association. RESULTS: Different inheritance models of rs12826786 C/T, rs920778 T/C, and rs1899663 G/T polymorphisms significantly enhanced the risk of RSA (p < 0.05), whereas the rs4759314 A/G polymorphism was correlated with diminished risk of developing RSA under recessive AA versus GA + GG (OR 0.42 [95% CI = 0.19-0.91]), log-additive GG versus GA vs. GG (OR 0.67 [95% CI = 0.48-0.93]), and allelic A versus G (OR 0.65 [95% CI = 0.47-0.92]) models. Moreover, the TGTC, TTCT, TTTC, CGTC, CGTT, CTCC, CTCT, CTTC, and CTTT haplotypes of rs920778/rs1899663/rs12826786/ significantly increased the risk of RSA. The studied variants were not in strong linkage disequilibrium. CONCLUSIONS: Our results indicated that variations in the HOTAIR gene might serve as beneficial biomarkers for determining susceptibility to RSA. To confirm these findings, replication studies with a larger population and different races are needed.

Effects of the MTOR and AKT1 genes polymorphisms on papillary thyroid cancer development.

Papillary thyroid cancer (PTC) is the most common form of thyroid cancer, comprising 80% of all thyroid malignancies. The phosphoinositide-3-kinase-protein kinase B/Akt (PI3K-PKB/Akt) pathway is a main pathway in control of cell growth. Activated mTOR and Akt are involved in the development and progression of the PTC. This study aimed to evaluate the effects of MTOR (rs2536 and rs2295080) and AKT1 (rs2494732, rs1130214, and rs1130233) polymorphisms on PTC susceptibility. This study was conducted on 131 PTC patients and 144 healthy subjects. Genotype analysis was done using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methods. Our results showed no statistically significant association between MTOR rs2536, AKT1 rs2494732, and rs1130214 polymorphisms and PTC development. However, MTOR rs2295080 polymorphism was found to be associated with a decreased risk of PTC in dominant and allelic models. The TT genotype of AKT1 rs1130233 was significantly higher in the PTC group in comparison to the controls, with a 3.5-fold increased risk for developing PTC. Furthermore, the allelic distribution also showed the T allele of rs1130233 as a risk factor for PTC occurrence. In conclusion, our results suggest the MTOR rs2295080 and AkT1 rs1130233 as the protective and risk factors for PTC development, respectively.

The effect of TP53 and P21 gene polymorphisms on papillary thyroid carcinoma susceptibility and clinical/pathological features.

Papillary thyroid cancer (PTC) is the most common thyroid malignancy. Genetic polymorphisms of the TP53 and P21 genes are the candidate variants in various cancers development. This study investigated whether the polymorphisms in TP53 (rs1042522) and P21 (rs1059234 and rs1801270) affect the risk of PTC and whether such the genotype of these polymorphisms is associated with pathological and clinical characteristics of PTC. A case-control study was conducted with 286 Iranian people, including 131 PTC cases and 155 healthy controls. The genetic polymorphisms were investigated by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Our results suggested that TP53-rs1042522 CC genotype was significantly associated with protection against PTC, in the dominant, recessive and allelic models (OR = 0.4, 95%CI: 0.2-0.8, P = .008; OR = 0.5, 95%CI: 0.3-0.9, P = .01; OR = 0.6, 95%CI: 0.4-0.8, P = .002, respectively). The rs1042522 was associated with PTC patients with tumor size greater than 1 cm in dominant and recessive models (OR = 0.2, 95%CI = 0.04-0.9, P = .04 and OR = 0.3, 95%CI = 0.1-0.7, P = .009, respectively) and was associated with vascular invasion in dominant model (OR = 0.3, 95%CI = 0.1-0.7, P = .01). No correlation was identified between P21 rs1059234 and rs1801270 polymorphisms and risk of PTC and pathological and clinical characteristics of PTC. Genetic variations in rs1042522 might alter the PTC risk, which could affect tumor size and cause lower incidence of vascular invasion in PTC cases. This was the first report suggesting that no correlation was found between P21 rs1059234 and rs1801270 polymorphisms and PTC risk. Thus, more studies with a larger population size and different ethnic groups and functional assays are needed to confirm our results.

The effects of placental long noncoding RNA H19 polymorphisms and promoter methylation on H19 expression in association with preeclampsia susceptibility.

