Influence Of Genetic Polymorphisms Research Articles

Влияние генетического полиморфизма эндотелиновой системы и дисфункции эндотелия на течение атеросклероза и результаты чрескожных коронарных вмешательств

Влияние генетического полиморфизма эндотелиновой системы и дисфункции эндотелия на течение атеросклероза и результаты чрескожных коронарных вмешательств

Influence of Genetic Polymorphisms on Mycophenolic Acid Pharmacokinetics and Patient Outcomes in Renal Transplantation.

Mycophenolic Acid (MPA) is an immunosuppressive drug widely used in the treatment of organ transplantation and autoimmune diseases. Pharmacokinetics and pharmacodynamics of MPA varies between individuals, the potential reasons being the genetic polymorphisms in key enzymes, drug transporters and target proteins of MPA. We try to provide pharmacogenomics information for drug selection and dose adjustment, aiming to improve drug efficacy and reduce side effects in clinical application of MPA. In this review, we summarize the literatures in Pubmed that reported MPA-related Single Nucleotide Polymorphisms (SNPs) of renal transplant patients in recent 15 years. Genetic polymorphisms involving uridine diphosphate glucuronosyltransferase enzymes, organic anion transport polypeptides, multidrug resistance-associated protein 2, inosine monophosphate dehydrogenase and immune- response mediators may be associated with the metabolism, efficacy and toxicity of MPA, thus resulting in different MPA exposure and patient outcomes in renal transplantation. Several SNPs show significant association with MPA pharmacokinetics and pharmacodynamics, but conflicting results are reported, and no studies on MPA genetic polymorphisms have been translated into clinical practice. More prospective studies are needed to clear the role of genetic polymorphisms on MPA in renal transplantation patients.

PHYSIOLOGY OF TASTE PERCEPTION: THE ROLE OF GENETIC AND ENVIRONMENTAL FACTORS IN THE FORMATION OF TASTE PREFERENCES

Taste perception has a significant impact on the formation of human food preferences. The basics of taste perception of the child are formed under the influence of genetic polymorphism and congenital taste preferences, developing under the influence of a number of environmental factors. A significant impact on the formation of taste hasthe mother’s nutrition during pregnancy, the nature of the child’sfeeding, the baby’s health during the first year of life, as well as national and family traditions of nutrition. The article describes the mechanisms of formation of different taste sensations, summarizes the results of modern research on the genetics of taste receptors, the role of individual environmental factors in the development of food preferences. Special attention is paid to the peculiarities of the child’s nutrition during the first year of life.

Influence of Genetic Polymorphism Towards Pulmonary Tuberculosis Susceptibility.

Tuberculosis (TB) is still remains the major threat for human health worldwide. Several case-control, candidate-gene, family studies and genome-wide association studies (GWAS) suggested the association of host genetic factors to TB susceptibility or resistance in various ethnic populations. Moreover, these factors modulate the host immune responses to tuberculosis. Studies have reported genetic markers to predict TB development in human leukocyte antigen (HLA) and non-HLA genes like killer immunoglobulin-like receptor (KIR), toll-like receptors (TLRs), cytokine/chemokines and their receptors, vitamin D receptor (VDR) and SLC11A1 etc. Highly polymorphic HLA loci may influence antigen presentation specificities by modifying peptide binding motifs. The recent meta-analysis studies revealed the association of several HLA alleles in particular class II HLA-DRB1 with TB susceptibility and valuable marker for disease development especially in Asian populations. Case-control studies have found the association of HLA-DR2 in some populations, but not in other populations, this could be due to an ethnic specific association of gene variants. Recently, GWAS conducted in case-control and family based studies in Russia, Chinese Han, Morocco, Uganda and Tanzania revealed the association of genes such as ASAP1, Alkylglycerol monooxygenase (AGMO), Forkhead BoxP1 (FOXP1), C-terminal domain phosphatase 1 (UBLCP1) and intergenic SNP rs932347C/T with TB. Whereas, SNP rs10956514A/G were not associated with TB in western Chinese Han and Tibetan population. In this review, we summarize the recent findings of genetic variants with susceptibility/resistance to TB.

