Determination of IL-6 Gene Promoter Polymorphism in Patients with Hepatitis C and Its Impact on RNA Secondary Structure.

Background and Objectives: A polymorphism in the promoter region of the IL-6 gene would influence the level of IL-6 expression in patients with HCV, resulting in a pro-inflammatory response. Few studies have shown the association between -174G>C (rs1800795) and -1363G>T (rs2069827) polymorphisms and HCV infection, and their results have been contradictory. There are no data published in our population to study such an IL-6 stimulus against HCV infection and its impact on RNA secondary structure. Therefore, we isolated human subjects from the province of Punjab, Pakistan. The objective was to screen for IL-6 gene promoter polymorphisms -174G/C and -1363G/T and those correlated with serum concentrations of IL-6 in patients with HCV and compared with a control. Materials and Methods: In conventional PCR, measurement of serum IL-6 by CLIA and statistical analysis were performed to observe the genotype association studies. By integrating bioinformatics and computational tools, our study aimed to provide a comprehensive understanding of how variations in the promoter region of IL-6 may have functional implications on gene expression. Results: The -174G>C and -1363G>T genotypes in the promoter region of patients with HCV were in strong allelic association (Δ = 0.97, p < 0.001). Interestingly, the bioinformatics analysis was well aligned with our experimental data. Conclusions: Based on the data, it can be inferred that IL-6 gene promoter polymorphisms are important in the dysregulation of IL-6 levels in patients with HCV.

Fibrinogen B ß promoter polymorphism may not be associated with pulmonary embolism.

OBJECTIVE: A prospective experiment was designed to explore all possible SNPs in the promoter region of fibrinogen B ß (FGB) and reveal the influence of these SNPs on susceptibility of pulmonary embolism. METHODS: In this 2-year randomized prospective study, we had totally recruited 203 volunteers. 58 PE patients (58 out of 145 VTE patients) and 114 healthy people were taken as case and control objects, respectively. FGB promoter was detected by gene sequencing. RESULTS: There were 6 SNPs in FGB promoter, which were ß-1420G/A, ß-993C/T, ß-854G/A, ß-455G/A, ß-249C/T, and ß-148C/T. Genotype frequencies of individual SNPs between the cases and controls were not statistically significant, all p > .05. After excluding subjects of COVID-19 infection within 6 months, the statistical results (35 PE patients vs 66 healthy people) were consistent. CONCLUSION: The susceptibility to pulmonary embolism may not be affected by any SNP in the FGB promoter region.

The Genetics of Glucose-6-Phosphate-Dehydrogenase (G6PD) and Uridine Diphosphate Glucuronosyl Transferase 1A1 (UGT1A1) Promoter Gene Polymorphism in Relation to Quantitative Biochemical G6PD Activity Measurement and Neonatal Hyperbilirubinemia.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency and polymorphism in uridine diphosphate glucuronosyl transferase 1A1 (UGT1A1) were associated with significant neonatal hyperbilirubinemia (NHB) and increased risk for kernicterus. However, quantitative screening tests for G6PD enzyme activity proved unsatisfactory in estimating the risk for significant NHB, especially in heterozygous females that could present phenotype overlap between normal homozygotes, heterozygotes, and deficient homozygotes, resulting in a continuum of intermediate G6PD activity. OBJECTIVE: To examine the association of genotype and phenotype in newborns with decreased G6PD activity and its relation to NHB. STUDY DESIGN: Quantitative G6PD enzyme activities were measured on umbilical cord blood samples. After accepting parental consent, samples were analyzed for G6PD mutations and UGT1A1 gene polymorphisms (number of TA repeats in the UGT1A1 promoter). The associations to quantitative G6PD activity and bilirubin levels were assessed. RESULTS: 28 females and 27 males were studied. The Mediterranean mutation (NM_001360016.2(G6PD): c.563C>T (p.Ser188Phe)) was responsible for most cases of G6PD deficiency (20 hemizygous males, 3 homozygous and 16 heterozygous females). The association between this mutation, decreased G6PD activity and higher bilirubin levels was confirmed. Heterozygosity to 6/7 TA repeats in the UGT1A1 promoter was associated with increased NHB, especially in female newborns with G6PD deficiency. However, it seems that the interaction between G6PD deficiency, UGT1A1 promoter polymorphism, and NHB is more complex, possibly involving other genetic interactions, not yet described. Despite genotyping females with G6PD deficiency, the overlap between the upper range of borderline and the lower range of normal G6PD activity could not be resolved. CONCLUSIONS: The results of this study highlight the possibility for future implementation of molecular genetic screening to identify infants at risk for significant NHB, especially UGT1A1 polymorphism in heterozygous females with borderline G6PD deficiency. However, further studies are needed before such screening could be applicable to daily practice.

