Influence Of Gene Polymorphisms Research Articles

Effect of angiotensin converting enzyme 2 rs1978124 gene polymorphism on the hemodynamic response to exercise

Angiotensin-converting enzyme 2 (ACE2) has a protective role in the regulation of blood pressure. To evaluate the influence of ACE2 rs1978124 gene polymorphism on the hemodynamic response after a six-minute walk submaximal aerobic test. A six-minute walk submaximal aerobic test was carried out in 47 men and 55 women, aged 22 ± 2 years. Blood pressure was recorded before and after the test. Pulse rate was recorded continuously. ACE2 polymorphism was determined in DNA extracted from a blood sample. For women, the genotype distribution did not deviate from Hardy-Weinberg equilibrium (x2 = 0.804, d.f. = 1, P = 0.4) and no significant differences in heart rate, systolic and diastolic blood pressure were observed between CC, CT and TT genotypes before and after the test. Among men no differences in these parameters were observed either between the three phenotypes. ACE2 rs1978124 gene polymorphism did not influence the hemodynamic response to submaximal exercise in these participants.

Influence of IL28B gene polymorphisms on PegINF-RBV-mediated HCV clearance in HIV-HCV co-infected patients: A meta-analysis

BackgroundPrevious studies suggested, variations in the IL28B gene can serve as predictors of sustained and rapid virological responses (SVR and RVR) in the treatment of HCV with pegylated interferon and ribavirin (pegINF-RBV) among HCV-HIV co-infected patients. Here, we explored the correlation between IL28B variants (rs12979860, rs8099917 and rs12980275) and treatment response for HCV among co-infected individuals using meta-analysis. MethodsRelevant studies were retrieved from PubMed, EBSCO, ISI Web of Knowledge, Cochrane databases, and the role of IL28B variants on SVR and RVR in co-infected patients treated with pegINF-RBV was evaluated. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by fixed- and random-effects models. ResultsForty-three studies consisting 3499 patients who achieved SVR/RVR and 4308 non-responders were included in our study. The CC, TT and AA genotypes of IL28B rs12979860, rs8099917 and rs12980275, respectively, were associated with SVR in the recessive model for all HCV genotypes: rs12979860, OR = 3.18 [95% CI (2.66, 3.79)]; P < 0.0001; rs8099917, OR = 3.6`9 [95% CI (2.74, 4.97)]; P < 0.0001; rs12980275, OR = 2.97 [95% CI (2.26, 3.89)]; P < 0.0001. Significant association of rs12979860 CC genotype with RVR was also found: OR = 2.31 [95% CI (1.54, 3.57)]; P < 0.0001. Stratification analysis of HCV genotypes revealed similar trends of association with the rs12979860 CC genotype for HCV-1, HCV-1/4 and HCV-4, but no association was found for HCV-2/3 and HCV-3. ConclusionsOur meta-analysis suggests that the CC, TT and AA genotypes of IL28B rs12979860, rs8099917 and rs12980275, respectively, are strong predictors for SVR, and the rs12979860 CC genotype has significant RVR predictive value in HCV-HIV co-infected patients treated with pegINF-RBV.

Influence of TLR-8 Gene Polymorphisms (rs3764880 and rs3788935) Associated to Pulmonary Tuberculosis in Kupang, Indonesia