Possible roles of genetic variations in chemotherapy related cardiotoxicity in pediatric acute lymphoblastic leukemia and osteosarcoma

BackgroundThe treatment of acute lymphoblastic leukemia (ALL) and osteosarcoma (OSC) is very effective: the vast majority of patients recover and survive for decades. However, they still need to face serious adverse effects of chemotherapy. One of these is cardiotoxicity which may lead to progressive heart failure in the long term. Cardiotoxicity is contributed mainly to the use of anthracyclines and might have genetic risk factors. Our goal was to test the association between left ventricular function and genetic variations of candidate genes.MethodsEchocardiography data from medical records of 622 pediatric ALL and 39 OSC patients were collected from the period 1989–2015. Fractional shortening (FS) and ejection fraction (EF) were determined, 70 single nucleotide polymorphisms (SNPs) in 26 genes were genotyped. Multivariate logistic regression and multi-adjusted general linear model were performed to investigate the influence of genetic polymorphisms on the left ventricular parameters. Bayesian network based Bayesian multilevel analysis of relevance (BN-BMLA) method was applied to test for the potential interaction of the studied cofactors and SNPs.ResultsOur results indicate that variations in ABCC2, CYP3A5, NQO1, SLC22A6 and SLC28A3 genes might influence the left ventricular parameters. CYP3A5 rs4646450 TT was 17% among ALL cases with FS lower than 28, and 3% in ALL patients without pathological FS (p = 5.60E-03; OR = 6.94 (1.76–27.39)). SLC28A3 rs7853758 AA was 12% in ALL cases population, while only 1% among controls (p = 6.50E-03; OR = 11.56 (1.98–67.45)). Patients with ABCC2 rs3740066 GG genotype had lower FS during the acute phase of therapy and 5–10 years after treatment (p = 7.38E-03, p = 7.11E-04, respectively). NQO1 rs1043470 rare T allele was associated with lower left ventricular function in the acute phase and 5–10 years after the diagnosis (p = 4.28E-03 and 5.82E-03, respectively), and SLC22A6 gene rs6591722 AA genotype was associated with lower mean FS (p = 1.71E-03), 5–10 years after the diagnosis.ConclusionsGenetic variants in transporters and metabolic enzymes might modulate the individual risk to cardiac toxicity after chemotherapy.

Pharmacology and pharmacogenetics of prednisone and prednisolone in patients with nephrotic syndrome

Nephrotic syndrome is one of the most common glomerular disorders in childhood. Glucocorticoids have been the cornerstone of the treatment of childhood nephrotic syndrome for several decades, as the majority of children achieves complete remission after prednisone or prednisolone treatment. Currently, treatment guidelines for the first manifestation and relapse of nephrotic syndrome are mostly standardized, while large inter-individual variation is present in the clinical course of disease and side effects of glucocorticoid treatment. This review describes the mechanisms of glucocorticoid action and clinical pharmacokinetics and pharmacodynamics of prednisone and prednisolone in nephrotic syndrome patients. However, these mechanisms do not account for the large inter-individual variability in the response to glucocorticoid treatment. Previous research has shown that genetic factors can have a major influence on the pharmacokinetic and dynamic profile of the individual patient. Therefore, pharmacogenetics may have a promising role in personalized medicine for patients with nephrotic syndrome. Currently, little is known about the impact of genetic polymorphisms on glucocorticoid response and steroid-related toxicities in children with nephrotic syndrome. Although the evidence is limited, the data summarized in this study do suggest a role for pharmacogenetics to improve individualization of glucocorticoid therapy. Therefore, studies in larger cohorts with nephrotic syndrome patients are necessary to draw final conclusions about the influence of genetic polymorphisms on the glucocorticoid response and steroid-related toxicities to ultimately implement pharmacogenetics in clinical practice.

Genetic variation in IL28B (IFNL3) and response to interferon-alpha treatment in myeloproliferative neoplasms.