Association of serotonin transporter promoter polymorphism (5-HTTLPR) with orocecal transit time in irritable bowel syndrome.

BACKGROUND: Irritable bowel syndrome (IBS) is a multifactorial disorder with altered intestinal motility, secretion, and sensation. Serotonin (5-HT) stimulates gut motility and alters serotonin signaling that may lead to both intestinal and extraintestinal symptoms in IBS. AIM: The aim of this study was to examine the association of serotonin transporter gene promoter polymorphism (5-HTTLPR) in IBS with orocecal transit time (OCTT) measured by lactulose hydrogen breath test. METHOD: This prospective case-control study included 151 IBS patients (mean±SD 37.4±11.6 years, median 36, range 19-68). Ninety-two patients were diarrhea-predominant IBS (D-IBS), 44 constipation-predominant IBS (C-IBS), 15 alternating diarrhea and constipation IBS (M-IBS), and 100 healthy controls (mean±SD 37.2±11.4 years, median 36, range 20-64 years). 5-HTTLPR gene polymorphism was studied by polymerase chain reaction-based method. 5-HT levels were measured by enzyme-linked immunosorbent assay (ELISA). Orocecal transit time (OCTT) was measured by a non-invasive lactulose hydrogen breath test. OCTT was also compared with respect to 5-HTTLPR genotypes in different IBS phenotypes. RESULTS: Serum serotonin levels were significantly higher in overall IBS patients (152±77 ng/mL, p<0.001), D-IBS (184±76 ng/mL, p<0.001), compared to healthy controls (129±56 ng/mL). There was no difference in 5-HT levels between C-IBS (124±53 ng/mL) and controls. In the case of M-IBS, 5-HT levels were (88±49 ng/mL p<0.05) significantly lower than that of controls. OCTT was significantly shorter in D-IBS patients (95±36 min) as compared to controls (112±41 min). In contrast, C-IBS showed significantly prolonged OCTT (136±54 min). There was a significant difference in OCTT between D-IBS and C-IBS patients (p<0.001). There was no significant association found between OCTT and 5-HTTLPR. CONCLUSIONS: Serum serotonin concentrations were increased in D-IBS compared to controls and C-IBS. OCTT was shorter in D-IBS and delayed in C-IBS patients. There was no association of 5-HTLPR polymorphism with OCTT.

Predictive Significance of Two MMP-9 Promoter Polymorphisms and Acetylated c-Jun Transcription Factor for Papillary Thyroid Carcinoma Advancement.

Papillary thyroid carcinoma represents a challenge from a prognostic standpoint. Molecular alterations responsible for PTC advancement include MMP-9 genetic promoter polymorphisms that bind transcription factors with varying degrees of affinity and, hence, constitute a predisposition for MMP-9 expression. We examined how two promoter polymorphisms (the -1562 C/T transition and -131 (CA)n tandem repeats) as well as levels of the c-Jun transcription factor and its modified form acetylated at Lys271 influence MMP-9 expression and PTC progression. A significant proportion of PTC samples were heterozygous for the (CA)n tandem repeat number, had a transcription-promoting T allele at -1562, and expressed high levels of c-Jun, acetylated c-Jun, and MMP-9 protein. The T allele at the -1562 position accompanied the elevated MMP-9 protein expression, while high acetylated c-Jun levels accompanied the high MMP-9 protein levels on mRNA. The -1562 C/T transition, MMP-9, and acetylated c-Jun were associated with the presence of extra-thyroid invasion and degree of tumor infiltration, while the T allele and acetylated c-Jun also correlated with tumor stage. We conclude that the -1562 MMP-9 polymorphism and levels of acetylated c-Jun affect PTC progression via modulation of MMP-9 levels. Genotyping the MMP-9 at -1562 and estimating the levels of MMP-9 and acetylated c-Jun in PTC may prove beneficial in identifying high-risk patients.