Toll-like receptor 8 (TLR-8) is known as part of intracellular signaling transduction for bacterial phagocytosis. Mycobacterium tuberculosis (Mtb) is intracellular pathogenic bacteria that is recognized by this receptor, and genetic variation of TLR-8 might alter susceptibility of the host towards pulmonary tuberculosis (PTB). This study aimed to determine whether TLR-8 gene polymorphisms were associated to PTB in Kupang, Indonesia. This case-control study compared demographic and clinical data between 115 PTB patients and 115 controls, then two TLR-8 single nucleotide polymorphisms (rs3764880 and rs3788935) were explored using the GoldenGate® Genotyping for VeraCode® / BeadXpress Illumina®. There is no significant difference between sex distribution of patient vs control groups. The polymorphisms (rs3764880 and rs3788935) are in Hardy-Weinberg Equilibrium in this population (p &gt; 0.05). The distribution of major vs minor genotypes and alleles of TLR-8 polymorphisms in PTB patients were as followed: rs3764880 (GG vs GA vs AA, 50.0% vs 21.4% vs 28.6% ; G vs A, 60.9% vs 39.1% ) and rs3788935 (GG vs GA vs AA, 53.0% vs 21.7% vs 25.3%; G vs A, 62.9% vs 37.1%). Neither genotypes nor alleles were associated with PTB in this population (P &gt; 0.05). Besides, when the analyses were stratified by gender, none of the alleles of polymorphism in both genders were associated with PTB cases. None of the TLR-8 polymorphisms have associated the risk of developing PTB in Kupang, East Nusa Tenggara population (as opposed to other studies in different ethnic groups). These might reflect the diversity of genetic polymorphisms in eastern Indonesia populations, suggesting different genetic backgrounds with western part of Indonesia.

Somatic cell score: gene polymorphisms and other effects in Holstein and Simmental cows.

ObjectiveThe aim of the study was to evaluate the influence of gene polymorphisms and nongenetic factors on the somatic cell score (SCS) in the milk of Holstein (n = 148) and Simmental (n = 73) cows and their crosses (n = 6).MethodsThe SCS was calculated by the formula SCS = log2(SCC/100,000)+3, where SCC is the somatic cell count. Polymorphisms in the casein alpha S1 (CSN1S1), beta-casein (CSN2), kappa-casein (CSN3), beta-lactoglobulin (LGB), acyl-CoA diacylglycerol transferase 1 (DGAT1), leptin (LEP), fatty acid synthase (FASN), stearoyl CoA desaturase 1 (SCD1), and 1-acylglycerol-3-phosphate O-acyltransferase 6 (AGPAT6) genes were genotyped, and association analysis to the SCS in the cow’s milk was performed. Further, the impact of breed, farm, year, month of the year, lactation stage and parity on the SCS were analysed. Phenotype correlations among SCS and milk constituents were computed by Pearson correlation coefficients.ResultsOnly CSN2 genotypes A1/A2 were found to have significant association with the SCS (p<0.05), and alleles of CSN1S1 and DGAT1 genes (p<0.05). Other polymorphisms were not found to be significant. SCS had significant association with the combined effect of farm and year, lactation stage and month of the year. Lactation parity and breed had not significant association with SCS. The phenotypic correlation of SCS to lactose content was negative and significant, while the correlation to protein content was positive and significant. The correlations of SCS to fat, casein, nonfat solids, urea, citric acid, acetone and ketones contents were very low and not significant.ConclusionOnly CSN2 genotypes, CSN1S1 and DGAT1 alleles did show an obvious association to the SCS. The results confirmed the importance of general quality management of farms on the microbial milk quality, and effects of lactation stage and month of the year. The lactose content in milk reflects the health status of the udder.

Genetic variations in the human immune system influence susceptibility to tegumentary leishmaniasis: a systematic review and meta-analysis

ABSTRACT Objectives The outcomes of tegumentary leishmaniasis (TL) rely on a complex interaction between the host immune system and the parasite. This study assessed the influence of polymorphisms in immune-related genes on TL. Methods Web of Science, Scopus, PubMed, and Embase databases were searched systemically. The meta-analysis used a retrospective model in examining alleles, heterozygotes, and homozygotes. A quality assessment and an analysis of cumulative evidence were performed. Results A total of 29 genes (encoding for cytokines, chemokines, and other immune receptors) and 84 polymorphisms were analyzed. The IL-1β_rs16944 (OR = 1.341, p = 0.003), TNF-α_rs1800629 (OR = 3.804, p = 0.004), MIF_rs755622 (OR = 3.357, p = 0.001), and INF- γ_rs243056 (OR = 1.670, p = 0.028) polymorphisms were speculated as risk factor for TL. They decrease the expression of the corresponding genes crucial for TL control. The quality assessment score was approximately 50%, suggesting the need for a clear method and polymorphism characterization for further comparison. The relevant risk of bias and other considerations resulted in low and moderate cumulative evidence confidence. Conclusions IL-1β_rs16944, TNF-α_rs1800629, MIF_rs755622, and INF-γ_rs2430561 polymorphisms were speculated as risk factor for TL, corroborating that IL-1β, TNF-α, INF-γ, and MIF are involved in the TL pathogenesis.