The effect of DNA methylation on gene expression triggered it as a susceptibility factor in various diseases including preeclampsia (PE). The pathogenesis of PE is closely associated with the methylation status and genetic variants of relevant genes. Therefore, the aim of the study was to investigate the possible impacts of the placental DNA methylation and rs3741219, rs217727, and rs2107425 polymorphisms of the H19 gene on the PE susceptibility as well as the its mRNA expression. Moreover, eight haplotypes of three loci in the H19 gene were analyzed. In this case-control study, the placentas of 107 preeclamptic and 113 non-preeclamptic women were collected after delivery. The methylation status was assessed by methylation-specific polymerase chain reaction (PCR). The H19 polymorphisms were genotyped using polymerase chain reaction-restriction fragment length polymorphism or amplification refractory mutation system-polymerase chain reaction methods. The quantitative real time PCR was used for mRNA expression assay. The placental H19 rs3741219 and rs2107425 polymorphisms were not associated with PE. However, H19 rs217727CT and TT genotypes might be associated with a 9.2- and 17.7-fold increased risk of PE, respectively. The Trs3741219 Crs217727 Crs2107425 and Trs3741219 Crs217727 Trs2107425 haplotypes were significantly lower, whereas the Trs3741219 Trs217727 Crs2107425 and Crs3741219 Trs217727 Crs2107425 haplotypes were significantly higher in PE women. Promoter but not upstream region hypermethylation of H19 gene could be led to decreased risk of PE (MM vs. UM + UU). No significant difference was observed in the placental mRNA expression between two groups. The H19 expression was significantly higher in women with unmethylated (UU), compared to methylated promoter (MM). The H19 expression was 17- and 15-fold higher in H19-rs2107425 CC and CT genotypes in PE women. In conclusion, the H19 rs2107425 polymorphism was associated with a higher risk of PE and increased H19 mRNA expression. The promoter hypermethylation of H19 gene was associated with a lower risk of PE and decreased H19 mRNA expression.

The effects of the genetic polymorphisms of antioxidant enzymes on susceptibility to papillary thyroid carcinoma.

Several lines of evidences have indicated that inflammation play an important role in the carcinogenesis. During the inflammatory processes, free radical species are produced from oxidative stress. In normal conditions, enzymatic and nonenzymatic antioxidants remove these products. Manganese superoxide dismutase (MnSOD), glutathione peroxidase-1 (GPx-1), and catalase (CAT) are three important enzymes. Therefore, this study aimed to evaluate the effects of MnSOD (SOD2), GPX-1, and CAT genetic polymorphisms on papillary thyroid carcinoma (PTC) susceptibility. A total of 134 patients with PTC and 151 healthy controls were recruited to participate in this study. All samples were genotyped for SOD2 rs4880, GPX1 1050450, and CAT rs7943316 polymorphisms by polymerase chain reaction-restriction fragment length polymorphism method. The frequencies of the rs1050450, rs4880, and rs7943316 alleles and genotypes were not different between PTC patients and controls. However, the TC genotype of SOD2 rs4880 polymorphism was significantly higher in males compared to that in females in PTC patients (odds ratio [OR], 3.9 [95% CI, 1.5-11], p = .007). The rs4880 polymorphism was also associated with higher stages (III-IV) of PTC in dominant model. No significant correlation was found between GPX1-rs1050450 and CAT-rs7943316 polymorphisms and demographic, clinical, and pathological features of the disease. The SOD2 rs4880CT genotype was more frequent in males with PTC and patients with higher stages (III-IV) of disease (OR, 2.9 [95% CI, 1.1-7.7], p = .04). However, no significant association was found between GPX1-rs1050450 and CAT-rs7943316 variants and PTC or its demographic, clinical, and pathological features.

The effects of DICER1 and DROSHA polymorphisms on susceptibility to recurrent spontaneous abortion.