The Pro-Inflammatory Deletion Allele of the NF-κB1 Polymorphism Is Characterized by a Depletion of Subunit p50 in Sepsis.

The functionally important NF-κB1 promoter polymorphism (-94ins/delATTG) significantly shapes inflammation and impacts the outcome of sepsis. However, exploratory studies elucidating the molecular link of this genotype-dependent pattern are lacking. Accordingly, we analyzed lipopolysaccharide-stimulated peripheral blood mononuclear cells from both healthy volunteers (n = 20) and septic patients (n = 10). All individuals were genotyped for the -94ins/delATTG NF-κB1 promoter polymorphism. We found a diminished nuclear activity of the NF-κB subunit p50 in ID/DD genotypes after 48 h of lipopolysaccharide stimulation compared to II genotypes (p = 0.025). This was associated with higher TNF-α (p = 0.005) and interleukin 6 concentrations (p = 0.014) and an increased production of mitochondrial radical oxygen species in ID/DD genotypes (p = 0.001). Although ID/DD genotypes showed enhanced activation of mitochondrial biogenesis, they still had a significantly diminished cellular ATP content (p = 0.046) and lower mtDNA copy numbers (p = 0.010) compared to II genotypes. Strikingly, these findings were mirrored in peripheral blood mononuclear cells taken from septic patients. Our results emphasize the crucial aspect of considering NF-κB subunits in sepsis. We showed here that the deletion allele of the NF-κB1 (-94ins/delATTG) polymorphism was associated with the lower nuclear activity of subunit p50, which, in turn, was associated with aggravated inflammation and mitochondrial dysfunction.

Characterization of congenital factor XII deficiency in Taiwanese patients: identification of one novel and one common mutation.

BACKGROUND: Factor XII (FXII) deficiency is an interesting condition that causes prolonged activated partial thromboplastin time without bleeding diathesis. FXII may be not important in hemostasis, but still plays roles in thrombosis and inflammation. In order to raise clinical awareness about this condition, we studied patients with severe FXII deficiency and their relatives. METHODS: Consecutive severely FXII deficient patients presenting from 1995 to 2020 were recruited from two medical centers in Taiwan. Index patients and their families were tested for FXII function, antigen and F12 gene. F12 variants were constructed into the pIRES-hrGFP vector and expressed on human embryonic kidney cells (HEK293T). FXII antigen and activity were analyzed. RESULTS: We found five severely FXII deficient patients, three women and two men, aged 44-71 years. FXII antigen results ranged from undetectable to 43.7%. Three different mutations were identified: c.1681C>A (p.Gly542Ser), c.1561G>A (p.Glu502Lys), and a novel mutation c.1556T>A (p.Leu500Gln). HEK293T cells expressed consistently low FXII activity with all mutations. FXII antigen expression was similar to the wild type in c.1681C>A (p.Gly542Ser), but reduced in c.1556T>A (p.Leu500Gln) and c.1561G>A (p.Glu502Lys). CONCLUSIONS: We report five unrelated patients with severe FXII deficiency, one of whom carried a novel, cross-reacting material negative mutation c.1556T>A (p.Leu500Gln).

Association between HO­1 gene promoter polymorphisms and diseases (Review).

Heme oxygenase­1 (HO­1) is an inducible cytoprotective enzyme that degrades heme into free iron, carbon monoxide and biliverdin, which is then rapidly converted into bilirubin. These degradation products serve an important role in the regulation of inflammation, oxidative stress and apoptosis. While the expression level of HO­1 is typically low in most cells, it may be highly expressed when induced by a variety of stimulating factors, a process that contributes to the regulation of cell homeostasis. In the 5'­non­coding region of the HO­1 gene, there are two polymorphic sites, namely the (GT)n dinucleotide and T(­413)A single nucleotide polymorphism sites, which regulate the transcriptional activity of HO­1. These polymorphisms have been shown to be closely associated with the occurrence and progression of numerous diseases, including cardiovascular, pulmonary, liver and kidney, various types of cancer and viral diseases. The present article reviews the progress that has been made in research on the association between the two types of polymorphisms and these diseases, which is expected to provide novel strategies for the diagnosis, treatment and prognosis of various diseases.

