Influence Of Genetic Polymorphisms Research Articles

Population pharmacokinetics of oxcarbazepine active metabolite in Chinese children with epilepsy.

Oxcarbazepine (OXC) is an antiepileptic drug whose efficacy is largely attributed to its monohydroxy derivative metabolite (MHD). Nevertheless, there exists significant inter-individual variability in both the pharmacokinetics and therapeutic response of this drug. The objective of this study is to explore the impact of patients' characteristics and genetic variants on MHD clearance in a population pharmacokinetic (PPK) model of Chinese pediatric patients with epilepsy. The PPK model was developed using a nonlinear mixed effects modeling method based on 231 MHD plasma concentrations obtained from 185 children with epilepsy. The one-compartment model and combined residual model were established to describe the pharmacokinetics of MHD. Forward addition and backward elimination were employed to evaluate the impact of covariates on the model parameters. The model was evaluated using goodness-of-fit, bootstrap, visual predictive checks, and normalized prediction distribution errors. In the two final PPK models, age, estimated glomerular filtration rate (eGFR), and a combined genotype of six variants (rs1045642, rs2032582, rs7668282, rs2396185, rs2304016, rs1128503) were found to significantly reduce inter-individual variability for MHD clearance. The inter-individual clearance equals to 1.38 × (Age/4.74)0.29 × (eGFR/128.66)0.25 × eθABCB-UGT-SCN-INSR for genetic variants included model and 1.30 × (Age/4.74)0.30 × (eGFR/128.66)0.23 for model without genetic variants. The precision of all parameters was deemed acceptable, and the model exhibited good predictability while remaining stable and effective. Conclusion: Age, eGFR, and genotype may play a significant role in MHD clearance in children with epilepsy. The developed PPK models hold potential utility in facilitating oxcarbazepine dose adjustment in pediatric patients. What is Known: • The adjustment of the oxcarbazepine regimen remains difficult due to the considerable inter- and intra-individual variability of oxcarbazepine pharmacokinetics. • Body weight and co-administration with enzyme-inducing antiepileptic drugs emerge as the most influential factors contributing to the pharmacokinetics of MHD. What is New: • A positive correlation was observed between eGFR and the clearance of MHD in pediatric patients with epilepsy. • We explored the influence of genetic polymorphisms on MHD clearance and identified a combined genotype (ABCB-UGT-SCN-INSR) that exhibited a significant association with MHD concentration.

Influence of genetic polymorphisms on arsenic methylation efficiency during pregnancy: Evidence from a Spanish birth cohort

BackgroundInorganic arsenic (iAs) is a widespread toxic metalloid. It is well-known that iAs metabolism and its toxicity are mediated by polymorphisms in AS3MT and other genes. However, studies during pregnancy are scarce. We aimed to examine the role of genetic polymorphisms in AS3MT, GSTO2, N6AMT1, MTHFR, MTR, FTCD, CBS, and FOLH1 in iAs methylation efficiency during pregnancy. MethodsThe study included 541 pregnant participants from the INMA (Environment and Childhood) Spanish cohort. Using high-performance liquid chromatography coupled to inductively coupled plasma-tandem mass, we measured arsenic (iAs and the metabolites monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA)) in urine samples collected during the first trimester. iAs methylation efficiency was determined based on relative concentrations of the As metabolites in urine (%MMA, %DMA, and %iAs). Thirty-two single nucleotide polymorphisms (SNPs) in nine genes were determined in maternal DNA; AS3MT haplotypes were inferred. We assessed the association between genotypes/haplotypes and maternal As methylation efficiency using multivariate linear regression models. ResultsThe median %MMA and %DMA were 5.3 %, and 89 %, respectively. Ancestral alleles of AS3MT SNPs (rs3740393, rs3740390, rs11191453, and rs11191454) were significantly associated with higher %MMA, %iAs, and lower %DMA. Pregnant participants with zero copies of the GGCTTCAC AS3MT haplotype presented a higher %MMA. Statistically significant associations were also found for the FOLH1 SNP rs202676 (β 0.89 95%CI: 0.24, 1.55 for carriers of the G allele vs. the A allele). ConclusionsOur study shows that ancestral alleles in AS3MT polymorphisms were associated with lower As methylation efficiency in early pregnancy and suggests that FOLH1 also plays a role in As methylation efficiency. These results support the hypothesis that As metabolism is multigenic, being a key element for identifying susceptible populations.