Influence of ABCB1 Gene Polymorphism on Rivaroxaban Blood Concentration and Hemorrhagic Events in Patients With Atrial Fibrillation.

Background and Objectives: Genetic data on the pharmacokinetics of rivaroxaban and identification of factors that affect its biotransformation, distribution, and excretion will allow for generation of algorithms for personalized use of this drug in patients with atrial fibrillation (AF). Here we tested the effects of ABCB1 (ATP-binding cassette subfamily B member 1) polymorphisms on the valley rivaroxaban blood concentration and on the frequency of hemorrhagic events in patients with AF and propose a personal anticoagulation therapy management protocol. Patients and Methods: This is a retrospective study. We enrolled Mongolian descent patients who met the criteria from May 2018 to August 2019 in Beijing and Fujian. Clinical data on gender, height, weight, liver and kidney functions, drug trough concentration, and drug dosage were collected; we recorded the bleeding events until 6 months after initiating the medication. ABCB1 single nucleotide polymorphisms including rs1128503, rs1045642, and rs4148738 were identified. After reaching the steady state of plasma concentration, the peripheral blood was collected to detect the trough rivaroxaban plasma concentrations before the next medication. Results: We included 155 patients in this study including 81 men and 74 women, with an average age of 71.98 ± 10.72 years. The distribution of ABCB1 genotypes conformed to the Hardy–Weinberg equilibrium. Multiple comparisons between wild (TT) and mutant (CT and CC) genotypes at the rs1045642 locus showed no significant differences of rivaroxaban trough concentrations (TT vs. CT, p = 0.586; TT vs. CC, p = 0.802; and CT vs. CC, p = 0.702). Multiple comparison between wild (TT) and mutant (CC) genotypes at the rs1128503 locus revealed a significant difference of rivaroxaban trough concentrations (TT vs. CC, p = 0.0421). But wild (TT) vs mutant (CT) genotypes and mutant CT vs mutant CC genotypes at the rs1128503 locus showed no significant differences of rivaroxaban trough concentrations (TT vs. CT, p = 0.0651; TT vs. CT, p = 0.6127). Multiple comparisons between wild (GG) and mutant (AG and AA) genotypes at the rs4148738 locus showed no significant differences of rivaroxaban trough concentrations (GG vs. AG, p = 0.341; GG vs. AA, p = 0.612; AG vs. AA, p = 0.649). There was no significant correlation between ABCB1 gene variation loci rs1045642, rs1128503, rs4148738 and bleeding events. Conclusion: rs1128503 locus variations are correlated with the serum concentration of rivaroxaban in patients of Mongolian descent. But no significant correlation between rs1128503 locus variations and bleeding events were obtained.

Влияние полиморфизмов гена CYP2C9 на эффективность применения лозартана у пациентов с артериальной гипертензией I–II степеней

Влияние полиморфизмов гена CYP2C9 на эффективность применения лозартана у пациентов с артериальной гипертензией I–II степеней

Association of FOXP3 gene polymorphisms with chronic immune thrombocytopenia in a Chinese Han population.

Forkhead box P3 (Foxp3) is encoded by the human FOXP3, an X-chromosome gene, and is a transcription factor that regulates regulatory T-cell (Treg) development and function. FOXP3 gene polymorphisms have recently been investigated as candidate risk factors in various autoimmune diseases. This study aimed to investigate the possible influence of FOXP3 gene polymorphisms on genetic predisposition to chronic immune thrombocytopenia (ITP). The study cohort comprised 329 chronic ITP patients and 279 healthy controls, who were genotyped for three polymorphisms in the promoter region of FOXP3 gene, -6054 del/ATT, -3279 A/C, and -924 A/G. Of the three polymorphisms identified, the -3279 AA genotype was more frequent in female patients with chronic ITP than in female controls (P=.035, OR 0.434, 95% CI 0.223-0.846), and the -3279 A carrier was shown to be associated with the risk of chronic ITP in female cohort (P=.003, OR 0.610, 95% CI 0.437-0.851). Furthermore, the female patients with chronic ITP had remarkably more frequent haplotype -6054 del/-3279 A/-924 A (P=.027, OR 3.584, 95% CI 1.148-11.186) and less haplotype -6054 del/-3279 C/-924 G (P=.039, OR 0.445, 95% CI 0.204-0.973) in comparison with female healthy controls. Although there were no significant differences in the male cohort, when the combined alleles and haplotypes of the two genders were analyzed, the results obtained were similar to those of females. According to our data, the -3279 A/C polymorphism of FOXP3 gene may be associated with the susceptibility to chronic ITP in Chinese Han population.

