Quantitative Assessment of the Effects of IL-1ß -511 C>T Variant on Breast Cancer Risk: An Updated Meta-Analysis of 3331 Cases and 3609 Controls.

OBJECTIVE: Growing evidence suggests that IL-1ß -511C>T, as a functional variant, affects the risk of developing breast cancer (BC); however, the results have not been conclusive. This meta-analysis was conducted to estimate the link between this variant and BC risk. METHODS: We retrieved available publications on IL-1ß -511C>T polymorphism by conducting a comprehensive literature search on the Web of Science, MEDLINE, PubMed, Scopus, and Google scholar databases (last search on February 25, 2020). RESULTS: The overall analysis indicates that IL-1ß -511C>T polymorphism conferred an increased risk of BC under a recessive TT vs CT+CC model by 1.14-fold and showed protection against BC under an overdominant CT vs TT+CC genetic contrast model (odds ratio = 0.84). Stratified analysis based on ethnicity revealed the protective effect of this single-nucleotide polymorphism against BC risk in Caucasian patients. CONCLUSION: Our data results provide a proof of concept for the association of IL-1ß -511C>T with BC risk. Larger, well-designed population-based studies are needed to confirm these findings.

Nitric oxide, 8-hydroxydeoxyguanosine, and total antioxidant capacity in human seminal plasma of infertile men and their relationship with sperm parameters.

OBJECTIVE: Oxidative stress plays a key role in the pathogenesis of male infertility. But, the adverse effects of oxidative biomarkers on sperm quality remain unclear. This study aimed to investigate the levels of nitric oxide (NO), 8-hydroxydesoxyguanosine (8-OHdG), and total antioxidant capacity (TAC) oxidative biomarkers in seminal plasma and their relationship with sperm parameters. METHODS: A total of 77 volunteers participated in the study, including fertile (n=40) and infertile men (n=37). NO, 8-OHdG, and TAC levels were measured using the ferric reducing ability of plasma, Griess reagent method and an enzyme-linked immunosorbent assay kit, respectively. RESULTS: The mean values of sperm parameters in the infertile group were significantly lower than those in the fertile group (p<0.001). The mean 8-OHdG in the seminal plasma of infertile men was significantly higher (p=0.013) than those of controls, while the mean TAC was significantly lower (p=0.046). There was no significant difference in NO level between the two groups. The elevated seminal 8-OHdG levels were negatively correlated with semen volume, total sperm counts and morphology (p<0.001, p=0.001 and p=0.052, respectively). NO levels were negatively correlated with semen volume, total sperm counts and morphology (p=0.014, p=0.020 and p=0.060, respectively). Positive correlations between TAC and both sperm count and morphology (p=0.043 and p=0.025, respectively) were also found. CONCLUSION: These results suggested that increased levels of NO and 8-OHdG in seminal plasma could have a negative effect on sperm function by inducing damage to the sperm DNA hence their fertility potentials. Therefore, these biomarkers can be useful in the diagnosis and treatment of male infertility.

Soluble guanylate cyclase isoenzymes: The expression of α1, α2, ß1, and ß2 subunits in the benign and malignant breast tumors.

Soluble guanylate cyclase (sGC) encompasses α and ß subunits. This study examined the expression of α1, α2, ß1, and ß2 subunits in the malignant and benign breast tumors using the Western blot analysis. Both benign and malignant tumors showed a significantly higher expression of the α1 subunit in comparison with normal tissues (p < 0.0001). In contrast, the expression of α2 and ß2 sGC were significantly lower in these tumors than normal tissues (p < .0015 and p < .001, p < .007 and p < .0001, respectively). The expression level of α1 sGC was significantly correlated with ER + PR+ (p < .0001). A significant correlation was also detected for sGC-α1 and -α2 expression with c-erbB2-negative status (p < .01). However, the expression level of sGC was not associated with tumor stage, tumor grade, or other clinicopathological features. In conclusion, as the expression of α1 sGC is upregulated and α2 and ß2 sGC are downregulated in malignant breast tumors. Variations in the expression of sGC isoenzymes may be suggested as an indicator to confirm the enzyme antitumor activity.