Analysis of <i>BMP2</i> gene polymorphism of bone morphogenetic protein-2 in reindeer

The BMP2 gene of reindeer was study by Sanger sequencing. The BMP2 gene is involved in the formation of bone tissue and skeletal muscle in mammals. The BMP2 gene is associated with an increase in height, size, and body weight in productive animals. For the first time, the nucleotidesequence of the coding and regulatory regions of the BMP2 gene was determined in populations of wild and domestic reindeer.As a result, a segment of the reindeer BMP2 candidate gene was sequence, including the first untranslated and second exons. Loci with low (exon1) and high (exon2) degree of polymorphism identified.Single nucleotide mismatches with the reference genome (white-tailed deer (Odocoileus virginianus texanus) genome) identified, which can be used for phylogenetic analysis of the evolution of orthologue genes, as well as for genetic identification of species. Twelve polymorphic loci of two types were identified: in/del and SNP. The most significant substitutions were also determined in accordance with the change in the amino acid composition of the protein and the chemical properties of the replaced amino acids. Calculations were made of the occurrence of genotypes and alleles according to the identified variants of genetic polymorphism in the analyzed populations of reindeer (Nenets and Evenk breeds, wild reindeer).The object of research was wild and domestic reindeer on the farms of the Taimyr Peninsula and Evenkia. The material for the study was DNA isolated by the classical phenol method from the blood of domestic reindeer of two breeds - Nenets (n=20) and Evenki (n=20), as well as from tissue samples of wild reindeer (n=20).The aim of the study was to search for and select potential variants of genetic polymorphism in the BMP2 gene as molecular genetic markers that can be recommend for use in the practice of reindeer breeding to increase meat productivity.For the first time, the nucleotide sequence of significant regions of the reindeer BMP2 gene was determined. The polymorphic loci in the BMP2 gene identified as a result of the studies had differences in the frequency of occurrence of alleles of mutant and wild types in the studied samples of domestic reindeer of the Nenets and Evenk breeds, as well as in the sample of wild reindeer. Differences in occurrence indicate the effect of selection factors on the region of the BMP2 gene. The revealed genetic variability of the studied region in reindeer breeds contrasting in productivity is a preliminary confirmation of the influence of genetic polymorphism in the BMP2 gene on the variability of phenotypes in terms of height and weight indicators. Indicators of growth and live weight are key to the formation of the meat productivity of reindeer. The results of studies of the effect of BMP2 gene polymorphism on growth and weight parameters in other animal species suggest that some of the identified variants of genetic polymorphism in the studied region of the BMP2 gene may turn out to be casual mutations that can affect the formation of quantitative traits in domestic reindeer.

Influence of genetic polymorphisms on serum biomarkers of cardiac health.

Cardiovascular diseases (CVDs) are a leading cause of death worldwide which is why early risk prediction is crucial. Discrete Polygenic risk score (PRS) measurement using saliva or dried blood spot samples collected at home poses a convenient means for early CVD risk assessment. The present study assessed the effects of 28 disease-associated single nucleotide polymorphisms (SNPs) on 16 serological cardiac markers and also aggregated the risk alleles into a PRS to evaluate its applicability in CVD-risk prediction. The study assessed genetic and serological markers in 184 individuals. The association between serological markers and individual genetic variants was evaluated using a two-tailed t test while the associations of serum markers with the PRS was analyzed using the Pearson correlation. The comparative analysis of genotypes revealed statistically significant associations between serum markers and CVD-associated SNPs with Apo B: Apo A-1, LDL Direct, Apo B, sdLDL, hsCRP, Lp(a), NT-proBNP, and PLAC levels being significantly associated with the risk alleles of the SNPs, rs12526453, rs5186, rs10911021, rs1801131, rs670, rs10757274, and rs10757278. Increased PLAC levels were associated with rs10757274 and rs10757278 (P < .05). The SNPs, rs1801133, rs1549758, rs1799983, rs5082, and rs5186 were significantly associated with an increase in the cardioprotective markers, HDL and ApoA1 (P < .05). Furthermore, the PRS was associated with increasing levels of several serum cardiac markers (r2 > 0.6). Significant correlations were observed between high PRSs and NT-proBNP and ox-LDL levels with the r2 values being 0.82 (95% CI = 0.13-0.99; P = .03) and 0.94 (95% CI = 0.63-0.99; P = .005), respectively. The present study reports that SNPs have differential effects on serum markers with rs12526453, rs5186, rs10911021, rs1801131, rs670, rs10757274, and rs10757278 showing significant associations with elevated marker levels, which are indicators of deteriorating cardiac health. A unified PRS using several SNPs was also associated with an increase in serum markers levels, especially, NT-proBNP and ox-LDL. Genetic assessment via a convenient at-home collection to calculate the PRS can serve as an effective predictive tool for early CVD-risk assessment. This may help identify the risk groups that may require increased serological monitoring.