Influence of potential gene polymorphisms on propofol dosage regimen in patients undergoing abdominal hysterectomy

Propofol (2,6-diisopropylphenol) is the most common intravenous anesthetic used in modern medicine. It is postulated that individual differences in genetic factors [polymorphism of single nucleotide polymorphisms (SNPs)] in the genes encoding metabolic enzymes, molecular targets and molecular binding sites of propofol can be responsible for susceptibility to propofol effects. The aim of our study was to investigate the influence of the cytochrome P450 2B6 isozyme CYP2B6 (rs3745274), γ-aminobutyric acid type A (GABAA) receptor α1 subunit GABRA1 (rs2279020) and ATP-binding cassette subfamily B member 1 ABCB1 (rs1045642) gene polymorphisms on propofol therapeutic outcomes in the patients undergoing abdominal hysterectomy. Ninety patients aged 29-74 years, with different ethnicities were included in this study. The presence of polymorphisms was analyzed using TaqMan SNP genotype analysis on Stratagene MxPro 3005P real-time polymerase chain reaction (qPCR). The distribution of all three genetic variants was within the Hardy-Weinberg equilibrium. There was no significant difference (p >0.05) in the allelic frequencies of polymorphic variants and genotype distributions between adult and older patients and between patients of different ethnicities. Our study did not detect a statistically significant influence of the CYP2B6 (c.516G>A), GABRA1 (c.1059+15G>A) and ABCB1 (c.3435T>C) variants on the variability of clinical parameters (doses for induction in anesthesia, additional doses, induction time and wake time after anesthesia and side effects of propofol). However, the observed trend on the possible influence of the CYP2B6 (c.516G>A) and GABRA1 (c.1059+15G>A) variants warrant an extension of these studies on a larger number of patients.

The influence of XRCC1 gene polymorphism on the prognosis and safety of stage Ⅲ patients with colorectal cancer who received oxaliplatin based adjuvant chemotherapy

Objective: To investigate the influence of X-ray repair cross complementing 1 (XRCC1) gene polymorphism on the prognosis and safety of stage Ⅲ patients with colorectal cancer (CRC) who received oxaliplatin based adjuvant chemotherapy. Methods: A total of 218 stage Ⅲ patients with CRC after R0 resection and received oxaliplatin based adjuvant chemotherapy in the department of gastrointestinal surgery of the First Affiliated Hospital of Zhengzhou University from March 2012 to December 2019 were included and the baseline characteristics were collected. There were 125 male and 93 female patients, aged from 18 to 78 years. Peripheral blood and peripheral blood mononuclear cell (PBMC) specimens of the colorectal cancer patients were preserved for genotyping of XRCC1 gene genetic variation and mRNA expression of XRCC1, respectively. The association between genotype status and prognosis was analyzed by Kaplan-Meier survival analysis. And the correlation between genotype status and adverse reactions was performed with χ2 test. Results: The median follow-up time were 4.9 (0.3-7.3) years. The median disease-free survival (DFS) of the 218 patients with CRC was 4.4 years and the median overall survival (OS) was 5.5 years. The prevalence of rs1799782 in XRCC1 gene among the 218 patients was: GG genotype 62.4% (136/218), GA genotype 33.0% (72/218) and AA genotype 4.6% (10/218), minor allele frequency was 0.21. And the distribution frequencies of the three genotypes were in accordance with the hardy-weinberg equilibrium (P=0.905). GA and AA genotypes were merged in the subsequent analysis. The median DFS [M (95%CI)] of GG genotype and GA/AA genotype was 5.2 (4.5-5.9) years and 3.8 (3.2-4.4) years, which was statistically significant (χ²=6.943, P=0.008). Furthermore, the median OS [M (95%CI)] of the two genotypes were 6.0 (5.3-6.7) years and 4.5 (3.9-5.1) years, which was statistically significant (χ²=5.538, P=0.010). The mRNA expression of XRCC1 in PBMC of the patients with GA/AA genotypes was 3.8±0.6,which was significantly higher than that of the GG genotype patients(2.8±0.7) (t=6.140, P<0.001). Conclusion: The prognosis of patients with CRC who received oxaliplatin based adjuvant chemotherapy may be influenced by XRCC1 rs1799782 through mediating the mRNA expression of XRCC1.