Association between vitamin D receptor gene FokI and TaqI variants with autism spectrum disorder predisposition in Iranian population.

BACKGROUND AND AIM: Autism spectrum disorder (ASD) is one of the neurodevelopmental and cognitive conditions that involves 1 in 160 children around the world. Several studies showed that there is a relationship between vitamin D receptor (VDR) gene polymorphisms with the neurodevelopmental behavioral disorders. In the current study, we aimed to highlight the association of VDR gene polymorphisms (FokI and TaqI) with the risk of autism in Birjand population. MATERIAL AND METHODS: In this case-control study eighty-one patients recognized with ASD and one hundred-eight healthy controls were recruited to the study from 2017 to 2018. Genotyping was carried out by polymerase chain reaction followed by restriction fragment length polymorphism (PCR-RFLP) technique for all subjects. RESULTS: Calculated odds ratio and P-value for the alleles of VDR gene FokI and TaqI variants between autistic patients and controls did not show a significant difference (P > 0.05). However, calculated homozygous recessive (tt) for TaqI polymorphism was statistically significant (P = 0.015) in control group and there was also statistically meaningful difference in both case and control groups in ft haplotype (P = 0.04). CONCLUSION: These results provide preliminary evidence that genetic variants of the VDR gene (FokI and TaqI) might have a possible reduced risk of ASD occurrence in children. The additional examination is needed to acquire more decisive and precise results in this area.

Differential expression of alternative transcripts of soluble guanylyl cyclase, GYCY1a3 and GUCY1b3 genes, in the malignant and benign breast tumors.

Extensive alterations in splicing is one of the molecular indicator for human cancers. Soluble guanylyl cyclase (sGC), an obligatory heterodimer, is composed of α1 and ß1 subunits. Each subunit is encoded by a separate gene, GUCY1a3 and GUCY1b3, correspondingly. sGC activity has been regulated by an alternative splicing and it has an important effect on the breast cancer. sGC alternative splicing has been evaluated in the 55 malignant, 25 benign and 30 normal breast tissues using qRT-PCR and RT-PCR. The differences between groups were analyzed by Mann-Whitney U. The expression of six different splice forms have been detected, three for α1 and three for ß1 sGC. Expressions of Tr1, Tr2 ß1 sGC and Tr7, Tr6 α1 sGC mRNA in the malignant breast tumors were significantly lower than those of benign and normal breast tissues. However, the expression of Tr3 α1 sGC mRNA was significantly higher than that of benign and normal tissues. Present data have provided some evidences for an alteration in the expression of α1 and ß1 sGC alternative splicing forms which may contribute to the loss of sGC functions in the breast cancer. The observed information might be discussed by the cGMP status.

Comparison of large-scale deletions of the sperm mitochondrial DNA in normozoospermic and asthenoteratozoospermic men.

BACKGROUND AND OBJECTIVE: Mitochondria play a crucial role in energy metabolism for the survival and motility of sperm during fertilization. The aim of this study was to determine the association of large-scale mitochondrial DNA deletions with abnormal sperm motility and morphology in asthenoteratozoospermic patients. MATERIALS AND METHODS: In this case-control study, 41 semen samples were collected from 18 normozoospermic healthy men and 23 asthenoteratozoospermic patients, according to the WHO guidelines. The swim-up technique was used for separation of spermatozoa on the basis of their motility. Long-range polymerase chain reaction (PCR) was used for screening of mitochondrial DNA (mtDNA) large-scale deletions, and primer shift PCR was used for confirmation of deletions. RESULTS: The mean sperm motility, normal morphology, and progressive motility in asthenoteratozoospermic patients were significantly lower than in the normozoospermic group (P < 0.0001). There was a positive significant correlation between motility and normal sperm morphology ( P < 0.0001, r = 0.741). The results of long-range PCR revealed the existence of 4866-bp deletion along with the two common 4977-bp and 7436-bp deleted mtDNA in both groups. However, the frequency of multiple mtDNA deletions in the asthenoteratozoospermic group (15/23, 65.22%) was significantly higher than that in the normozoospermic group (7/18, 38.89%). Direct sequencing of the 534-bp PCR product revealed that it was amplified from the mtDNA with a 4866-bp deletion flanked by a seven-nucleotide direct repeat (5'-ACCCCCT-3'). CONCLUSIONS: Our findings suggested that these large-scale deletions of mtDNA may be genetic risk factors for poor sperm quality in asthenoteratozoospermia-induced male infertility. Thus, it is necessary to understand the mechanisms behind the generation of these deletions.

