Presence Of Genetic Polymorphisms Research Articles

Association of Interleukin-6 (rs1800795) and Interleukin-10 (rs1800896) Genetic Polymorphisms with the Outcome of COVID-19 Infection: A Single Center Study.

The corona virus disease-2019 (COVID-19) pandemic has affected most of the world with varying degrees of morbidity and mortality. The presence of genetic polymorphisms may be associated with the severity and outcome of COVID-19 infection. This work aimed to evaluate the genetic polymorphisms of interleukin (IL-6) and IL-10 genes with the outcome of COVID-19 infection. This cross-sectional study was conducted on 354 patients who were classified into moderate and severe cases (including alive and deceased cases). All individuals were genotyped for one SNP for IL-6 (rs1800795) and one SNP for IL10 (rs1800896) using allelic discrimination real-time PCR technique. In this study, 198 cases were moderate, and 156 cases were severe. The risk of allele carriage of the minor allele of IL-6 rs1800795 (C) was significantly higher among the severe group when compared with that of the moderate group (p < 0.0001), while there was a mild significant difference of same allele carriage among alive cases when compared to that of deceased one (p < 0.04). Furthermore, the risk of the C allele of IL-10 rs1800896 was significantly increased in severe cases when compared with the moderate group (p < 0.0001), while there was no significant difference of the risk of the C allele in deceased cases when compared with that of alive ones (p > 0.05). In conclusion, the C allele (rs1800795) of IL-6 and the C allele (rs1800896) of IL-10 were highly significant in severe cases than in moderate cases. The C allele carriage of IL-6 showed only a significant difference between alive and deceased patients and not with the C allele of IL-10.

Physiologically Based Pharmacokinetic Modeling to Unravel the Drug-gene Interactions of Venlafaxine: Based on Activity Score-dependent Metabolism by CYP2D6 and CYP2C19 Polymorphisms.

Venlafaxine (VEN) is a commonly utilized medication for alleviating depression and anxiety disorders. The presence of genetic polymorphisms gives rise to considerable variations in plasma concentrations across different phenotypes. This divergence in phenotypic responses leads to notable differences in both the efficacy and tolerance of the drug. A physiologically based pharmacokinetic (PBPK) model for VEN and its metabolite O-desmethylvenlafaxine (ODV) to predict the impact of CYP2D6 and CYP2C19 gene polymorphisms on VEN pharmacokinetics (PK). The parent-metabolite PBPK models for VEN and ODV were developed using PK-Sim® and MoBi®. Leveraging prior research, derived and implemented CYP2D6 and CYP2C19 activity score (AS)-dependent metabolism to simulate exposure in the drug-gene interactions (DGIs) scenarios. The model's performance was evaluated by comparing predicted and observed values of plasma concentration-time (PCT) curves and PK parameters values. In the base models, 91.1%, 94.8%, and 94.6% of the predicted plasma concentrations for VEN, ODV, and VEN + ODV, respectively, fell within a twofold error range of the corresponding observed concentrations. For DGI scenarios, these values were 81.4% and 85% for VEN and ODV, respectively. Comparing CYP2D6 AS = 2 (normal metabolizers, NM) populations to AS = 0 (poor metabolizers, PM), 0.25, 0.5, 0.75, 1.0 (intermediate metabolizers, IM), 1.25, 1.5 (NM), and 3.0 (ultrarapid metabolizers, UM) populations in CYP2C19 AS = 2.0 group, the predicted DGI AUC0-96h ratios for VEN were 3.65, 3.09, 2.60, 2.18, 1.84, 1.56, 1.34, 0.61, and for ODV, they were 0.17, 0.35, 0.51, 0.64, 0.75, 0.83, 0.90, 1.11, and the results were similar in other CYP2C19 groups. It should be noted that PK differences in CYP2C19 phenotypes were not similar across different CYP2D6 groups. In clinical practice, the impact of genotyping on the in vivo disposition process of VEN should be considered to ensure the safety and efficacy of treatment.

NeuroPredict: study of the predictive value of ABCB1 genetic polymorphisms and associated clinical factors in chronic chemotherapy-induced peripheral neuropathy (CIPN).

Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a common entity (30%-40%) and can significantly limit the quality of life of patients, especially those that persist for more than 6months after treatment (chronic neuropathy). Studies have shown a possible association between the presence of genetic polymorphisms in ABCB1 and the development of acute CIPN, although this relationship with chronic CIPN remains unexplored. This is an analytical observational case-control study defined by the presence (cases) or absence (controls) of CIPN at 6 months after the end of the neurotoxic drug. Our aim is to demonstrate whether these ABCB1 polymorphisms also influence the chronification of this toxicity, as well as the clinical factors that can help us to predict it. Methods: The study included 152 patients treated with tri-weekly oxaliplatin (O) or weekly paclitaxel (P); 86 cases and 66 controls. Clinical and analytical parameters were analysed including the study of ABCB1 genetic polymorphisms in a blood sample. Results: ABCB1 genetic polymorphisms C1236T (rs1128503) and C3435T (rs1045642) are associated with the development of chronic CIPN in patients treated with P. No differences were found in patients treated with O. Other predictive factors to be considered in the development of this toxicity are age >60 years, BMI ≥30, toxic habits and cardiovascular risk factors. Conclusion: CIPN is a common and understudied toxicity, despite being a limiting factor in the quality of life of many patients. As described in acute CIPN, our study demonstrates the relationship between chronic neuropathy and being a carrier of specific polymorphisms (C1236T and C3435T) of the ABCB1 gene in patients treated with P. In addition, there are modifiable factors (obesity, smoking, or alcohol) that may influence its development. Further prospective studies are needed to investigate genetic and clinical modifiable factors predisposing to CIPPN to develop prevention and treatment strategies.

Association of polymorphism in leptin receptor gene with susceptibility of adolescent idiopathic scoliosis.

Abnormal leptin bioavailability has play key roles in the etiology of adolescent idiopathic scoliosis (AIS). Both leptin and its receptor levels may be modulated by the presence of genetic polymorphisms. This study aimed to evaluate the role of polymorphisms in the leptin (LEP) and its main receptor (LEPR) genes in the AIS susceptibility in girls. A retrospective case-control study was conducted with 189 AIS and 240 controls. LEP rs2167270 and LEPR rs2767485 polymorphisms were genotyped using a TaqMan validated assay. Associations were evaluated by odds ratios (OR) and 95% confidence intervals (CI). The AIS group showed a predominance of girls under 18years old (n = 140, 74.1%), 148 (78.3%) had low or normal BMI, 111 (58.7%) had Cobb ≥ 45º and 130 (68.7%) were skeletally mature. Minor allele frequencies of rs2167270 and rs2767485 were 35.7% and 18.3%, for AIS and 35.6% and 25.4% for controls, respectively. LEPR rs2767485 T and TC + TT were associated with higher risk of AIS (OR = 1.53; 95% CI = 1.09-2.13 and OR = 1.84; 95% CI = 1.69-2.01, respectively), since CC genotype was only present in the control group. In addition, the LEP rs2167270 GA + AA was more frequent in low weight group (BMI ≤ 24.9) of girls with AIS. There was no significant association between LEP rs2167270 and AIS susceptibility, and LEPR rs2767485 and BMI. The LEPR rs2767485 was associated with the genetic susceptibility of AIS and LEP rs2167270 with low BMI. These data can contribute to the identification of genetic biomarkers to improve the diagnosis and treatment.

Clinical implications of drug-metabolizing genes CYP3A4 and GSTP1 single nucleotide polymorphisms in oral cancer patients undergoing induction chemotherapy.