In myeloproliferative neoplasms (MPN), interferon-alpha (IFN-α) is an effective treatment with disease-modifying properties but currently with no clear predictors of treatment outcome. Recent genomewide association studies in chronic hepatitis C have found a strong influence of genetic polymorphism near the IL28B (IFNL3) gene in response to IFN-α treatment. In this study, we sought to evaluate the prognostic impact of IL28B rs12979860, rs8099917, and rs12980275 on IFN-α treatment response in myeloproliferative neoplasms. We retrospectively evaluated 100 patients with MPN treated with IFN-α. The hematologic treatment response on IFN-α was compared between patients and correlated with host genetic variations in IL28B. The genotypes of IL28B were determined by allelic discrimination assays. The CC genotype of rs12979860 was found significantly associated with hematologic response in polycythemia vera (PV) with a complete response (CR) in 79% (CC) compared to 48% (non-CC), (P=.036). No association between the genotypes and treatment response on hydroxyurea was found. These results imply an effect of IL28B genotype on the outcome of IFN-α treatment in MPN.

BMX 레이서의 신체적 · 심리적 요인에 대한 CNTF 및 COMT 유전자 다형성의 영향

BMX 레이서의 신체적 · 심리적 요인에 대한 CNTF 및 COMT 유전자 다형성의 영향

Influence of genetic polymorphisms of IL23R, STAT3, IL12B, and STAT4 on the risk of aplastic anemia and the effect of immunosuppressive therapy

Studies have suggested that IL-23/STAT3 and IL-12/STAT4 signaling pathways associate with aplastic anemia (AA) occurrence. Polymorphisms in pathway-related genes may contribute to AA risk. In the current study, we investigated the association between polymorphisms in genes of IL23R, STAT3, IL12B, and STAT4 and occurrence, severity, and immunosuppressive outcome of AA in the Han population in southwest China. In the current 164 AA cases and 211 controls study, we found T allele and TT genotype of rs7574865 were more frequent in the cases than that in the controls. In the additive model, individual carrying rs7574865 T allele demonstrated a 37% (OR (95% CI) = 1.37 (1.02-1.85), Pper = 0.036) increased AA risk. In the recessive model, carrier with rs7574865 TT genotype showed a 2.08-fold increased AA risk (OR (95% CI) = 2.08 (1.14-3.70), Pper = 0.017). Additionally, we showed that G allele and GG genotype of rs11209032 were more frequent in the 88 non-severe AA cases than that in the 76 severe AA ones. Our study also found G allele and GG genotype of rs11209032, and GG-genotype of rs744166 associated with the immunosuppressive therapy outcome in AA patients. Current study results support that functional STAT4 (rs7574865), IL23R (rs11209032), and STAT3 (rs744166) variants may associate with occurrence, severity, and immunosuppressive outcome of AA in the Han population in southwest China.

Uticaj genetičkog polimorfizma citohroma R-450 izoformi 2S9 i 1A2 na metabolizam varfarina

The influence of genetic polymorphism on the scope of drug metabolism is now well-known, since the metabolism of drugs depends on the amount of active enzyme in human tissues, primarily in the liver. The aim of the paper is to process data related to genetic polymorphism of isoforms of cytochrome enzymes that are important for metabolism and dosing of warfarin, considering that serious adverse effects can sometimes end with a fatal outcome. In addition, the systemic review article pointed to the importance of pharmacogenomic studies prior to the introduction of warfarin in therapy. A systematic research of literature using the medical databases 'Pub Med' and ‘Google Scholar’ found a total of 251 publications. The results included eight publications that met the criteria for inclusion. The extraction of the most important data from all works necessary for an adequate evaluation was performed and presented in seven tables containing general data of studies and pharmacokinetic parameters related to the metabolism of warfarin. The therapeutic effect of coumarin derivatives such as warfarin is influenced by genetic factors, but also other factors related to the patient. The frequent mutations of the gene encoding the cytochrome P450 isoform CYP2C9, but also the vitamin K-epoxide reductase with one or more polymorphic combinations, are responsible for reducing the required dose of warfarin or even for resistance to warfarin. Although genotyping data improves the accuracy of dose prediction, the improvement in controlling the anticoagulant effect and warfarin metabolism has yet to be proven in terms of effectiveness and cost-effectiveness in future prospective clinical studies.