Positive correlation between interleukin-1 receptor antagonist gene 86bp VNTR polymorphism and colorectal cancer susceptibility: a case-control study.

Colorectal cancer (CRC) is one of the most common malignancies worldwide. Genetic variations in cytokine genes and their receptors lead to the severity of the disease. The interleukin-1 receptor antagonist (IL1RN) is a cytokine that inhibits interleukin-1 (IL-1) activity by binding to IL-1 receptors. Also, interleukin-4 (IL-4) is an anti-inflammatory cytokine that can play an important role in several cancers. The present case-control study was aimed to evaluate the association of IL-4 and IL1RN VNTR polymorphisms with the susceptibility to CRC in a sample of Iranian population provided by the Research Center for Gastroenterology and Liver Disease at Taleghani Hospital, Tehran. A total of 123 patients diagnosed with CRC and 152 healthy controls were recruited in the present study. Genomic DNA was extracted by salting out method from whole blood and genotyping of IL1RN and IL-4 VNTR polymorphisms were determined by PCR-based technology. Our study manifested the frequency of 1/2 and 2/4 genotypes of IL1RN 68bp VNTR polymorphism are significantly different between both groups (p = 0.0001 and p = 0.01 respectively). However, we could not find any correlation between IL-4 VNTR polymorphism and CRC cancer. It seems that 1/2 and 2/4 genotypes of IL1RN are correlated with CRC susceptibility in our population, although, more studies are needed to confirm our results.

Positive correlation between vitamin D receptor gene FokI polymorphism and colorectal cancer susceptibility in South-Khorasan of Iran.

Colorectal cancer (CRC) is a global public health problem. Despite the major milestone in early diagnosis and treatment of colorectal cancer, the prevalence of CRC rates is still rising. The etiology of CRC is still unknown but we know CRC is influenced by both of environment and genetic factors. In this study, we aimed to elucidate the role of vitamin D receptor gene polymorphic regions; FokI and TaqI single nucleotide polymorphisms, in increasing the risk of colorectal cancer in Birjand population. One hundred patients with CRC and 100 healthy controls recruited to the study. Genotyping was performed by PCR-RFLP (restriction fragment length polymorphism) method technique for all individuals. There were statistically significant differences between ff genotype and f allele of FokI SNP in case and control groups. Our results manifested positive correlation between ff genotype and f allele of FokI SNP with colorectal cancer predisposition (P = 0.035, P = 0.0001 respectively) in South Khorasan population. The present study showed that FokI polymorphism but not TaqI polymorphism may contribute to CRC susceptibility. In addition, ff genotype of FokI polymorphism was associated with CRC risk.

Interleukin-1ß (IL-1ß) & IL-4 gene polymorphisms in patients with systemic lupus erythematosus (SLE) & their association with susceptibility to SLE.

BACKGROUND & OBJECTIVES: Interleukin-1 (IL-1) is one of the pro-inflammatory cytokines that plays a main role in the regulation of immune and inflammatory responses. Interleukin 4 (IL-4) as an anti-inflammatory cytokine regulates balance between Th1 and Th2 immune responses. this study was undertaken to investigate the IL-1ß and IL-4 genes polymorphisms in patients with systemic lupus erythematosus (SLE) and also association between the polymorphisms and susceptibility to SLE. METHODS: One hundred and sixty three SLE patients and 180 healthy controls were genotyped for the IL-4 VNTR (variable number tandem repeat), IL-1ß C-511T and IL-1ß T-31C polymorphisms by polymerase chain reaction (PCR) or PCR-RFLP (restriction fragment length polymorphism) method. RESULTS: The frequencies of CC genotype and C allele of the IL-1ß T-31C polymorphism were significantly (P<0.01) lower in SLE patients than controls. Moreover, the frequencies of RP1/RP2 genotype and RP2 allele of IL-4 VNTR polymorphism were significantly (P<0.05) higher in the SLE patients. No association was observed between IL-1ß C-511T polymorphism and increased risk of SLE. We observed increased frequency of CT and TT genotypes of IL-1ß C-511T polymorphism in SLE patients with malar rash compared to SLE patients without this manifestation. INTERPRETATION & CONCLUSIONS: The present findings suggest that IL-1ß T-31C and IL-4 VNTR polymorphisms but not IL-1ß C-511T polymorphism may contribute in SLE pathogenesis. In addition, CT and TT genotypes of IL-1ß C-511T polymorphism were associated with SLE.