95 Background: Despite well-established induction chemotherapeutics for advanced-stage oral cavity cancer (OCC), there are no reliable markers to detect drug-induced toxicity and clinical efficacy. The presence of genetic polymorphisms can cause certain enzymes to behave differently in various populations, which can lead to varied outcomes. Thus, we analyzed the effect of metabolizing (CYP3A4) and detoxifying (GSTP1) genes involved in taxane/platinum/5-fluorouracil (TPF) or paclitaxel/carboplatin (PC) metabolism and their clinical outcomes in OCC patients. Methods: The current study included 121 OCC patients who received fixed dose of TPF or PC-based chemotherapy. PCR-RFLP was used to assess the polymorphism of the metabolising gene. SNPs were tested for toxicity and progression-free survival. Results: The grade ≥2 patients (47.9%) having higher fever (33.8%) and vomiting (34.7%) as a result of chemotherapy, showed significant association with the gene CYP3A4 (rs2687105) in both the PM and IM genotypes. For PM genotypes, the odd ratio (OR) of CYP3A4 for fever was 2.33E8 (95% CI: 4.702E7-1.154E9, p = 0.000), and for IM genotypes, it was 6.99E8 (95% CI: 1.89E8-2.581E9, p = 0.000). Meanwhile, the patients with grade ≥2 (58.6%) having anaemia (11.5%) and nausea (32.2%) also found to be significantly associated with GSTP1 (rs749174) in PM genotypes; the odds ratio was (OR: 8; 95%CI:1. 1001-63.963; p=0.05) and (OR: 2.667; 95%CI:1.043-6.815; p=0.04). Moreover, patients with these SNPs showing poor survival rate, however there was no significant association observed between the genotypes of each SNPs with progression-free survival (PFS). Conclusions: In conclusion, our data showed that the rs2687105 in CYP3A4 and the rs749174 in GSTP1 were associated with adverse events of TPF or PC chemotherapeutic regimens among the oral cancer patients. Therefore these genes might be used as predictive markers for minimising the adverse effects caused by chemotherapy and for optimization of drug dose in oral cancer patients.

Immune system gene polymorphisms associated with severe dengue in Latin America: a systematic review.

One of the main challenges in the clinical management of dengue is the early identification of cases that could progress to severe forms of the disease. A biomarker that may enable this identification is the presence of genetic polymorphisms in genes associated with immune responses. The objective of this study was to perform a systematic review of the Latin American literature on these genes. An electronic literature search was carried out in PubMed, Scopus, Lilacs, and the Virtual Health Library, and reference lists of systematic reviews in the area. Case-control studies conducted in Latin American countries examining at least one form of genetic polymorphism related to immune responses against severe dengue were included. In total, 424 articles were identified and 26 were included in this systematic review. Of the 26 selected articles, 16 reported polymorphisms associated with the risk of developing severe dengue (Risk); Similarly, 16 articles reported polymorphisms associated with a decreased risk of severe dengue (Protective). The final analysis revealed that multiple polymorphisms in immune system genes were early markers of the progression of dengue in Latin Americans and found that polymorphisms of the TNF-alpha gene may have a critical role in dengue pathogenesis.

The Effect of TNF-Alpha Gene Polymorphisms At -376 G/A, -806 C/T, and -1031 T/C on The Likelihood of Becoming a Non-Responder to Etanercept in A Sample of Iraqi Rheumatoid Arthritis Patients

Tumor necrosis factor-alpha (TNF-α) antagonists’ therapy are expensive and has a non-responsive rate between 30% to 40% in rheumatoid arthritis patients. Genetic variation plays a vital role in the responsiveness to this type of therapy.The aim of this study is to investigate if the presence of genetic polymorphism in the TNF-α gene promoter region at locations -376 G/A (rs1800750), -806 C/T (rs4248158), and -1031 T/C (rs1799964) affects rheumatoid arthritis patient's tendency to be a non-responder to etanercept. Eighty RA patients on etanercept (ETN) for at least six months were recruited from the Rheumatology Unit at Baghdad Teaching Hospital. Based on The European League Against Rheumatism response (EULAR) criteria, patients were divided into two groups: responders and non-responders. After polymerase chain reaction amplification of their DNA, the amplified DNA was sequenced by Sanger method to determine the polymorphisms at the positions -376G/A, -806 C/T, and -1031T/C. The results of this study found that equally Phi correlation and binary logistic regression analysis revealed a non-significant association for all genotypes in the three polymorphic sites with the tendency for being non-responder. Moreover, there was no significant difference in TNF-α mean level or the change in disease activity score for 28 joints (DAS28) after six months of etanercept therapy between all genotypes for each polymorphic site. The present study concludes that there was no correlation between the polymorphisms in the TNF-α promoter region at -376G/A, -806 C/T, and -1031T/C with the tendency for being non-responder to ETN.

Is severe COVID-19 a cytokine storm syndrome: a hyperinflammatory debate.