Shorter (GT)n repeats in the haem-oxygenase 1 gene promoter are associated with better mid-term survival in subjects with coronary artery disease and abnormal ejection fraction.

BACKGROUND: Haem oxygenase (HO)-1 is a rate-limiting enzyme for degrading haem into carbon monoxide. Subjects with longer GT repeats in the HO-1 gene (HMOX1) promoter are more likely to have coronary artery disease (CAD) and cardiovascular events. METHODS: We retrospectively enrolled CAD subjects with an abnormal ejection fraction (EF) <50% from our catheterisation data (N = 670). Polymerase chain reactions were performed for amplifying the HMOX1 promoter GT repeating segment to determine the number of repeats. RESULTS: In a median follow-up period of 40 months, 213 patients died. The distribution of genotype for HMOX1 promoter GT repeating segments SS, SL, and LL were significantly different (p < 0.001) between the dead (44.6%, 36.2%, 19.2%, respectively) and the survived (53.8%, 37.4%, 8.8%, respectively) (S allele: ≤30 repeats, L allele: >30 repeats). In Cox regression analysis, carrier of S allele (hazard ratio 0.665, p = 0.027), a higher EF (hazard ratio 0.037, p = 0.001), and revascularization with PCI were all negatively associated with all-cause death in subjects with CAD and abnormal EF. CONCLUSIONS: Carrier of shorter (GT)n repeats of HMOX1 gene promoter was negatively correlated with death events in CAD patients with abnormal EF.

The Correlation Between FGB Promoter Polymorphism and Clotting Function in Patients With Idiopathic Lower Extremity Deep Venous Thrombosis.

To explore the possible single nucleotide polymorphisms (SNPs) sites in the promoter region of fibrinogen B ß (FGB), and construct logistic regression model and haplotype model, so as to reveal the influence of FGB promoter SNPs on susceptibility, hemodynamics and coagulation function of lower extremity deep venous thrombosis (LEDVT) in the genetic background. LEDVT patients (120) and healthy people (120) were taken as case and control objects, respectively. SNPs and their genotypes of FGB promoter were detected by promoter sequencing and PCR-RFLP. The parameters of coagulation system were evaluated. There were 6 SNPs in FGB promoter, which were ß-148C/T, ß-249C/T, ß-455G/A, ß-854G/A, ß-993C/T and ß-1420G/A. The genotype and allele frequency of ß-1420 G/A, ß-455G/A, ß-249c/T and ß-148C/T were significantly different between the LEDVT group and the control group, but not ß-993C/T and ß-854G/A. In addition, we found that the higher the content of Fibrinogen (FG), the higher the risk of LEDVT. The risk of LEDVT increased by 4.579 times for every unit increase of fibrinogen. We also found that FG, PT and APTT in LEDVT group were higher than those in control group, while TT was lower than those in control group; Furthermore, there was no significant difference in all coagulation indexes among 6 SNP genotypes in LEDVT group, while a significant difference was found between the 2 genotypes of ß-993C/T in the control group. ß-993C/T may indirectly affect the susceptibility of LEDVT by improving the basic level of plasma FG.

The effect of single-nucleotide polymorphism in the promoter region of bovine alpha-lactalbumin (LALBA) gene on LALBA expression in milk cells and milk traits of cows.

Polymorphisms of milk protein genes have been proposed as candidate markers for dairy production traits in cattle. In the present study, a polymorphism was detected in the 5'-flanking (promoter) region of the bovine alpha-lactalbumin (LALBA) gene, a T/C transition located at nucleotide -1,001 relative to the transcription start site g.-1001T > C (NC_037332.1:g.31183170T > C), which is recognizable with PstI restriction endonuclease. In silico analyses showed that this mutation created novel retinoid X receptor alpha and vitamin D receptor transcription factor binding sites. Real-time PCR found that cows with different genetic variants of the promoter demonstrated different levels of expression of LALBA mRNA in milk somatic cells (MSCs). The TT genotype cows demonstrated low expression, whereas those with CT demonstrated much higher expression (P < 0.05). ELISA analysis found milk LALBA protein levels also differed between the TT and CT cows (P < 0.05) and that these levels were not correlated with the mRNA abundance in MSC. Association analysis found that the g.-1001T > C polymorphism in the promoter region of the LALBA gene influenced milk production traits in Polish Holstein-Friesian cows. High daily milk yield and dry matter yield, and high lactose yield and concentration were associated with the TT genotype. The TT genotype cows also had a lower number of somatic cells in the milk, considered as an indicator of udder health status. Therefore, the TT genotype could be more desirable from the breeder's perspective.