BACKGROUND: Recurrent spontaneous abortion (RSA) is a serious problem in pregnancy. The exact etiology of RSA is unknown in more than 50% of all the patients. However, genetic variations are known as susceptibility factors for idiopathic RSA. Considering the role of miRNA biosynthesis machinery in the miRNA production and effect of miRNAs on various diseases, this study aimed to evaluate the effects of DICER1 rs3742330 and DROSHA rs6877842 polymorphisms on RSA risk. METHODS: In this case-control study, 150 RSA patients and 195 age-matched healthy female controls were recruited. Both polymorphisms were genotyped using PCR-RFLP method. RESULTS: The frequency of DICER1 rs3742330AG genotype was higher in the control group (P = .022). There was a statistically significant association between rs3742330 polymorphism and a reduced RSA risk in dominant and allelic models (P = .013 and P = .007, respectively). No statistically significant association was found between DROSHA rs6877842 variant and RSA risk. The combination of AG and GC genotypes and G-G alleles of DICER1 rs3742330 and DROSHA rs6877842 polymorphisms led to a decreased RSA risk. However, the synergic effect of rs3742330A and rs6877842G alleles (A-G) and AA-GG genotypes was associated with an increased RSA risk. CONCLUSION: the DICER1 rs3742330AG genotype and combination of AG and GC genotypes and G-G alleles of DICER1 rs3742330 and DROSHA rs6877842 polymorphisms were associated with a reduced RSA risk.

The possible role of maternal and placental vitamin D receptor polymorphisms and haplotypes in pathogenesis of preeclampsia.

Purpose: Vitamin D deficiency may be a main causative agent in the pathogenesis of preeclampsia (PE). The actions of the active form of vitamin D are mediated via the vitamin D receptor (VDR), which is expressed in numerous organs including placenta. Therefore, we evaluated the potential relationship between maternal and placental VDR polymorphisms and the predisposition to PE in an Iranian population.Methods: This case-control study surveyed 152 PE and 160 normotensive pregnant women. The polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was performed to examine the maternal and placental VDR Fok1 rs2228570, Bsm1 rs1544410, Taq1 rs731236, and Apa1 rs7975232 polymorphisms.Results: The maternal but not placental VDR FokI Ff genotype, was significantly lower in PE women (P = .02 and P = .06, respectively). The maternal and placental VDR FokI polymorphism was associated with lower PE risk in the dominant model (Ff+ff vs. FF) and these genotypes could decrease PE risk (OR, 0.5 [95% CI, 0.3-0.8], P = .007 and OR, 0.5 [95% CI, 0.3-0.9], P = .02, respectively). The haplotype analysis revealed that the maternal and placental TABf haplotype may lead to decreased risk of PE. In addition, the placental TABF haplotype was associated with higher risk of PE. No relationship was observed between PE susceptibility and the maternal and placental VDR Bsm1, Taq1 and Apa1 polymorphisms. There was also no relationship between the maternal and placental VDR polymorphisms and PE severity.Conclusions: the maternal and placental VDR FokI variant was associated with decreased risk of PE in the dominant model.

The Impact of TRAIL (C1595T and G1525A) and DR4 (rs20576) Gene Polymorphisms on Systemic Lupus Erythematosus.

Apoptosis dysregulation is a distinct hallmark of several disorders like systemic lupus erythematosus (SLE). In fact, SLE has two special features for apoptosis: irregular apoptosis and decline in clearing of apoptotic bodies. Tumor Necrosis Factor (TNF)-Related Apoptosis-Inducing Ligand (TRAIL) is a death ligand that causes to apoptosis via attaching to its receptors such as death receptor-4 (DR4). The present study aimed to evaluate the effects of TRAIL G1525A and C1595T and DR4 A683C (rs20576) gene polymorphisms on SLE development. 160 SLE patients and 160 healthy individuals as the control group participated in the study. Genotype analysis was performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). With regard to TRAIL (C1595T) polymorphism, the frequency of CT genotype was significantly higher in the case group than the control with 3-fold increase in SLE development risk (P = 0.0001). Furthermore, the frequency of the TT genotype also was higher in the case group than the control group with 3.2-fold increase in SLE development risk. The allelic distribution analysis defined the T allele as a risk factor for SLE development (P = 0.0001). The frequency of AA genotype and allele A of TRAIL (G1525A) polymorphism also was statistically higher in the case group than the control group (P = 0.0001). There was no significant association between DR4 rs20576 polymorphism and SLE development. TRAIL C1595T and G1525A gene polymorphisms are suggested as the risk factors for SLE development, although the results showed no association between DR4 rs20576 polymorphism and SLE.