The influence of lipoprotein lipase gene polymorphism in Czech East Friesian sheep on the fatty acid profile in milk and yoghurt drinks – a preliminary study

The influence of lipoprotein lipase gene polymorphism in Czech East Friesian sheep on the fatty acid profile in milk and yoghurt drinks – a preliminary study

Radio-adaptive response and correlation of non-homologous end joining repair gene polymorphisms [XRRC5 (3R/2R/1R/0R), XRCC6(C/G) and XRCC7 (G/T)] in human peripheral blood mononuclear cells exposed to gamma radiation

BackgroundRadio-adaptive response (RAR) is transient phenomena, where cells conditioned with a small dose (priming) of ionizing radiation shows significantly reduced DNA damage with a subsequent high challenging dose. The role of DNA double strand break repair gene polymorphism in RAR is not known. In the present study attempt was made to find out the influence of NHEJ repair gene polymorphisms [a VNTR; XRCC5 (3R/2R/1R/0R); two single nucleotide polymorphisms (SNPs); XRCC6 (C/G) and XRCC7 (G/T)] with DNA damage, repair and mRNA expression in human PBMCs in dose and adaptive response studies. Genomic DNA extracted from venous blood samples of 20 random healthy donors (16 adaptive and 4 non-adaptive) and genotyping of NHEJ repair genes was carried out using PCR amplified length polymorphism.ResultsThe dose response study revealed significant positive correlation of genotypes at XRRC5 (3R/2R/1R/0R), XRCC6(C/G) and XRCC7 (G/T) with DNA damage. Donors having genotypes with 2R allele at XRCC5 showed significant positive correlation with mRNA expression level (0R/2R: r = 0.846, P = 0.034; 1R/2R: r = 0.698, P = 0.0001 and 2R/2R: r = 0.831, P = 0.0001) for dose response. Genotypes C/C and C/G of XRCC6 showed a significant positive correlation (P = 0.0001), whereas, genotype T/T of XRCC7 showed significant negative correlation (r = − 0.376, P = 0.041) with mRNA expression.ConclusionInterestingly, adaptive donors having C/G genotype of XRCC6 showed significantly higher (P < 0.05) mRNA expression level in primed cells suggesting their role in RAR. In addition, NHEJ repair gene polymorphisms play crucial role with radio-sensitivity and RAR in human PBMCs.

Influence of polymorphisms in anthracyclines metabolism genes in the standard induction chemotherapy of acute myeloid leukemia.

Genetic variability in anthracycline metabolism could modify the response and safety of acute myeloid leukemia (AML) induction. Polymorphisms in genes that encodes enzymes of anthracyclines metabolic pathway (CBR3: rs1056892, rs8133052, NQO1: rs1800566, NQO2: rs1143684, NOS3: rs1799983, rs2070744) were evaluated in 225 adult de novo AML patients. The variant CBR3 rs8133052 was associated with lower hepatotoxicity (P = 0.028). Wild-type genotype of NQO2 rs1143684 was related to higher complete remission (P = 0.014), and the variant allele with greater gastrointestinal toxicity (P = 0.024). However, the variant genotype of NQO1 rs1800566 was associated with mucositis (P = 0.018), but heterozygous genotype showed less gastrointestinal toxicity (P = 0.028) and thrombocytopenia (P = 0.009). Protective effects against nephrotoxicity and thrombocytopenia were reported with variant NOS3 rs1799983 (P = 0.006, P = 0.014), whereas carriers of NOS3 rs2070744 showed higher hepatotoxicity and thrombocytopenia (P = 0.017, P = 0.013). This study supports the influence of genetic variability of idarubicin metabolizing could be critical in predicting anthracycline-induced toxicities.