Immunological Profile of Vasospasm after Subarachnoid Hemorrhage.

Subarachnoid hemorrhage (SAH) carries high mortality and disability rates, which are substantially driven by complications. Early brain injury and vasospasm can happen after SAH and are crucial events to prevent and treat to improve prognosis. In recent decades, immunological mechanisms have been implicated in SAH complications, with both innate and adaptive immunity involved in mechanisms of damage after SAH. The purpose of this review is to summarize the immunological profile of vasospasm, highlighting the potential implementation of biomarkers for its prediction and management. Overall, the kinetics of central nervous system (CNS) immune invasion and soluble factors' production critically differs between patients developing vasospasm compared to those not experiencing this complication. In particular, in people developing vasospasm, a neutrophil increase develops in the first minutes to days and pairs with a mild depletion of CD45+ lymphocytes. Cytokine production is boosted early on after SAH, and a steep increase in interleukin-6, metalloproteinase-9 and vascular endothelial growth factor (VEGF) anticipates the development of vasospasm after SAH. We also highlight the role of microglia and the potential influence of genetic polymorphism in the development of vasospasm and SAH-related complications.

Influence of genetic polymorphisms in P2Y12 receptor signaling pathway on antiplatelet response to clopidogrel in coronary heart disease

BackgroundsRemarkable interindividual variability in clopidogrel response is observed, genetic polymorphisms in P2RY12 and its signal pathway is supposed to affect clopidogrel response in CHD patients.Methods539 CHD patients treated with clopidogrel were recruited. The platelet reaction index (PRI) indicated by VASP-P level were detected in 12–24 h after clopidogrel loading dose or within 5–7 days after initiation of maintain dose clopidogrel. A total of 13 SNPs in relevant genes were genotyped in sample A (239 CHD patients). The SNPs which have significant differences in PRI will be validated in another sample (sample B, 300 CHD patients).ResultsCYP2C19*2 increased the risk of clopidogrel resistance significantly. When CYP2C19*2 and CYP2C19*3 were considered, CYP2C19 loss of function (LOF) alleles were associated with more obviously increased the risk of clopidogrel resistance; P2RY12 rs6809699C > A polymorphism was also associated with increased risk of clopidogrel resistance (AA vs CC: P = 0.0398). This difference still existed after stratification by CYP2C19 genotypes. It was also validated in sample B. The association was also still significant even in the case of stratification by CYP2C19 genotypes in all patients (sample A + B).ConclusionOur data suggest that P2RY12 rs6809699 is associated with clopidogrel resistance in CHD patients. Meanwhile, the rs6809699 AA genotype can increase on-treatment platelet activity independent of CYP2C19 LOF polymorphisms.

Influence of genetic polymorphisms on mechanical pain sensitivity and endogenous pain modulation of trigeminal and spinal areas.