Role of MDM2 309T>G (rs2279744) and I/D (rs3730485) polymorphisms and haplotypes in risk of papillary thyroid carcinoma, tumor stage, tumor size, and early onset of tumor: A case control study.

Murine double minute clone 2 (MDM2) protein plays an important role in the regulation of p53 tumor suppressor. Genetic polymorphisms of the MDM2 gene are the candidate variants in susceptibility to various cancers. In the present study, we aimed to investigate the possible effects of MDM2 309T>G (rs2279744) and I/D (rs3730485) polymorphisms on papillary thyroid carcinoma (PTC) susceptibility and clinical or pathological features of the disease. A case control study was carried out involving in a total of 131 patients with PTC and 144 healthy controls. Both cases and controls were genotyped for MDM2 309T>G and I/D polymorphisms. There was no significant difference regarding MDM2 309T>G and I/D genotypes between patients with PTC and controls in neither dominant nor recessive and allelic models. The frequency of G-D haplotype was higher in patients with PTC and this haplotype was associated with a 1.7-fold increased risk of PTC. The MDM2 309T>G polymorphism was associated with a higher risk of III-IV stages in patients with PTC. The MDM2 ID genotype was significantly higher in patients with PTC less than 40 years and associated with larger tumor size (≥1 cm). In conclusion, the G-D haplotype but not MDM2 309T>G and I/D polymorphisms were associated with higher risk of PTC. MDM2 309T>G polymorphism was associated with a higher incidence of III-IV stages, however, I/D polymorphism was associated with larger tumor size and a lower age of disease occurrence.

Genetic polymorphisms of miRNA let7a-2 and pri-mir-34b/c are associated with an increased risk of papillary thyroid carcinoma and clinical/pathological features.

microRNAs (miRNAs) as a group of short noncoding RNAs are crucial molecules in transcriptional and translational regulation of oncogenes and tumor suppressor genes. Evidence showed there was an association between the miRNA polymorphisms and various cancers, including papillary thyroid carcinoma (PTC). The present study aims to evaluate the possible effects of let7a-2 rs1143770 and pri-mir-34b/c rs4938723 polymorphisms on PTC susceptibility. A total of 120 patients with PTC and 130 age, sex, and race matched controls were enrolled in the case-control study. The polymerase chain reaction-restriction fragment length polymorphism method was used for genotyping of let7a-2 rs1143770 and pri-mir-34b/c rs4938723 polymorphisms. The let7a-2 rs1143770 CT and TT genotypes were associated with a 1.9-fold and 2.2-fold higher risk of PTC, respectively (P = 0.027 and P = 0.041). Moreover, the let7a-2 rs1143770 polymorphism was associated with increased PTC risk in both dominant (2-fold, P = 0.015) and the allelic model (1.5-fold, P = 0.03). The frequency of pri-mir-34b/c rs4938723TC genotype was significantly higher in patients with PTC and associated with a two-fold higher risk of PTC (P = 0.013). In addition, this polymorphism was associated with a 1.8-fold increased risk of PTC in dominant model (P = 0.021). The let7a-2 rs1143770CT genotype was associated with a 3.5-fold increased risk of N1 stage in PTC patients (P = 0.04), however, pri-mir-34b/c rs4938723TC genotype was associated with a 3.4-fold and 5.1-fold increased risk of III-IV stage and vascular invasion in PTC group, respectively (P = 0.04 and P = 0.04). In conclusion, the present study shows that let7a-2 rs1143770 and pri-mir-34b/c rs4938723 polymorphisms could be susceptible factors for PTC and some clinical features.

Renalase rs10887800 polymorphism is associated with severe pre-eclampsia in southeast Iranian women.