Влияние генетического полиморфизма ангиотензин-I-превращающего фермента на клинические результаты чрескожных коронарных вмешательств у больных ишемической болезнью сердца

Влияние генетического полиморфизма ангиотензин-I-превращающего фермента на клинические результаты чрескожных коронарных вмешательств у больных ишемической болезнью сердца

HPA axis multilocus genetic profile score moderates the impact of interpersonal stress on prospective increases in depressive symptoms for offspring of depressed mothers.

Although offspring of depressed mothers are at an increased risk for depression themselves, not all of these children develop depression, highlighting the need to identify specific environmental and genetic moderators of risk. The goal of this study was to examine the aggregate influence of genetic polymorphisms associated with the regulation of the hypothalamic-pituitary-adrenal (HPA) axis as a potential moderator of the relation between environmental stress and prospective changes in depressive symptoms for offspring of depressed mothers. Participants were 238 mother-offspring dyads recruited from the community based on the mother's lifetime history of major depression during the youth's lifetime (present vs. absent). Mothers and youth completed assessments every 6 months for 2 years (5 total). Results indicated that offspring of depressed mothers showing the greatest increases in depressive symptoms during the follow up were those who had higher HPA multilocus genetic profile scores and who experienced the highest levels of interpersonal stress. These relations were significant for interpersonal stress and were not observed for noninterpersonal stress. These findings suggest that HPA multilocus genetic profile scores may be important genetic markers of stress reactivity and depression risk for offspring of depressed mothers. They also highlight interpersonal stress as a potentially modifiable risk factor for these high-risk youth. (PsycINFO Database Record

Population pharmacokinetics of gabapentin in healthy Korean subjects with influence of genetic polymorphisms of ABCB1.

The objective of this study was to perform population pharmacokinetic (PK) analysis of gabapentin in healthy Korean subjects and to investigate the possible effect of genetic polymorphisms (1236C>T, 2677G>T/A, and 3435C>T) of ABCB1 gene on PK parameters of gabapentin. Data were collected from bioequivalence studies, in which 173 subjects orally received three different doses of gabapentin (300, 400, and 800mg). Only data from reference formulation were used. Population pharmacokinetics (PKs) of gabapentin was estimated using a nonlinear mixed-effects model (NONMEM). Gabapentin showed considerable inter-individual variability (from 5.2- to 8.7-fold) in PK parameters. Serum concentration of gabapentin was well fitted by a one-compartment model with first-order absorption and lag time. An inhibitory Emax model was applied to describe the effect of dose on bioavailability. The oral clearance was estimated to be 11.1 L/h. The volume of distribution was characterized as 81.0 L. The absorption rate constant was estimated at 0.860h-1, and the lag time was predicted at 0.311h. Oral bioavailability was estimated to be 68.8% at dose of 300mg, 62.7% at dose of 400mg, and 47.1% at dose of 800mg. The creatinine clearance significantly influenced on the oral clearance (P<0.005) and ABCB1 2677G>T/A genotypes significantly influenced on the absorption rate constant (P<0.05) of gabapentin. However, ABCB1 1236C>T and 3435C>T genotypes showed no significant effect on gabapentin PK parameters. The results of the present study indicate that the oral bioavailability of gabapentin is decreased when its dosage is increased. In addition, ABCB1 2677G>T/A polymorphism can explain the substantial inter-individual variability in the absorption of gabapentin.

Welcome Address

Occupational and environmental exposure to pesticides may induce harmful effects on human health by promoting the development of a wide range of disorders. Some of the most recently hypothesized mechanisms are oxidative stress and epigenetic modifications, however biological effects seem to be modulated mainly by the occurrence of genetic polymorphisms. The susceptibility to exposure can be evaluated by studying the most common polymorphisms of genes involved in the metabolism of organophosphorus compounds (cytochrome P450, glutathione transferase, acetyltransferases or paraoxonase 1). The aim of this article is to review recent literature data concerning the influence of genetic polymorphisms on pesticides-induced oxidative damage.