Variants in CDHR3, CACNAC1, and LTA Genes Predisposing Sensitivity and Response to Warfarin in Patients with Cardiovascular Disease.

IntroductionWarfarin has been in use for more than 60 years; however, it has serious side effects including major bleeding. The high interpatient variability in the required dose impacts the sensitivity and responsiveness to warfarin in different patients. This study aims to assess the influence of CDHR3, CACNAC1, and LTA gene polymorphisms on the variability of warfarin dose requirements and susceptibility to coronary heart disease in the Jordanian population.MethodsThis study was conducted in the anti-coagulation clinic in Queen Alia Heart Institute in Amman, with 212 patients in total. Three SNPs were genotyped within CDHR3 (rs10270308), CACNAC1 (rs216013), and LTA (rs1041981) genes.ResultsOur findings revealed that patients with LTA polymorphism are more prone to warfarin sensitivity than others. Furthermore, carriers of the LTA polymorphism needed a lower initial dose of warfarin and are associated with less variation in doses required to achieve target INR.ConclusionThe current study could help in understanding the role of genetic variability in warfarin dosing and matching patients to different treatment options. Clinical applications of these findings for warfarin treatment may also contribute to improving the efficacy and safety of warfarin treatment in Jordanian patients with cardiovascular disease.

Association of Genetic Variances in ADRB1 and PPARGC1a with Two-Kilometre Running Time-Trial Performance in Australian Football League Players: A Preliminary Study.

Genetic variants in the angiotensin-converting enzyme (ACE) (rs4343), alpha-actinin-3 (ACTN3) (rs1815739), adrenoceptor-beta-1 (ADRB1) (rs1801253), and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PPARGC1A) (rs8192678) genes have previously been associated with elite athletic performance. This study assessed the influence of polymorphisms in these candidate genes towards endurance test performance in 46 players from a single Australian Football League (AFL) team. Each player provided saliva buccal swab samples for DNA analysis and genotyping and were required to perform two independent two-kilometre running time-trials, six weeks apart. Linear mixed models were created to account for repeated measures over time and to determine whether player genotypes are associated with overall performance in the two-kilometre time-trial. The results showed that the ADRB1 Arg389Gly CC (p = 0.034) and PPARGC1A Gly482Ser GG (p = 0.031) genotypes were significantly associated with a faster two-kilometre time-trial. This is the first study to link genetic polymorphism to an assessment of endurance performance in Australian Football and provides justification for further exploratory or confirmatory studies.

Influence of Diabetes and M235Tangiotensinogen Gene Polymorphism on Lipid Metabolism in Patients with Heart Failure

Influence of Diabetes and M235Tangiotensinogen Gene Polymorphism on Lipid Metabolism in Patients with Heart Failure

TLR4 rs1927914 polymorphism contributes to serum TLR4 levels in patients with aortic aneurysm