Purpose of reviewThe COVID-19 pandemic is a global public health crisis with considerable mortality and morbidity. A role for cytokine storm and therapeutic immunomodulation in a subgroup of patients with severe COVID-19 was proposed early in the pandemic. The concept of cytokine storm in COVID-19 has been criticised, given the lack of clear definition and relatively modest cytokinaemia (which may be necessary for viral clearance) compared with acute respiratory distress syndrome and bacterial sepsis. Here we consider the arguments for and against the concept of cytokine storm in COVID-19.Recent findingsSeveral criteria have been proposed to identify the subgroup of COVID-19 patients exhibiting a cytokine storm. The beneficial effects of corticosteroids and interleukin-6 inhibition suggest that inflammation is a modifiable pathogenic component of severe COVID-19. The presence of genetic polymorphisms and pathogenic auto-autoantibodies in severe COVID-19 also suggests a significant contribution of immune dysregulation to poor outcomes.SummaryHyperinflammation is a key component of severe COVID-19, residing underneath the cytokine storm umbrella term, associated with poor outcomes. Better understanding of the aetiopathogenesis, with identification of biomarkers to predict treatment responses and prognosis, will hopefully enable a stratified and ultimately precision medicine approach.

Association of Val16Ala Polymorphism of Manganese Superoxide Dismutase (MnSOD) with Food Intake and Cardiometabolic Risk Factors in the Elderly in Primary Care in Porto Alegre.

The aging process causes physiological changes on its own. The combination of an unhealthy lifestyle with the presence of genetic polymorphisms, such as the Val16Ala of the antioxidant enzyme manganese-dependent superoxide dismutase (MnSOD) may contribute to a greater occurrence of cardiometabolic risk factors. This study aimed to verify the association of Val16Ala-MnSOD polymorphism with food intake, caloric expenditure, and cardiometabolic risk factors in the elderly. A cross-sectional study with a sample size of 270 elderly individuals assisted in primary health care in the city of Porto Alegre, RS, Brazil. Val16Ala polymorphism, glucose, lipid profile, insulin, HOMA-IR, blood pressure, waist circumference, PCR-us, IL-6, food consumption, and caloric expenditure were evaluated. The average age of the elderly was 68.6 ± 7.6 years. There were statistically significant differences regarding the consumption of two or more servings of fruits and vegetables daily between the elderly VV versus AV (P=0.017). There were also statistically significant differences regarding the consumption of two or more daily servings of legumes and eggs between the elderly AA versus VV (P=0.002). The median of insulin was higher in the elderly AA versus AV (P=0.025) and the median of HOMA-IR was higher in the elderly VV versus AV (P=0.029). AA elderly individuals had higher means of high-density lipoprotein (HDL-c), compared to AV (P=0.029). The results suggest that Val16Ala -MnSOD polymorphism is associated with the consumption of fruits, vegetables, legumes, and eggs, as well as with cardiometabolic risk factors in the elderly.

Functional phenotyping of the CYP2D6 probe drug codeine in the horse

BackgroundIn humans, the drug metabolizing enzyme CYP2D6 is highly polymorphic resulting in substantial differences in the metabolism of drugs including anti-arrhythmics, neuroleptics, and opioids. The objective of this study was to phenotype a population of 100 horses from five different breeds and assess differences in the metabolic activity of the equine CYP2D6 homolog using codeine as a probe drug. Administration of a probe drug is a common method used for patient phenotyping in human medicine, whereby the ratio of parent drug to metabolite (metabolic ratio, MR) can be used to compare relative enzyme function between individuals. A single oral dose of codeine (0.6 mg/kg) was administered and plasma concentrations of codeine and its metabolites were determined using liquid chromatography mass spectrometry. The MR of codeine O-demethylation [(codeine)/(morphine + morphine-3-glucuronide + morphine-6-glucuronide)] was determined using the area under the plasma concentration-time curve extrapolated from time zero to infinity (AUC0-∞) for each analyte and used to group horses into predicted phenotypes (high-, moderate-, and low-MR).ResultsThe MR of codeine O-demethylation ranged from 0.002 to 0.147 (median 0.018) among all horses. No significant difference in MR was observed between breeds, age, or sex. Of the 100 horses, 11 were classified as high-MR, 72 moderate-MR, and 17 low-MR. Codeine AUC0-∞ and O-demethylation MR were significantly different (p < 0.05) between all three groups. The mean ± SD MR was 0.089 ± 0.027, 0.022 ± 0.011, and 0.0095 ± 0.001 for high-, moderate-, and low-MR groups, respectively. The AUC for the morphine metabolites morphine-3-glucuronide and morphine-6-glucuronide were significantly different between high-and low-MR groups (p < 0.004 and p < 0.006).ConclusionsThe MR calculated from plasma following codeine administration allowed for classification of horses into metabolic phenotypes within a large population. The range of codeine metabolism observed among horses suggests the presence of genetic polymorphisms in CYP2D82 of which codeine is a known substrate. Additional studies including CYP2D82 genotyping of high- and low-MR individuals are necessary to determine the presence of CYP2D polymorphisms and their functional implications with respect to the metabolism of therapeutics.