Impact of Fas/Fasl Gene Polymorphisms on Susceptibility Risk and Imatinib Mesylate Treatment Response in Chronic Myeloid Leukaemia Patients.

BACKGROUND: The FAS mediated apoptosis pathway involving the FAS and FASL genes plays a crucial role in the regulation of apoptotic cell death and imatinib mesylate (IM) mechanism of action. Promoter polymorphisms FAS-670 A>G and FAS-844 T>C which alter the transcriptional activity of these genes may grant a risk to develop cancer and revamp the drug activities towards the cancer cell. We investigated the association of these two polymorphisms with the susceptibility risk and IM treatment response in Malaysian chronic myeloid leukaemia (CML) patients. METHODS: This is a retrospective study, which included 93 CML patients and 98 controls. The polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) method was used to genotype the FAS and FASL polymorphisms. Data nanlysis was done using SPSS Version 22. The associations of the genotypes with susceptibility risk and IM response in CML patients were assessed by means of logistic regression analysis and deriving odds ratio with 95% CI. RESULTS: We observed a significant association between FASL-844T>C polymorphism and CML susceptibility risk and IM response. Variant C allele and FASL-844 CC variant genotype carriers had significantly higher risk for CML susceptibility (OR 1.756, CI 1.163-2.652, p=0.007 and OR 2.261, CI 1.013-5.047, p=0.047 respectively). Conversely, the heterozygous genotype FASL-844 TC conferred lower risk for CML susceptibility (OR 0.379, CI 0.176-0.816, p=0.013). The heterozygous and homozygous variant genotypes and variant C alleles were found to confer a lower risk for the development of IM resistance with OR 0.129 (95% CI: 0.034-0.489 p=0.003), OR 0.257 (95% CI: 0.081-0.818, p=0.021), and OR 0.486 (95% CI: 0.262-0.899, p=0.021) respectively. We also found that FAS-670 A>G polymorphism was not associated with CML susceptibility risk or IM response. CONCLUSION: The genetic polymorphism FASL-844 T>C may contribute to the CML susceptibility risk and also IM treatment response in CML patients. Accodringly, it may be useful as a biomarker for predicting CML susceptibility risk and IM resistance.

Subjects with coronary artery disease and reduced ejection fraction have longer (GT)n repeats in the heme-oxygenase 1 gene promoter.

Heme oxygenase (HO)-1 is a rate-limiting enzyme for degrading heme into carbon monoxide. Longer (GT)n repeat of the HO-1 gene (HMOX1) promoter has a lower transcription rate. Subjects with longer GT repeats in the HMOX1 promoter are more likely to have coronary artery disease (CAD) and cardiovascular events. We retrospectively enrolled CAD subjects with an abnormal ejection fraction (EF) < 50% from our catheterization data (N = 670). Polymerase chain reactions were performed for amplifying the HMOX1 promoter GT repeating segment to determine the number of repeats. Two subgroups, reduced EF < 40% (N = 256), and mid-range EF 40-49% (N = 414), were compared. The distribution of genotypes of SS, SL and LL were significantly different in reduced EF (29%, 48%, 23%) vs. mid-range EF CAD (64%, 30%, 5%) (S allele: ≤ 30 repeats, L allele: > 30 repeats) (p < 0.001). The patients with reduced EF had a significantly longer average (GT)n (median 27.5 vs. 26.5, p = 0.004) than those with the mid-range EF. In multivariate analysis, the carrier of L allele (odds ratio 4.437, p < 0.001) was a significant predictor for the diagnosis of reduced vs. mid-range EF CAD. In conclusion, CAD patients with reduced EF had longer HMOX1 promoter (GT)n repeats than those with mid-range EF.

Effect of TNF-α -308G/A (rs1800629) Promoter Polymorphism on the Serum Level of TNF-α Among Iraqi Patients with Generalized Vitiligo.