Previous evidence indicates significant association between genetic polymorphisms and phenotypes related to pain sensitivity in patients with temporomandibular disorders (TMD). Despite the important advances in cataloguing diverse factors such as sleep disorders, anxiety and depression, the interrelated mechanisms of painful TMD aetiopathogenesis still need investigation. This case-control study aimed to evaluate the influence of genetic polymorphisms (rs6296, rs6295, rs1799971, rs4680, rs4633, rs4818) and psychosocial factors on the mechanical pain sensitivity and endogenous pain modulation in women with painful TMD and asymptomatic controls. We evaluated six independent variables: anxiety levels, depression, stress, sleep quality, pain catastrophising and genetic polymorphisms, and four dependent variables: mechanical pain threshold (MPT), pressure pain threshold (PPT), wind-up ratio (WUR) and conditioned pain modulation (CPM) collected at masseter (trigeminal) and hand (spinal) areas in a sample of 95 painful TMD patients and 85 controls. A regression model was used to test the possible effect of the independent variables on dependent variables. The regression model was significant for MPT (F11,168 =9.772; R2 =.390). Painful TMD diagnoses and sleep quality were associated with trigeminal MPT (B coefficient=-.499; and B coefficient=-.211, respectively). WUR was associated with rs6295 and rs6746030, respectively, for the spinal and the trigeminal area. Genetic polymorphisms had a slight contribution to endogenous pain modulation as indicated by the significant association with WUR but did not contribute to mechanical pain sensitivity. On the other hand, the presence of painful TMD and the sleep quality contributed significantly to mechanical pain sensitivity.

Influence of genetic polymorphisms on arsenic methylation efficiency during pregnancy

Influence of genetic polymorphisms on arsenic methylation efficiency during pregnancy

Study of the Association of Single Nucleotide Polymorphisms in Candidate Genes With Sevoflurane.

The susceptibility of different individuals to anesthetics varies widely, and sevoflurane is no exception. We hypothesized that polymorphisms in genes involved in pharmacokinetics and pharmacodynamics may explain this variation. A total of 151 individuals undergoing otorhinolaryngology surgery were included. The influence of genetic polymorphisms on sevoflurane sensitivity were investigated through SNaPshot technology. Individuals carrying KCNK2 rs6686529 G>C, MTRR rs3733784 TT, rs2307116 GG, or rs1801394 AA polymorphisms had a higher sensitivity to the sedative effect of sevoflurane than those without those polymorphisms. The univariate linear regression analysis indicated that MTRR rs3733784 TT, rs2307116 GG, and rs1801394 AA were potentially significant predictors of higher sensitivity to the sedative effect of sevoflurane. Moreover, CYP2E1 rs3813867 G>C and rs2031920 C>T, GABRG1 rs279858 T>C, KCNK3 rs1275988 CC, GRIN2B rs1806201 GG, MTRR rs2307116 G>A, and rs1801394 A>G were associated with a higher sensitivity to the cardiovascular effect of sevoflurane. Our results suggested that 9 single nucleotide polymorphisms in genes involved in metabolizing enzymes, transport proteins, target proteins of sevoflurane and folate metabolism may help to explain individual differences in the susceptibility to the sedative or cardiovascular effect of sevoflurane.

GENETIC POLYMORPHISM AND PRESENCE OF INTERLEUKINS IL-1β AND IL-17 IN APICAL PERIODONTITIS: INTEGRATIVE REVIEW

<h3>Objectives</h3> Apical Periodontitis (AP) is a host-mediated inflammatory response against the bacterial infection of root canals. Its pathogenesis is complex and involves inflammatory mediators in which production varies among individuals, a process that can be explained by genetic polymorphism. This integrative review aims to analyze studies that evaluate the influence of genetic polymorphism and the presence of interleukins IL-1β and IL-17 in AP, in the period from January 2016 to March 2021. <h3>Study Design</h3> Searches were done in MEDLINE/PubMed, BVS, and SciELO databases using descriptors from DeCS and MeSH. After defining the eligibility criteria, titles and abstracts were analyzed. The findings and the quality of the studies were added into a standardized table and evaluated according to the evidence level. <h3>Results</h3> Of the 14 analyzed studies, 50% were published in oral and maxillofacial pathology journals, and 43% were classified as level I of evidence. <h3>Conclusions</h3> The authors agree about the correlation between AP and the increase of proinflammatory cytokine serum levels. The studies point to an important role of IL-1β in the maintenance of the inflammatory process of AP, whereas IL-17 seems to be related to flare-up processes, severity level, and repair.