Deoxyribonuclease I gene polymorphism and susceptibility to systemic lupus erythematosus.

The DNASE1 gene is regarded as one of the susceptible genes for systemic lupus erythematosus (SLE). Recent studies have detected the presence of a variable number of tandem repeat (VNTR) polymorphisms at intron 4 in this gene. The current study aimed to investigate the influence of current polymorphism on SLE susceptibility in a sample of the Iranian population. The study included 163 patients and 180 unrelated healthy controls. The VNTR polymorphisms in the DNASE1 gene were determined by polymerase chain reaction (PCR). The genotypic frequency investigation indicated that 3/6 genotype frequency in patients affected with SLE was more than healthy controls (P = 0.004). Moreover, 3/4 and 4/6 genotype frequencies in healthy cohort were further in comparison with patient cohort (P = 0.0001). Findings of the present study manifested that 3/6 genotype in patients affected with SLE was significantly more than healthy controls, thus it can be regarded as a risk factor, while 3/4 and 4/6 genotypes were significantly higher in healthy controls which can be considered as a protective factor.

Association of interleukin-1 receptor antagonist VNTR polymorphism and risk of pre-eclampsia in southeast Iranian population.

AIM: Pre-eclampsia (PE) is an obstetric disorder that may result in maternal and neonatal mortality and morbidity. Growing evidence indicates that cytokines, such as interleukins, are involved in the pathogenesis of this complication. Hence the current study aimed to assess the possible association between interleukin-1 receptor antagonist (IL-1Ra) VNTR polymorphism, and PE susceptibility in southeast Iranian women. MATERIAL AND METHODS: The IL-Ra VNTR polymorphism was evaluated in 192 PE women and 186 age-matched normotensive pregnant women by the polymerase chain reaction method. RESULTS: The frequency of the A2 allele and the A2A2 genotype of IL-Ra VNTR polymorphism was significantly lower in PE patients compared to controls: therefore, A2 allele may play a protective role in PE development (odds ratio = 0.13 95% CI, [0.04-0.03]; P < 0.0001). In addition, there was no relation between the IL-Ra VNTR polymorphism and severity of the disease. CONCLUSION: The A2 allele of the IL-Ra VNTR polymorphism could be a protective factor for PE susceptibility.

Association Between Functional Polymorphisms of DNA Double-Strand Breaks in Repair Genes XRCC5, XRCC6 and XRCC7 with the Risk of Systemic Lupus Erythematosus in South East Iran.

DNA repair is reduced in patients suffering from systemic lupus erythematosus (SLE), and it can induce the production of autoreactive antibodies due to the accumulation of DNA damage and nucleoprotein that produce immunogenic antigens. The accumulations of anti-Ku and DNA-PKcs antibodies, which are involved in nonhomologous DNA end joining pathway, have been detected in SLE patients. The present study was designed to evaluate the association of XRCC5, XRCC6, and XRCC7 polymorphisms with SLE susceptibility. Polymerase chain reaction (PCR) was performed to genotype 163 SLE patients and 180 healthy controls for the XRCC5 variable number of tandem repeat (VNTR) polymorphism. The genotype analysis of XRCC6-61C>G and XRCC7 6721G>T polymorphisms was performed using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. There was a significant association between XRCC5 VNTR, XRCC7 6721G>T polymorphisms and risk of SLE development. Notably, the frequency of XRCC5 VNTR 0R allele and genotypes with 2R allele was greatly enhanced in SLE patients with Malar rash (p=0.032 and p=0.024, respectively). Moreover, a higher frequency of genotypes with the XRCC5 VNTR 2R allele was observed in SLE patients with a positive antinuclear antibody (ANA) test (p=0.03). The present study shows an association between the XRCC5 VNTR, XRCC7 6721G>T polymorphisms and SLE. These polymorphisms might be genetic risk factors for SLE susceptibility and some SLE manifestations in the population southeast of Iran.