BACKGROUND: Vitiligo is a chronic acquired pigmentary disorder of the skin; it results from immunological distruction of functioning melanocytes. The cytokine TNF-α plays a central role in the initiation of melanocyte apoptosis in vitiligo. Single nucleotide polymorphism (SNP) in the promoter region of the gene coding for serum TNF-α may affect its production. OBJECTIVE: The aim of this study is to assess serum TNF-α as a risk factor for generalized vitiligo among Iraqi patients and to rule out that polymorphism at the -308 position affects serum TNF-α. MATERIALS AND METHODS: This case-control study was conducted at Sulaymaniyah Dermatology Teaching Center (SDTC), Iraq. Serum concentration of TNF-α was measured using enzyme linked immunosorbent assay (ELISA) technique in 80 patients with generalized vitiligo and 40 clinically healthy controls. The amplification refractory mutation system polymerase chain reaction (ARMS-PCR) technique was used for detection of TNF-308G/A gene polymorphism. TNF-α level correlated with TNF-308G/A gene polymorphism. Serum concentration and TNF -308G/A gene polymorphism have been analyzed in correlation with demographic features and clinical characteristics of patients with generalized vitiligo. RESULTS: Statistically significant elevation of serum TNF-α seen in patients compared to a control group (p-value 0.01). Significantly higher TNF-α level (p-value 0.01) found among patients with active generalized vitiligo. Elevated serum levels of TNF-α were significantly associated with both TNFA1 (TNF-308G) allele (p-value 0.04) and TNFA2 (TNF-308A) allele (p-value 0.03). TNF-α -308GA polymorphism was not affected by demographic features and clinical characteristics of patients with generalized vitiligo. CONCLUSION: TNF-α in the serum is a risk factor for generalized vitiligo among Iraqi patients. Patients with active vitiligo have a higher serum TNF-α level. No difference was found between serum level of TNF-α with TNF-α polymorphism at position -308 (TNF -308). This involves substituting G allele for the A allele.

Heme oxygenase-1 modulation: A potential therapeutic target for COVID-19 and associated complications.

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to infect hundred thousands of people every day worldwide. Since it is a novel virus, research continues to update the possible therapeutic targets when new evidence regarding COVID-19 are gathered. This article presents an evidence-based hypothesis that activating the heme oxygenase-1 (HO-1) pathway is a potential target for COVID-19. Interferons (IFNs) have broad-spectrum antiviral activity including against SARS-CoV-2. Induction of HO-1 and increase in the heme catabolism end-product confer antiviral activity. IFN activation results in inhibition of viral replication in various viral infections. COVID-19 induced inflammation as well as acute respiratory distress syndrome (ARDS), and coagulopathies are now known major causes of mortality. A protective role of HO-1 induction in inflammation, inflammation-induced coagulation, and ARDS has been reported. Based on an association of HO-1 promoter polymorphisms and disease severity, we propose an evaluation of the status of these polymorphisms in COVID-19 patients who become severely ill. If an association is established, it might be helpful in identifying patients at high risk. Hence, we hypothesize that HO-1 pathway activation could be a therapeutic strategy against COVID-19 and associated complications.

New Knowledge About CCR5, HIV Infection, and Disease Progression: Is "Old" Still Valuable?

C-C chemokine receptor (CCR) 5 (CCR5) is the main HIV-1 coreceptor involved in virus entry and cell-to-cell spread during acute and chronic infections: such CCR5 and T cell tropic viruses are adapted to and replicate in CD4+ memory T cells. Polymorphisms in CCR5 regulate CCR5 expression, which, in turn, influences HIV infection acquisition and subsequent disease progression. Among these polymorphisms, a 32-bp deletion in the CCR5 open reading frame (CCR5 Δ32) and a single nucleotide polymorphism (SNP) in the promoter (-2459G/A) are the most well-characterized polymorphisms. CCR5 Δ32 provides partial to full protection against HIV infection and, therefore, serves as a basis for gene deletion studies attempting to achieve a permanent HIV cure. Recent studies have discovered that certain SNPs in the CCR region, not within CCR5, also affect CCR5 expression, HIV infection, and disease progression. Although these studies provide further valuable information regarding the role of human genetic variation in HIV/AIDS, they did not incorporate -2459G/A. In this article, the author summarizes the knowledge gained through the discovery of these new SNPs and introduces the idea that by not incorporating -2459G/A, less comprehensive conclusions may have been reached. Until a strategy that delivers a cure to the millions is found, every piece of information that may help curtail the HIV/AIDS threat to public health should be considered useful.