Temporomandibular disorder in construction workers associated with ANKK1 and DRD2 genes.

The study aimed to explore the influence of genetic polymorphisms in ANKK1 and DRD2 on the signs and symptoms of temporomandibular disorder (TMD) in construction workers. This cross-sectional study included only male subjects. All construction workers were healthy and over 18 years age. Illiterate workers and functionally illiterate workers were excluded. The diagnosis of TMD was established according to the Research Diagnostic Criteria for TMD (RDC/TMD). Genomic DNA was used to evaluate the genetic polymorphisms ANKK1 (rs1800497) and DRD2 (rs6275; rs6276) using Real-Time PCR. Chi-square or Fisher exact tests were used to evaluate genotypes and allele distribution among the studied phenotypes. The established alpha of this study was 5%. The sample included a total of 115 patients. The age of the patients ranged from 19 to 70 years (mean age 38.2; standard deviation 11.7). Chronic pain (87.7%), disc displacement (38.2%), and joint inflammation (26.9%) were the most frequently observed signs and symptoms. The genetic polymorphism rs6276 in DRD2 was associated with chronic pain (p=0.033). In conclusion, our study suggests that genetic polymorphisms in DRD2 and ANKK1 may influence TMD signs and symptoms in a group of male construction workers.

Physical activity associates empathy in Japanese young adults with specific gene variations of oxytocin receptor and vasopressin V1B receptor

BackgroundEmpathy, consisting of cognitive empathy and affective empathy, is essential for creating relationships with others. Since the genetic polymorphism of oxytocin receptor (OXTR) and arginine-vasopressin V1B receptor (AVPR1B) relate to prosocial behavior and empathy, it would need to innovate strategies for treating human empathy by considering individual genetic variations. Physical activity is expected as a possible strategy; here, we investigated the influences of genetic polymorphisms in OXTR SNP rs53576 and AVPR1B SNP rs28373064, on the relationships of self-reported empathy with physical activity. MethodsThe saliva is collected from a hundred Japanese college students for determining the individual polymorphism of OXTR SNP rs53576 (AA, AG, or GG genotype) and AVPR1B SNP rs28373064 (TT, TC, or CC genotype). In addition, the participants’ self-reported cognitive and affective empathy, amounts of physical activity, and sitting time were evaluated with questionaries. ResultsThe participants with OXTR SNP rs53576 GG genotype showed a significant negative correlation between sitting time and cognitive empathy adjusted by age, gender, and sports experience. Further, there was a trend to correlate between physical activity amounts and cognitive empathy in the participants carrying the G variant in OXTR SNP rs53576 (AG or GG). As for AVPR1B SNP rs28373064, the persons with TT genotype exhibited a negative correlation trend between sitting time and cognitive empathy. ConclusionsThere are possible correlations between the self-reported cognitive empathy and physical activity amounts in the persons carrying the G variant of OXTR rs53576 or with the TT genotype for AVPR1B SNP rs28373064.

Association study identifies genetic determinants and non-genetic factors on steady-state plasma and therapeutic outcome of galantamine in mixed dementia.

This study aimed to evaluate the influence of genetic polymorphisms of drug-metabolizing enzyme genes, transporter gene, pathological gene (APOE), and non-genetic factors on therapeutic outcomes as well as steady-state plasma concentrations (Cpss) of galantamine in Thai patients with mixed dementia. Fifty-one Thai patients with mixed dementia who received galantamine for at least 6months were recruited. CYP2D6, CYP3A5, and ABCB1 polymorphisms were detected by TaqMan® Genotyping Assay. UGT1A1 and APOE polymorphism was detected by direct Sanger sequencing technique and restriction fragment length polymorphism technique. Cpss of galantamine was measured by ultra-performance liquid chromatography. Associations of genetic and non-genetic factors with Cpss and clinical outcomes (change in cognitive function as measured by the Thai Mental State Examination (ΔTMSE) scores) were determined by using univariate and multivariate analysis. The multivariate regression model revealed that patients who carried one or more detrimental allelic variant (CYP2D6, CYP3A5, and UGT1A1) showed a tendency toward a higher galantamine adjusted Cpss (B = 34.559, 95% CI = 0.741-68.377, p value = 0.045). Logistic regression analysis also revealed CYP2D6*10 carriers were significantly associated with higher ΔTMSE (B = 5.227, 95% CI = 2.395-8.060, p value = 0.001). UGT1A1 mutant alleles and non-genetic factors including concomitant use of statin drugs and higher education level can attenuate therapeutic outcomes of galantamine. Pharmacokinetic-related genes including CYP2D6*10 and UGT1A1 mutant alleles were significantly associated with galantamine adjusted Cpss and cognitive function. Determination of Cpss and genotype could be an adjunct examination to provide further explanation in interindividual variability of galantamine therapeutic outcome.