The relationship between CHRNA5/A3/B4 gene cluster polymorphisms and lung cancer risk: An updated meta-analysis and systematic review.

Background:Genetic polymorphisms in the 15q25 region have been associated with the risk of lung cancer (LC). However, studies have yielded conflicting results.Methods:Searches were conducted in databases, including PubMed, EMbase, Web of Science, CNKI, and Wanfang, for case-control studies up to August 1, 2019. After retrieving eligible studies and data extraction, we calculated pooled odds ratios with 95% confidence intervals. In the meta-analysis, we included 32 publications with a total of 52,795 patients with LC and 97,493 control cases to evaluate the polymorphisms in the CHRNA5/A3/B4 gene cluster in the 15q25 region.Results:Data of the meta-analysis showed a significantly increased risk of LC in the presence of genetic polymorphisms (rs1051730, rs16969968, rs8034191). In the smoking subgroup, the CHRNA3 rs1051730 polymorphism was found to contribute to LC risk using following 5 models: the allelic model, the homozygous model, the heterozygous model, the dominant model, and the recessive model. Thus, the rs1051730 polymorphism may modify LC susceptibility under the condition of smoking. Stratification studies for CHRNA5-rs8034191 showed that Caucasian groups with the wild-type genotype (C/C) may be susceptible to LC in all 5 models. No significant relationship between CHRNA3 rs6495309 or rs3743073 and LC susceptibility was found. However, Asians with the rs3743037 B-allele showed an obviously higher risk of LC susceptibility than the Caucasian population, observed via allelic, heterozygous, and dominant models.Conclusions:The 3 polymorphisms of rs1051730, rs16969968 and rs8034191 in the CHRNA5/A3/B4 gene cluster in the 15q25 region were associated with LC risk, which might be influenced by ethnicity and smoking status.

Physiologically based pharmacokinetic modeling of tramadol to inform dose adjustment and drug-drug interactions according to CYP2D6 phenotypes.

The objective of this study was to establish physiologically based pharmacokinetic (PBPK) models of tramadol and its active metabolite O-desmethyltramadol (M1) and to explore the influence of CYP2D6 gene polymorphism on the pharmacokinetics of tramadol and M1. Furthermore, we used PBPK modeling to prospectively predict the extent of drug-drug interactions (DDIs) in the presence of genetic polymorphisms when tramadol was co-administered with the CYP2D6 inhibitors duloxetine and paroxetine. Plasma concentrations of tramadol and M1 were used to adjust the turnover frequency (Kcat ) of CYP2D6 for phenotype populations with different CYP2D6 genotypes. PBPK models were developed to capture the pharmacokinetics between CYP2D6 extensive metabolizers (EMs), intermediate metabolizers (IMs), poor metabolizers (PMs), and ultra-rapid metabolizers (UMs). The validated models were then used to support dose adjustment in different CYP2D6 phenotypes and to predict the extent of CYP2D6-mediated DDIs when tramadol was co-administered with paroxetine or duloxetine. The PBPK models we built accurately describe tramadol and M1 exposure in the population with different CYP2D6 phenotypes. In our prediction, the area under the concentration-time curve (AUCinf-tDlast ) of M1 is 70% lower in PMs than in EMs, 27% lower in IMs, and 15% higher in UMs. Based on the models we built, we suggest that the oral dose of tramadol should be 50% higher for IMs and 25% lower for UMs to achieve an approximately equivalent plasma exposure of M1 as in EMs. When tramadol was co-administered with paroxetine or duloxetine, the magnitude of the inhibitor-substrate interaction was lowest in EMs (0.45), secondary in IMs (0.39), and highest in PMs (0.18) in terms of M1. The current example uses the PBPK model to guide dose adjustment of tramadol and to predict the effect of CYP2D6 genetic polymorphisms on DDIs for rational clinical use of tramadol in the future.