Scientific Program

Occupational and environmental exposure to pesticides may induce harmful effects on human health by promoting the development of a wide range of disorders. Some of the most recently hypothesized mechanisms are oxidative stress and epigenetic modifications, however biological effects seem to be modulated mainly by the occurrence of genetic polymorphisms. The susceptibility to exposure can be evaluated by studying the most common polymorphisms of genes involved in the metabolism of organophosphorus compounds (cytochrome P450, glutathione transferase, acetyltransferases or paraoxonase 1). The aim of this article is to review recent literature data concerning the influence of genetic polymorphisms on pesticides-induced oxidative damage.

Polymorphisms of MTHFR, eNOS, ACE, AGT, ApoE, PON1, PDE4D, and Ischemic Stroke: Meta-Analysis

The association between ischemic stroke and genetic polymorphisms of methylenetetrahydrofolate reductase (MTHFR; 677C>T and 1298A>C), endothelial nitric oxide synthase (eNOS; -786T>C, +894G>T, and variable number tandem repeat [VNTR]), phosphodiesterase 4D (PDE4D; SNPs 83 and 87), angiotensin-converting enzyme (ACE) I/D, angiotensinogen (AGT) 235M>T, paraoxonase 1 (PON1) 192Q>R, and apolipoprotein E (ApoE) ε2ε3ε4 remains inconclusive. Therefore, this updated meta-analysis aimed to clarify the presumed influence of genetic polymorphisms on ischemic stroke by meta-analyzing the comprehensive coverage of all individual association studies. All case-control studies published in different languages such as English, Japanese, Korean, Spanish, Chinese, Hungarian, Ukrainian, or Russian were identified from databases. The pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated via fixed- and random-effect models. Sensitivity analysis, heterogeneity test, Hardy Weinberg Equilibrium, and Egger's regression analyses were performed in this study. A total of 490 case-control studies with 138,592 cases and 159,314 controls were included in this meta-analysis. Pooled ORs from all the genetic models indicated that MTHFR 677TT and 1298CC, eNOS +894TT and VNTR, PDE4D SNP 83, ACE DD, AGT 235TT, PON1 192RR, and ApoE ε4 polymorphisms were increasing the risks of ischemic stroke. Nevertheless, PDE4D SNP 87 and eNOS -786T>C polymorphisms are not associated with ischemic stroke risks. Hence, the evidence from this meta-analysis concluded that MTHFR (677C>T and 1298A>C), eNOS (+894G>T and VNTR), PDE4D SNP 83, ACE I/D, AGT 235M>T, PON1 192Q>R, and ApoE ε2ε3ε4 polymorphisms predispose individuals to ischemic stroke.

Relationship between clinical toxicities and ERCC1 rs3212986 and XRCC3 rs861539 polymorphisms in cervical cancer patients.

Several studies have suggested that there are single nucleotide polymorphisms (SNPs) that can be considered potential biomarkers in the prognosis and therapeutic response of cancer patients. The present study investigated the association between ERCC1 rs3212986 and XRCC3 rs861539 polymorphisms and clinical toxicities induced by chemoradiotherapy (CRT) in cervical cancer. This hospital-based retrospective cohort study included 260 patients with cervical cancer, FIGO stages Ib2-IVa, who underwent CRT (cisplatin). Genetic polymorphisms analysis was performed by allelic discrimination with real-time polymerase chain reaction (RT-PCR). Our results indicated a link between ERCC1 rs3212986 and the onset of late gastrointestinal toxicity (p = 0.038). Furthermore, using a recessive model (AA vs. CC/CA), we found that patients carrying AA homozygous genotype presented a fourfold increased risk of developing late gastrointestinal toxicity when compared with patients with the C allele (odds ratio = 3.727, 95% confidence interval, 1.199-11.588; p = 0.017). No association was found regarding the XRCC3 rs861539 polymorphism and any clinical toxicity event. This is the first study evaluating the relationship between these polymorphisms and clinical toxicities in cervical cancer patients submitted to CRT with cisplatin. These results may contribute toward a better understanding of the influence of genetic polymorphisms in genes associated with DNA repair in the clinical response to CRT of patients with cervical cancer.