The pharmacokinetics of tacrolimus in peripheral blood mononuclear cells and limited sampling strategy for estimation of exposure in renal transplant recipients.

Intracellular exposure of tacrolimus (TAC) may be a better marker of therapeutic effect than whole blood exposure. We aimed to evaluate the influence of genetic polymorphism on the pharmacokinetics of TAC in peripheral blood mononuclear cells (PBMCs) and develop limited sampling strategy (LSS) models to estimate the area under the curve (AUC0-12h) in the PBMC of Chinese renal transplant patients. Ten blood samples of each of the 23 renal transplant patients were collected 0-12h after 14 (10-18) days of TAC administration. PBMCs were separated and quantified. The TAC level in PBMCs was determined, and pharmacokinetic parameters were estimated by noncompartmental study. The AUC0-12h of TAC in whole blood was estimated by Bayesian approach based on a population pharmacokinetic model established in 65 renal transplant patients. The influence of CYP3A5 and ABCB1 genotypes on exposure was estimated. By applying multiple stepwise linear regression analysis, LSS equations for TAC AUC0-12h in the PMBC of renal transplant patients were established, and the bias and precision of various equations were identified and compared. We found a modest correlation between TAC exposure in whole blood and PBMC (r2 = 0.5260). Patients with the CYP3A5 6986GG genotype had a higher AUC0-12h in PBMCs than those with the 6986 AA or GA genotype (P = 0.026). Conversely, patients with the ABCB1 3435TT genotype had a higher AUC0-12h in PBMC than those with the 3435 CC and CT genotypes (P = 0.046). LSS models with 1-4 blood time points were established (r2 = 0.570-0.989). The best model for predicting TAC AUC0-12h was C2-C4-C6-C10 (r2 = 0.989). The model with C0.5-C6 (r2 = 0.849) can be used for outpatients who need monitoring to be performed in a short period. The CYP3A5 and ABCB1 genotypes impact TAC exposure in PBMCs, which may further alter the effects of TAC. The LSS model consisting of 2-4 time points is an effective approach for estimating full TAC AUC0-12h in Chinese renal transplant patients. This approach may provide convenience and the possibility for clinical monitoring of TAC intracellular exposure.

Population pharmacokinetics of tacrolimus in Chinese adult liver transplant patients.

Tacrolimus is widely used in organ transplantation to prevent rejection. However, the narrow therapeutic window and the large inter-and intra-individual variability in the pharmacokinetics (PK) of tacrolimus make it difficult for individualization of dosing. This study aimed at developing a population pharmacokinetic model for estimating the oral clearance of tacrolimus in Chinese liver transplant patients, and identifying factors that contribute to the PK variability of tacrolimus. Data of 151 liver transplant patients who received tacrolimus were analyzed in this study. The population PK model was analyzed and the covariates including population demographic and biochemical characteristics, drug combination, and genetic polymorphism were explored using non-linear mixed-effects modeling approach. A single-compartment population PK model was developed, and the final model was CL/F=(14.6-2.38×cytochrome P450 (CYP) 3A5-3.72×WZC+1.04 × (POD/9)+2.48×COR)×Exp(ηi ), where CYP3A5 was 1 for CYP3A5*3/*3, Wuzhi Capsule (WZC) was 1 when patients took tacrolimus combined with WZC, otherwise it was 0, corticosteroids (COR) was 1when patients take tacrolimus combined with COR, otherwise, it was 0, POD was the post-operative day. Visual inspection and bootstrap indicated that the final model was stable and robust. In this study, we developed the first tacrolimus population PK model in Chinese adult liver transplant patients. We first determined the influence of WZC on tacrolimus in these people, which could provide useful PK information for the drug combination of tacrolimus and WZC. We also revealed the influence of genetic polymorphism of CYP3A5, POD, and a combination of COR on tacrolimus PK. Therefore, these significant factors should be taken into consideration in optimizing dosage regimens.