Failure of Achieving Tacrolimus Target Blood Concentration Might Be Avoided by a Wide Genotyping of Transplanted Patients: Evidence from a Retrospective Study.

Precise tacrolimus treatment in transplanted patients is achieved in the clinical setting by performing therapeutic drug monitoring (TDM) and consequently adjusting therapy. The aim of this study was to retrospectively analyze the variability in tacrolimus blood levels throughout 2 years of observation in 75 transplanted patients and to investigate if tacrolimus blood levels correlate with presence of genetic polymorphisms, thus modifying tacrolimus pharmacokinetics. CYP3A5*1 (G6986A), CYP3A4*1B (A392G), CYP3A4*22, ABCB1 (C3435T; C1236T; G2677A/T), SLCO1B1 (T521C), polymorphisms were analyzed. Based on the effect of their genotypes, patients were stratified into 5 groups: (1) reduced tacrolimus metabolism (RM), (2) increased metabolism (IM), (3) transporters polymorphisms (TM), (4) metabolism and transporter polymorphisms (AM) and (5) no mutations (Wild Type, WT). The percentage of the samples out of therapeutic range was significantly higher in the IM group than in the WT group (p = 0.001), as well as compared to the TM group (p = 0.004). Only IM pattern (p = 0.015) resulted as an independent predictor of number of tacrolimus blood levels out of therapeutic range. RM pattern (p = 0.006) was inversely related to the administered dose. Therefore, genotyping could become a standard practice before tacrolimus prescription thus decreasing side effects, increasing efficacy and reducing the economic burden for the national health system.

Development and Validation of a Reverse-Phase High-Performance Liquid Chromatography with Fluorescence Detection (RP-HPLC-FL) Method to Quantify Ruxolitinib in Plasma Samples

Ruxolitinib is a JAK 1/2 inhibitor approved in 2011 by the Food and Drug Administration (FDA) for the treatment of patients with myelofibrosis. Currently, side effects related to the use of ruxolitinib are routinely managed through therapeutic dose adjustment and blood count monitoring. However, the evaluation of plasma concentration of this compound and other tyrosine kinase inhibitors is becoming of increasing importance, since the therapeutic efficacy of this class of drugs is characterized by a marked variability caused by the presence of genetic polymorphisms, drug–drug interactions, and potential poor patient adherence. Therapeutic drug monitoring of these compounds is thus required to ensure both an optimal response and the reduction of potential adverse effects. In this manuscript, we describe the development and validation of a reverse-phase high-performance liquid chromatography (RP-HPLC) method for the quantification of ruxolitinib in plasma, using a liquid chromatographic system equipped with a fluorometric detector (FL) and a mobile phase at pH 4.8 composed of 67:33 water:acetonitrile. The excitation and emission wavelengths were set to 320 nm and 386 nm, respectively. The lower limit of quantification in plasma was 0.1 ng/mL, and the response was linear across the concentration range from 0.2 to 500 ng/mL. The developed methodology, based on a simple extraction procedure and on a rapid chromatographic analysis involving a 5 minutes total analysis time, was validated according to the European Medicines Agency (EMA) guidelines, and may be considered as alternative and complementary to other previously proposed approaches.

Abstract WP193: Genetic Polymorphisms Negatively Impact Upper Limb Motor Recovery After Stroke - A Meta-analysis