Transcriptional activity of FIGLA, NEUROG2, and EGR1 transcription factors associated with polymorphisms in the proximal regulatory region of GPR54 gene in cattle.

Activity of transcription factors affect synthesis of G-protein coupled receptor 54 (GPR54), an important factor in regulation of initiation of puberty. Expression of the GPR54 gene in cattle is associated with polymorphisms in the proximal regulatory region (PRR) of the GPR54 gene. Transcription resulting in production of GPR54 mRNA transcript occurs as a result of transcription factor (TF) interactions in the PRR. Polymorphisms in the PRR may be associated with extent of activity of these TFs. Folliculogenesis-specific BHLH TF (FIGLA), neurogenin 2 (NEUROG2), and early growth response 1 (EGR1) are important in modulation of ovarian follicle development and neurons synthesizing GnRH, thus, regulating biosynthesis of luteinizing hormone. The aim of this study, therefore, was to assess the transcription-activating potential of binding sites for FIGLA, NEUROG2, and EGR1 TFs in the GPR54 promoter of cattle. Two luciferase-based promoters, ATC and CCT, which contain three single nucleotide polymorphisms (SNPs), A/C-794, T/C-663, and C/T-601, in the GPR54 PRR, were analyzed to evaluate gene expression and activation of different promoters by FIGLA, NEUROG2, and EGR1. The FIGLA induced GPR54 transcription through the CCT, whereas NEUROG2 and EGR1 induced GPR54 transcription through the ATC promoter-binding site. The CCT-activating effects of FIGLA were greater (2.56-fold) than the ATC-activating effects (P < 0.05). The ATC-activating effects of NEUROG2 and EGR1 were markedly greater (12.91- and 8.41-fold; P < 0.01) than CCT-activating effects. The polymorphisms, CCT and ATC, of the cattle GPR54 affect the activity of transcription factors, therefore, have an important effect on production of GPR54 mRNA transcript.

Evaluation of Relationship Between Arylesterase-Based Activity and Genetic Variants of Paraoxonase1 in T2DM Patients within Golestan Province.

Arylesterase activity of Paraoxonase-1 (PON1) enzyme may be play important role in initiation and progression of several diseases. Activity or serum level of Arylesterase can be affected by many genetic alterations such as SNPs. The reduction in the activity and serum level of Arylesterase could be involved in Type2 diabetes mellitus (T2DM). The aim of this investigation is to examine the association between Arylesterase activity and promoter polymorphism (- 108C > T) of PON1gene in patients with T2DM in Golestan Province, northern area of Iran. Achievement of this purpose was due to DNA obtaining from blood then SNP determination using PCR-RFLP and Arylesterase activity measurement in the serum of 90 normal individuals and 90patients suffering diabetes. Data was processed by SPSS software version 16. The significant association was observed between the Arylesterase activity and three genotypes of PON1 gene such as CC, CT, and TT in subjects with T2DM. In the present study, it has been shown level of Arylestrase activity of PON1 in patients (117.33 ± 63.96) is lower than it in control group (289.33 ± 68.38); P < 0.05. Our results declared that activity of Arylesterase in diabetic patients was significantly lower than the healthy individuals.

Subjects with microvascular angina have longer GT repeats polymorphism in the haem oxygenase-1 gene promoter.

Objective: Few studies have investigated haem oxygenase-1 gene (HMOX1) promoter polymorphism in microvascular angina (MVA).Materials and methods: HMOX1 promoter (GT)n repeats were examined in healthy controls (N = 220) and MVA subjects (N = 181).Results: The distribution of genotype of SS, SL and LL were significantly different in MVA (17%, 51%, 33%) vs. normal controls (35%, 46%, 20%) (p < 0.001, S allele: ≤30 repeats, L allele: >30 repeats). In multivariate analysis, carrier of L allele (odds ratio 2.772, p < 0.001) was a significant predictor for the diagnosis of MVA.Conclusions: Subjects with MVA had longer HMOX1 promoter (GT)n repeats than the healthy controls. Trial registration number: NCT01198730 at https://clinicaltrials.gov.