XRCC1 Arg399Gln and Arg194Trp polymorphisms and risk of systemic lupus erythematosus in an Iranian population: a pilot study.

BACKGROUND: Evidences are suggesting that DNA damage is implicated in development of systemic lupus erythematosus (SLE). Therefore we focused on two common XRCC1 polymorphisms (Arg399Gln and Arg194Trp) in SLE susceptibility in South East of Iran. METHODS: Peripheral blood DNA was extracted from 163 SLE patients and 180 healthy controls. PCR-restriction fragment length polymorphism method was used for genotyping of XRCC1 Arg399Gln and Arg194Trp polymorphisms. RESULTS: The frequency of Arg/Gln genotype of the XRCC1 Arg399Gln polymorphism was significantly lower in SLE patients than controls. Moreover, lower frequency of Arg/Gln genotype was found in SLE patients with malar rash compared to patients without this manifestation. No association was observed between XRCC1 Arg194Trp polymorphism and increased risk of SLE in studied population. Haplotype analysis revealed no correlation between four haplotypes of XRCC1 Arg399Gln and Arg194Trp polymorphisms and SLE risk. CONCLUSION: These findings suggest that XRCC1 399 Arg/Gln heterozygous genotype plays a protective role in SLE susceptibility.

Possible association of IL-4 VNTR polymorphism with susceptibility to preeclampsia.

Preeclampsia (PE) is a pregnancy-specific disorder that results in maternal mortality and morbidity. Growing evidence indicated that cytokines are involved in the pathogenesis of PE and interleukin-4 VNTR polymorphism could be implicated in altering the PE risk. The aim of this study was to evaluate the possible association between IL-4 VNTR polymorphism and susceptibility to PE in Iranian population for the first time. Genetic polymorphism was evaluated in 192 PE and 186 healthy control women by polymerase chain reaction method. We found that the VNTR polymorphism of IL-4 gene has significantly increased the risk of preeclampsia (RP2/RP1 versus RP1/RP1, OR, 2.8 [95% CI, 1.7 to 8.8]; P = 0.0001 and RP2/RP2 versus RP1/RP1; P = 0.002). The results showed that carriage of IL-4 VNTR RP2 allele has positive association with preeclampsia susceptibility.

KE and EE genotypes of ICAM-1 gene K469E polymorphism is associated with severe preeclampsia.

BACKGROUND: Preeclampsia (PE) is one of the most important complications of pregnancy that is associated with significant mortality and morbidity in mother and fetus. Since the etiologic factors in its development are still unclear, we aimed to examine the intercellular adhesion molecule-1 (ICAM-1) gene K469E polymorphism in preeclamptic and control healthy women. MATERIALS AND METHODS: Genetic polymorphism was analyzed in 192 PE and 186 healthy control women. PCR-RFLP method was used to identify K469E polymorphism. RESULTS: The frequency of KK, KE, and EE genotypes of ICAM-1 gene was not different between PE patients and healthy pregnant women. Whereas, the frequency of KE and EE genotypes was significantly higher in severe PE than mild PE women and control group, and the risk of severe PE was 2.4-fold higher in subjects with KE genotype (OR, 2.4 [95% CI, 1 to 5.9]; P = 0.03) and 3.3-fold higher in subjects with EE genotype (OR, 3.3 [95% CI, 1.2 to 9]; P = 0.015) compared to individuals with KK genotype. CONCLUSION: We concluded that KE and EE genotypes of K469E polymorphism could increase risk of severe PE.