Evidence has shown that pre-eclampsia (PE) is associated with an increased level of catecholamines. Renalase is a catecholamine-metabolizing enzyme, which contributes to the occurrence of hypertension. In the current study, we aimed to assess the relation between two renalase gene ( RNLS) polymorphisms, including rs2576178 at the 5'-flanking region and rs10887800 at intron 6, near the exon/intron border and PE susceptibility. In this case-control study, 179 women with PE and 202 normotensive pregnant women were genotyped for RNLS rs2576178 and rs10887800 polymorphisms by the polymerase chain reaction-restriction fragment length polymorphism method. There was no association between RNLS rs10887800 and rs2576178 polymorphisms and PE, neither in the dominant nor in the recessive model. Although there was no association between RNLS rs10887800 polymorphism and mild PE, this polymorphism was associated with 2.2-fold higher risk of severe PE in the recessive model (odds ratio [OR], 2.2; 95% confidence interval [CI], 1.2-4.4; P = 0.01) but not in the dominant model. The RNLS rs2576178 and rs10887800 polymorphisms were not associated with PE severity. The RNLS rs10887800 and rs2576178 GG/GG combined genotypes were associated with 8.4- and 16.7-fold higher risk of PE and severe PE, respectively (OR, 8.4; 95% CI, 1-71.1; P = 0.048 and OR, 16.7; 95% CI, 1.6-167; P = 0.018). Also, the G-G haplotype was associated with 1.7-fold risk of PE and mild PE (OR, 1.7; 95% CI, 1.1-2.4; P = 0.009 and OR, 1.7; 95% CI, 1.1-2.5; P = 0.02). The RNLS rs10887800 polymorphism was associated with severe PE. The RNLS rs10887800 and rs2576178 GG/GG combined genotypes and G-G haplotype were associated with higher risk of PE.

Genetic and epigenetic analysis of the BAX and BCL2 in the placenta of pregnant women complicated by preeclampsia.

The current study examined the effects of BAX and BCL2 polymorphisms and methylation as well as mRNA expression on susceptibility to PE. After delivery, the placentas were collected from 92 women with PE, as well as 106 normotensive pregnant women. The BAX rs4645878 and BCL2 rs2279115 polymorphisms were genotyped by the PCR-RFLP method. Methylation-specific PCR (MSP) was used for analysis of promoter methylation. mRNA expression was assayed by Quantitative RT-PCR. In addition, in silico analysis was performed by bioinformatics tools. There was no relationship between PE and placental BAX rs4645878 and BCL2 rs2279115 polymorphisms. The groups were not significantly different regarding the promoter methylation of BAX gene. Nonetheless, the MM status of BCL2 promoter had a significantly higher frequency in the PE group and was associated with 2.7-fold higher risk of PE (OR = 2.7, 95% CI = 1.3-5.6; P = 0.01). The relative mRNA expression of BCL2 was decreased in the placentas of PE women (P < 0.0001). The expression of BAX gene was not significantly different between the two groups. There was no association between placental BAX rs4645878 and BCL2 rs2279115 polymorphisms and mRNA expression levels. In silico analysis indicated that BAX rs4645878 and BCL2 rs2279115 polymorphisms were located in the core recognition site of different transcription factors and these substitutions of wild allele resulted in the loss and/ or change of these binding sites and subsequently may alter BCL2 and BAX expression. This study showed that the BAX and BCL2 polymorphisms and BAX promoter methylation were not associated with PE risk. The BCL2 promoter methylation was associated with lower BCL2 expression and higher PE susceptibility.

Impact of HOTAIR variants on preeclampsia susceptibility based on blood and placenta and in silico analysis.

HOX transcript antisense RNA (HOTAIR) as a lncRNA involves in epigenetic regulation of various genes. Several studies have been suggested the effects of HOTAIR polymorphisms on different diseases. The aim of the present study was to evaluate the effect of maternal and placental HOTAIR polymorphisms on risk of preeclampsia (PE). The maternal blood of 203 preeclamptic and 202 nonpreeclamptic pregnant women as well as the placentas of 87 of preeclamptic and 95 nonpreeclamptic pregnant women were genotyped for HOTAIR polymorphisms. There was no association between maternal and placental HOTAIR polymorphisms (rs12826786, rs920778, and rs1899663) and PE risk. However, the maternal rs4759314AG and dominant model genotypes were associated with increased risk of PE. The maternal and placental HOTAIR rs10783618 polymorphism was associated with PE risk in recessive and allelic models. Haplotype analysis showed that, the maternal CTGAT and CCTAT and placental CTGAT haplotypes were significantly higher and maternal CTGAC, TCTAT, and TTGAT and placental CTGAC haplotypes were significantly lower in PE women. In silico analysis revealed that HOTAIR rs1899663 had a main effect on the secondary structure of mRNA, however, HOTAIR rs4759314 variant had potential alteration of splicing. In conclusion, the maternal and placental HOTAIR rs10783618 polymorphism might increase PE susceptibility. © 2019 IUBMB Life, 71(9):1367-1381, 2019.