ОЛЬ ПОЛИМОРФИЗМА ГЕНА MDR1 ДЛЯ НАЗНАЧЕНИЯ НЕСТЕРОИДНЫХ ПРОТИВОВОСПАЛИТЕЛЬНЫХ ПРЕПАРАТОВ ПРИ БОЛЕВОМ СИНДРОМЕ

Introduction. One of the key roles in the excretion of a number of drugs, in particular nonsteroidal anti- inflammatory drugs, has a transport protein glycoprotein P, encoded by the MDR1 gene. In this connection, the influence of genetic polymorphism of glycoprotein P on the pharmacokinetics of these drugs contributes to the prediction of clinical consequences. Aim. The aim of the current study was to study the associations of polymorphic markers C1236T and C3435T of the MDR1 gene encoding glycoprotein P with the development of undesirable drug reactions in patients with pain syndrome. Material and methods. The study included 69 patients with pain syndrome and were divided into 2 groups depending on the presence of adverse drug reactions: NLR+ - 20 patients and NLR - - 49 patients with pain syndrome. The association of the polymorphic marker C3435T of the MDR1 gene was also studied among 22 patients with adverse drug reactions (ADR+) and 47 patients with pain syndrome without the presence of adverse drug reactions (ADR-). Molecular genetic studies were carried out on the basis of the Laboratory of medical genetics of NIIG and the PC of the Ministry of Health of the Republic of Uzbekistan. Results and discussion. During the genotyping, it was found that the occurrence of alleles and genotypes of the polymorphic marker C3435T of the MDR1 gene had significantly significant differences among the patients of the examined groups, depending on adverse drug reactions. Conclusion. The association of the polymorphic marker C3435T of the MDR1 gene with the development of undesirable drug reactions in pain syndrome, the TT genotype and the T allele may be genetic risk factors (OR=4.0 and 8.25; 95% CI 1.78-9.09 and 2.56-26.57, respectively) predisposing to the development of undesirable drug reactions in patients with pain syndrome. Therefore, further study is necessary in order to carry out genotyping of the polymorphic marker C3435T of the MDR1 gene to increase the effectiveness and safety of therapy of nonsteroidal anti-inflammatory drugs.

Children's exposure to polycyclic aromatic hydrocarbon (PAHs): a review on urinary 1-hydroxypyrene and associated health effects.

This article reviewed the published studies on theenvironmental exposure to polycyclic aromatic hydrocarbons (PAHs) among children and assessed the urinary 1-hydroxypyrene (1-OHP) level as a biomarker of exposure to PAHs. The current knowledge of the potential health effects of increased 1-OHP in children was reviewed. Additionally, the influence of genetic polymorphism on the urinary 1-OHP level was discussed in this review. The assembled data showed that children who are attending schools or living close to industrial and polluted urban areas might have greater exposure to higher concentrations of PAHs with a higher level of urinary 1-OHP when compared to those children living in rural areas. Urinary 1-OHP may be a reliable biomarker for determining the genotoxic effects, oxidative stress and inflammation caused by exposure to PAHs. Strong research evidence indicated that the total body burden of PAHs should be evaluated by biomonitoring of 1-OHP in line with other urinary PAHs metabolites (with 2-3 rings) to evaluate recent total exposure to PAHs. Overall, the study suggests implementing a mitigation plan to combat air pollution to provide a cleaner environment for children.

Genetic polymorphism of matrix metalloproteinase 9 and susceptibility to chronic obstructive pulmonary disease: A meta-analysis.