Influence of PRKCH gene polymorphism on antihypertensive response to amlodipine and telmisartan

ABSTRACTThis study aimed to evaluate the effect of PRKCH rs2230500 genetic polymorphism on efficacy of amlodipine and telmisartan for patients with hypertension. A total of 136 essential hypertension (EH) patients were treated with amlodipine (70 patients) or telmisartan (66 patients), respectively. Genetic polymorphism was genotyped by Sanger sequencing. Both baseline and post-treatment blood pressure (BP) and heart rate were measured to evaluate the influence of genetic polymorphism on the antihypertensive response. No significant difference in the absolute decrease in diastolic blood pressure (DBP),systolic blood pressure (SBP), and mean arterial pressure (MAP) was observed among PRKCH rs2230500 genotypes after 4-week amlodipine or telmisartan therapy (p > 0.05). However, when compared with carriers or GG genotype, the antihypertensive effect of PRKCH rs2230500 GA/AA carriers was superior in telmisartan treatment group. PRKCH rs2230500 gene polymorphism is significantly related to the efficiency in telmisartan therapy (p = 0.02). The PRKCH rs2230500 may influence the antihypertensive efficacy of telmisartan in Chinese EH patients, and further studies are needed to confirm these findings.

Association of Polymorphisms in Pharmacogenetic Candidate Genes with Propofol Susceptibility

Significant individual susceptibility to intravenous anesthetic propofol exists. The etiology of individual variability in the response to propofol may be influenced by genetic polymorphisms in metabolic and functional pathways. With current pharmacogenetics and modern molecular biology technologies, it is possible to study the influence of genetic polymorphisms on susceptibility to propofol. When inducing general anesthesia with intravenous propofol, high individual susceptibility to propofol was found. Using Sequenom MassARRAY single-nucleotide polymorphism (SNP) genotyping, we identified a mutation (rs6313) in the 5HT2A gene that was correlated to individual susceptibility to propofol effect-site concentration (Cep) and onset time of propofol induction. Carriers of the minor allele (G) of 5HT2A rs6313 required less propofol (20% decrease in Cep) and less time (40% decrease in onset time) to induce anesthesia. Moreover, associations were found between the gamma-aminobutyric acid (GABA) receptor SNP rs2279020 and the SCN9A SNP rs6746030 and the susceptibility of bispectral index (BIS) after propofol-induced anesthesia. In addition, dominant mutations in GABAA1 rs2279020, GABAA2 rs11503014, and CHRM2 rs1824024 were putatively associated with cardiovascular susceptibility to propofol anesthesia. No gene-gene interactions were found through a standardized measure of linkage disequilibrium and a multifactor dimensionality reduction analysis. Our results suggest that genetic polymorphisms related to mechanisms of propofol anesthesia are involved in propofol susceptibility.

Thiopurine S-methyltransferase polymorphisms in acute lymphoblastic leukemia, inflammatory bowel disease and autoimmune disorders: influence on treatment response.

The thiopurine S-methyltransferase (TPMT) gene encodes for the TPMT enzyme that plays a crucial role in the metabolism of thiopurine drugs. Genetic polymorphisms in this gene can affect the activity of the TPMT enzyme and have been correlated with variability in response to treatment with thiopurines. Advances in the pharmacogenetics of TPMT allowed the development of dosing recommendations and treatment strategies to optimize and individualize prescribing thiopurine in an attempt to enhance treatment efficacy while minimizing toxicity. The influence of genetic polymorphisms in the TPMT gene on clinical outcome has been well-documented and replicated in many studies. In this review, we provide an overview of the evolution, results, conclusions and recommendations of selected studies that investigated the influence of TPMT pharmacogenetics on thiopurine treatment in acute lymphoblastic leukemia, inflammatory bowel disease and autoimmune disorders. We focus mainly on prospective studies that explored the impact of individualized TPMT-based dosing of thiopurines on clinical response. Together, these studies demonstrate the importance of preemptive TPMT genetic screening and subsequent dose adjustment in mitigating the toxicity associated with thiopurine treatment while maintaining treatment efficacy and favorable long-term outcomes. In addition, we briefly address the cost-effectiveness of this pharmacogenetics approach and its impact on clinical practice as well as the importance of recent breakthrough advances in sequencing and genotyping techniques in refining the TPMT genetic screening process.