Analysis of polymorphisms, promoter methylation, and mRNA expression profile of maternal and placental P53 and P21 genes in preeclamptic and normotensive pregnant women.

BACKGROUND: Preeclampsia (PE), as a multisystem disorder, is associated with maternal hypertension and proteinuria. Apoptosis seems to be involved in the pathophysiology of PE, although its precise pathogenic mechanisms are not well established. In this study, we aimed to identify the association between maternal TP53-rs1042522, P21-rs1801270, and P21-rs1059234 polymorphisms and PE. In addition, we examined the effects of promoter methylation and TP53 and P21 polymorphisms on placental mRNA expression in PE women. METHODS: The blood of 226 PE women and 228 normotensive pregnant women was examined in this study. In addition, the placentas were genotyped in 109 PE and 112 control women. The methylation status was assessed by a methylation-specific PCR assay, while mRNA expression was examined via Quantitative Real Time PCR. RESULTS: The maternal and placental P21-rs1801270 CA genotype had a significant association with the reduced risk of PE. In the dominant, recessive, and allelic models, maternal/placental P21-rs1059234 polymorphism had no statistically significant association with the risk of PE. On the other hand, the reduced risk of PE was associated with maternal, but not placental TP53-rs1042522 polymorphism in the dominant and recessive models. The maternal and placental P21-rs1801270 polymorphism was associated with PE risk. The maternal P21 Trs1059234Crs1801270 haplotype was associated with 3.4-fold increase in PE risk, However the maternal P21 Trs1059234Ars 1801270 haplotype and placental Crs1059234CA rs1801270 haplotype led to 0.5 and 0.4-fold decrease in PE risk, respectively. PE women showed 5.6 times higher levels of placental mRNA expression of TP53 gene, although it was not associated with rs1042522 polymorphism. The relative placental mRNA expression of P21 gene was 0.2 in PE women. It was also 2.4 times higher in individuals with rs1801270CA genotype than those with AA genotype. The hyper-methylation of P21 and TP53 genes in the promoter region was associated with a 3.4-fold and 3-fold increase in PE risk, respectively. However, no association was found between P21 and TP53 mRNA expression and promoter methylation. CONCLUSION: In conclusion, P21-rs1801270 and TP53-rs1042522 polymorphisms were involved in reduced risk of PE. P21-rs1801270 was associated with decreased P21 mRNA expression. The hyper-methylation of P21 and TP53 genes in the promoter region was associated with a higher PE risk.

The effect of GPx-1 rs1050450 and MnSOD rs4880 polymorphisms on PE susceptibility: a case- control study.

Preeclampsia (PE) is a serious pregnancy complication whose etiology is not fully understood. However, previous reports have suggested that oxidative stress and genetic variants may contribute to the development of PE. This study aimed to examine the relationship between the Glutathione peroxidase-1(GPx-1) and Manganese Superoxide dismutase (MnSOD) polymorphisms and preeclampsia (PE) risk in Iranian women. Genotyping of the studied women, including 179 preeclamptic cases and 202 controls, for GPx-1 rs1050450 and MnSOD rs4880 polymorphisms was conducted using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Our results showed a 1.7- to 1.6-fold increased risk of PE in the rs1050450 CT and CT + TT (dominant model) genotypes compared to CC genotype (OR = 1.7, 95%CI 1.1-2.7; P = 0.01 and OR = 1.6, 95%CI 1.1-2.4; P = 0.02; respectively). We also found a marked correlation between TC and CC genotypes of MnSOD rs4880 polymorphism and a 1.9- to 2.3-fold increase risk of PE (OR = 1.9, 95%CI 1.2-2.9; P = 0.005 and OR = 2.3, 95%CI 1-5.1; P = 0.04, respectively). The rs4880 MnSOD polymorphism was correlated with increased risk of PE in the allelic and dominant models (OR = 1.8, 95% CI 1.2-2.5, P = 0.002; OR = 1.9, 95%CI 1.3-3, P = 0.002, respectively). High frequency of TC/CC genotype of MnSOD rs4880 and CT genotypes of rs1050450 polymorphism in PE patients compared to controls showed the contribution of these variants to PE susceptibility.