Upper limb (UL) hemiparesis is one of the most disabling consequences of a stroke. In addition to spontaneous recovery, post-stroke motor recovery is associated with adaptive neuroplasticity and motor learning. Factors affecting motor learning and adaptive neuroplasticity include the presence of genetic polymorphisms. Evidence is emerging that these polymorphisms can influence UL motor recovery. However, the implications of these polymorphisms on rehabilitation are unclear. Using a systematic review and meta analysis, we examined the influence of genetic polymorphisms on post-stroke UL motor recovery. We conducted a systematic review of the published literature in English language. The Down’s and Black checklist helped evaluate the quality of the published studies. We compared changes in UL motor impairment and activity levels between groups with and without the polymorphisms using standardized mean differences and derived summary effect sizes. Seven studies that examined the effects of genetic polymorphisms on UL motor recovery were obtained. The studies examined the effects of polymorphisms (presence of met alleles) in brain derived neurotrophic factor (BDNF, 5 studies) and Catechol- O -Methyltransferase (COMT, 1 study). One study assessed the effects of Apolipoprotein polymorphism (ApoE ε4). The Fugl Meyer Assessment and Wolf Motor Function Test outcomes assessed motor impairment and activity levels respectively. The quality of the published studies ranged from fair to good. The meta analysis revealed that presence of met allele in BDNF negatively influenced the recovery of motor impairment (moderate effect size -0.47). In addition, recovery of activity levels for people with moderate and high levels of motor ability (effect sizes -1.39 and -7.37 respectively) were also negatively impacted by the presence of met allele in BDNF. The met allele in COMT also negatively influenced recovery of motor impairment (effect size -2.66). Presence of ApoE ε4 did not influence UL motor recovery. In conclusion, the presence of genetic polymorphisms negatively influences the recovery of UL motor impairment and activity. These factors need to be considered while selecting rehabilitation interventions to maximize levels of UL motor recovery post-stroke.

Modern Possibilities of the Use of Non-Invasive Serological Biomarkers Severe in Population Studies

The ethnic and the gender factors materially affect the prevalence of gastric atrophy.? All the patients were divided into five ethnic groups: Russians, Karachays, Abazins, Circassians, Nogais. The decrease in serum gastrin-17 less than 10 pmol/l is a sensitive and specific biomarker for antral mucosal atrophy, pepsinogen-I less than 25 µg/l is a corpus mucosal atrophy biomarker (Se - 89% and 92%, Sp - 97% and 96%). Gastrin-17 and pepsinogen-I are also sensitive and specific biomarkers for mild, moderate, severe atrophy of the antrum and corpus (for severe antral mucosal atrophy Se - 96%, Sp - 92%, for severe corpus mucosal atrophy Se - 88%, Sp - 97%). A total of 75 patients with multifocal atrophic gastritis were examined histologically. 67 patients had gastrin-17 <10 pmol/l and pepsinogen-I <25 µg/l at the same time. 7 patients had gastrin-17 from 10 to 11.5 pmol/l, 1 patient had gastrin-17 = 19 pmol/l (Se - 89%). Therefore, the level of gastrin-17 and pepsinogen-I simultaneously decreases among patients with multifocal atrophic gastritis. The prevalence of atrophic gastritis is significantly different among some ethnic populations living in the same territory under the same environmental and living conditions. These differences prove the presence of genetic polymorphism in different ethnic groups of the population.

An infected late miscarriage associated with a genetically determined enhanced immune response in patients with recurrent viral and bacterial infections

Microbiological and genetic examinations of patients previously treated for an infected late miscarriage were performed. Materials and methods. Women (n=36) with viral excretion of cytomegalovirus, bacterial vaginosis, two or more relapses of herpes virus infection localized in the genital area within 6 months, and absence of any other reproductively significant infections were selected. All patients underwent vaginal microbiocenosis studies in dynamics, as well as polymorphisms associated with the enhanced immune response, NOS3 (4a/4b), PAI-1 (4G/5G), IL1B (C3954T, C511T), TNFA (G238A, G308A), PPARG (Pro12Ala), PGC1A (Gly482Ser), GSTM1 (del), GSTT1 (del), MMP1 (1G/2G). Results. In the course of the correlation analysis within the group between qualitative signs (recurrent bacterial vaginosis) and the presence of genetic polymorphisms, it was established that the presence of polymorphisms in matrix metalloproteinase - collagenase-1 (r=0.59) and tumor necrosis factor a (r=0.51) genes is associated with a recurrent course bacterial vaginosis. There is no reliable correlation between the polymorphism of the studied genes and the virus release of the cytomegalovirus. The conclusion. As a preparation for pregnancy, patients with an infected miscarriage in anamnesis or with recurrent viral and bacterial infections require the appointment of therapy aimed at regulating the immune response. One of the drugs of choice is inosine pranobex (Isoprinosine®), which stimulates cellular immune response that contributes to a change in the cytokine profile and increases the functional activity of the effector cells.