BackgroundTo systematically analyze the influence of genetic polymorphisms of matrix metalloproteinase 9 (MMP9) on susceptibility to chronic obstructive pulmonary disease (COPD).MethodsRelevant literatures reporting MMP9 and susceptibility to COPD in PubMed, Web of Science, VIP, Wanfang and CNKI databases were searched using the key words "matrix metalloproteinases 9/MMP9, COPD/chronic obstructive pulmonary disease". Data of eligible literatures were extracted and analyzed for the odds ratio (OR) and corresponding 95% CI.ResultsA total of 16 independent studies reporting MMP9-1562C/T and COPD patients were enrolled and analyzed. None of the genetic models revealed the relationship between MMP9-1562C/T and susceptibility to COPD. Subgroup analyses identified lower risk of COPD in Chinese population carrying the TT genotype for theMMP9 rs3918242 relative to those carrying CT and CC genotypes (P=0.03, OR=0.67, 95% CI=0.46-0.97).ConclusionsChinese population carrying the TT genotype for the MMP-9 rs3918242 present lower susceptibility to COPD relative to those carrying CT and CC genotypes.

Genetic polymorphisms and protein levels in vocal fold leukoplakia: a systematic review.

Vocal fold leukoplakia (VFL) has a risk of malignant transformation. Therefore, patients can have symptoms such as dysphonia, vocal strain, difficulty breathing, and dysphagia. Additionally, there is a genetic predisposition that can be associated with genetic polymorphisms. We aimed to evaluate the influence of genetic polymorphisms and protein levels in the etiology of VFL. Our study followed the PRISMA checklist and was registered on PROSPERO database. The questions were: “Are genetic polymorphisms involved in the etiology of VFL? Are protein levels altered in patients with VFL?”. Eligibility criteria were case control studies that compared the presence of polymorphisms or/and protein levels of subjects diagnosed with VFL and healthy controls. Of the 905 articles retrieved, five articles with a total of 1038 participants were included in this study. The C allele of the single nucleotide polymorphisms (SNP)-819 T/C IL-10, A allele of the SNP -592 A/C IL-10, CT genotype of the SNP rs11886868 C/T BCL11A, GG genotype of the SNP rs4671393 A/G BCL11A, LL genotype, and L allele of (GT)n repeat polymorphisms of the HO-1 were risk factors for VFL development. Nevertheless, there was a lack of association between VFL and the -1082 A/G IL-10, rs14024 CK-1, and -309 T/G Mdm2 SNPs. The concentrations of the MDM2, BCL11A, and HO-1 proteins were modified, while IL-10 levels were normally expressed in these subjects. In conclusion, most markers evaluated in this review could be potential indicators to develop effective therapies, avoiding a malignant transformation of the lesion.

Atorvastatin population pharmacokinetics in a real‐life setting: Influence of genetic polymorphisms and association with clinical response

The purpose of this study was to investigate the potential clinical relevance of estimating the apparent clearance (CL/F) of atorvastatin through population pharmacokinetic (PopPK) modeling with samples collected in a real‐life setting in a cohort of ambulatory patients at risk of cardiovascular disease by using an opportunistic sampling strategy easily accessible in clinical routine. A total of 132 pharmacokinetic (PK) samples at a maximum of three visits were collected in the 70 included patients. The effects of demographic, genetic, and clinical covariates were also considered. With the collected data, we developed a two‐compartment PopPK model that allowed estimating atorvastatin CL/F relatively precisely and considering the genotype of the patient for SLCO1B1 c.521T>C single‐nucleotide polymorphism (SNP). Our results indicate that the estimation of the CL/F of atorvastatin through our PopPK model might help in identifying patients at risk of myalgia. Indeed, we showed that a patient presenting a CL/F lower than 414.67 L h−1 is at risk of suffering from muscle discomfort. We also observed that the CL/F was correlated with the efficacy outcomes, suggesting that a higher CL/F is associated with a better drug efficacy (i.e., a greater decrease in total and LDL‐cholesterol levels). In conclusion, our study demonstrates that PopPK modeling can be useful in daily clinics to estimate a patient’ atorvastatin clearance. Notifying the clinician with this information can help in identifying patients at risk of myalgia and gives indication about the potential responsiveness to atorvastatin therapy.