Pharmacogenetics, tobacco, alcohol and its effect on the risk development cancer

Cancer is the second leading cause of death in the world, causing 8.8 million deaths in 2015 according to the World Health Organization (WHO). Risk factors for cancer include smoking and alcohol con sumption. In Chile, 33.6% of the population and 21.2% of young people smokes. Alcohol consump tion in the Chilean population is 74.5% and 12.2% in young people. Among the physiological factors that influence the development of cancer, the genetic factor plays a relevant role. It has been shown that the presence of genetic polymorphisms that alter the ability of the body to eliminate contami nants increase the risk of developing cancer. The same applies to polymorphisms that prevent DNA repair due to damage caused by environmental pollutants such as cigarette smoke. The objective of this review is to analyze the state of the art of the relationship between pharmacogenetics, smoking, and alcohol consumption as risk factors for the development of cancer. In conclusion, the results suggest that the presence of polymorphisms that alter the function of biotransformation enzymes phase I (CYP1A1, CYP1E1) and phase II (GST), as well as polymorphisms in DNA repair enzymes (ERCC1 / ERCC2), increase the risk of cancer induced by smoking and alcohol consumption. This association is important considering that smoking and drinking alcohol are highly prevalent among the Chilean population.

Folate, vitamin B12, homocysteine and polymorphisms in folate metabolizing genes in children with congenital heart disease and their mothers.

The objective of the study was to assess the role of variations in serum folate, vitamin B12, homocysteine and the presence of genetic polymorphisms as risk factors for congenital heart disease (CHD) in children. A total of 32 children with CHD, and their mothers and 32 normal children and their mothers formed the study and control groups, respectively. Serum folate, vitamin B12 and homocysteine as well as genetic polymorphisms MTHFR C677→︀T, MTHFR A1298→︀C, MTR A2756→︀G and MTRR A66→︀G were assessed. Low serum folate and genetic polymorphisms MTHFR C677→︀T and MTRR A66→︀G among children and their mothers and high homocysteine among mothers were noted as risk factors for CHD (P<0.05). Vitamin B12 levels were normal and showed no association. Presence of MTHFR C677→︀T and MTRR A66→︀G, both concurrently among children as well as mothers and simultaneously among mother-child pairs, showed several fold increase in the risk for CHD. On multivariate analysis, the risk factors noted for CHD were presence of MTHFR C677→︀T among children and their mothers and MTRR A66→︀G among mothers. Analyses for nutrient-gene interaction revealed significant associations between low serum folate and high serum homocysteine levels, and the presence of selected genetic polymorphisms. Low serum folate, high homocysteine and presence of selected genetic polymorphisms among children and their mothers were noted as risk factors for CHD. Nutrient-gene interaction being a modifiable risk factor, the study recommends the use of peri-conceptional folate supplementation with vitamin B12 sufficiency for primary prevention of CHD.

Influence of Genetic Variations in Selenoprotein Genes on the Pattern of Gene Expression after Supplementation with Brazil Nuts.

Selenium (Se) is an essential micronutrient for human health. Its beneficial effects are exerted by selenoproteins, which can be quantified in blood and used as molecular biomarkers of Se status. We hypothesize that the presence of genetic polymorphisms in selenoprotein genes may: (1) influence the gene expression of specific selenoproteins and (2) influence the pattern of global gene expression after Brazil nut supplementation. The study was conducted with 130 healthy volunteers in Sao Paulo, Brazil, who consumed one Brazil nut (300 μg/Se) a day for eight weeks. Gene expression of GPX1 and SELENOP and genotyping were measured by real-time PCR using TaqMan Assays. Global gene expression was assessed by microarray using Illumina HumanHT-12 v4 BeadChips. Brazil nut supplementation significantly increased GPX1 mRNA expression only in subjects with CC genotype at rs1050450 (p < 0.05). SELENOP mRNA expression was significantly higher in A-carriers at rs7579 either before or after supplementation (p < 0.05). Genotype for rs713041 in GPX4 affected the pattern of blood cell global gene expression. Genetic variations in selenoprotein genes modulated both GPX1 and SELENOP selenoprotein gene expression and global gene expression in response to Brazil nut supplementation.