Toll-like receptor 4 (TLR4) is a crucial regulator of inflammatory reactions and vascular remodeling. Elevated TLR4 expression has been proved to be correlated with an increased risk of aortic aneurysm (AA). This study aimed to explore the influence of TLR4 gene polymorphisms on TLR4 expression levels and its probable functional significance in AA disease. A total of 294 AA patients and 285 controls were enrolled in the study and serum TLR4 levels were detected by ELISA. All the participants were genotyped for two tag-SNPs in TLR4 (rs1927914 in the promoter region and rs11536889 in the 3′-untranslated region) using the KASP method. Relative luciferase activity was measured by the dual-luciferase reporter assay system. The rs1927914 TC, TC/CC genotypes and C allele showed associations with increased serum TLR4 levels in the total population and AA patients (all P<0.05). Further stratified analysis demonstrated that AA subjects with TC or TC/CC genotype of rs1927914 had significantly higher serum levels of TLR4 than those with TT genotype in male, age>60y, hypertension, diabetes, TAA type and size>5.0 cm subgroups (all P<0.05). In binary logistic analysis, rs1927914 TC genotype and dominant model presented significant associations with high TLR4 levels (OR = 1.579 and 1.431, P = 0.020 and 0.049, respectively) after adjusting age, hypertension and diabetes. However, rs11536889 polymorphism had no significant influence on serum TLR4 levels. Regarding rs1927914, luciferase activity of the C allele construct was significantly increased in comparison with the T allele construct (0.589 ± 0.004 vs. 0.340 ± 0.014, P<0.001). Our results provided evidence that rs1927914 polymorphism contributed to serum TLR4 levels, possibly by influencing promoter activity of TLR4, and could be a novel genetic factor in the formation of AA.

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.

Evaluation of influence of IL-6 C-572G gene polymorphism and clinical factors on positive platelet antibody test

Background: Interleukin-6 (IL-6) promotes antibody production. The objective of this study was to investigate whether IL-6 C-572G single nucleotide polymorphisms (SNP) and clinical factors are associated with positive platelet antibody test. Materials and methods: Thirty platelet recipients with platelet antibodies (responders) and 20 platelet recipients without platelet antibodies (non-responders) were randomly selected. The -572 C&gt;G (rs 1800796) SNPs in the promoter region of IL-6 gene were genotyped by polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) method. Solid phase red cell adherence assay (SPRCA) was used for platelet antibody detection. Results: Age, sex, percentage patients with benign diseases, and percentage of patients with homozygotes for the C allele at position -572 of the IL-6 gene were similar between responders and non-responders. Although the amounts of platelets pheresis transfused to patients with hematologic diseases were higher than those of non-hematologic diseases (47.2 ± 54.2 vs. 17.4 ± 13.8 units, p = 0.019), detection rate of platelet antibodies was lower in patients with hematologic diseases than that in patients with non-hematologic diseases (42.3% vs. 79.2%, p = 0.01). Conclusion: There was no association between IL-6 C-572G gene polymorphism and positive reactivity in solid phase platelet antibody detection method in platelet recipients.

Influence of ADRB1, ADRB2, and COMT Genetic Polymorphisms on Postoperative Outcomes of Patients Undergoing Cardiac Valve Surgery

PurposeThe aim of this study is to prospectively investigate the influence of ADRB and COMT gene polymorphisms on postoperative outcomes of patients undergoing cardiac surgery. MethodsThis prospective cohort study included 223 patients undergoing elective cardiac valve surgery using cardiopulmonary bypass. Demographic information, intraoperative data, postoperative data, and blood samples were collected. Patients were genotyped for single-nucleotide polymorphisms (SNPs) of ADRB1 rs1801253, ADRB2 rs1042713, and COMT rs4680. Major adverse cardiovascular and cerebrovascular events (MACCEs) were used as the primary outcome to evaluate the postoperative prognosis of patients. Secondary outcomes included the duration of mechanical ventilatory support, intensive care unit stay, postoperative hospital stay, and postoperative need of inotropic or vasoactive agents. FindingsThe overall incidence of MACCEs was 15.2%. Among 3 SNP loci, only different genotyped carriers of ADRB2 rs1042713 had statistically significant differences in the incidence of MACCEs (P = 0.005), especially for acute kidney injury (P = 0.023). The proportions of postoperative norepinephrine demand of patients carrying the AA genotype of ADRB2 rs1042713 (P = 0.016) and the AG genotype of COMT rs4680 (P = 0.018) were low. The duration of mechanical ventilatory support (P = 0.034) and postoperative hospital stay (P = 0.045) of patients carrying the AG genotype of COMT rs4680 was shortest. After multiple logistic regression analysis, we found that the G allele carriers of ADRB2 rs1042713 had a higher risk of MACCEs (AG vs AA genotype: odds ratio [OR] = 4.348; 95% CI, 1.529–12.359, P = 0.006; GG vs AA genotype: OR = 3.722; 95% CI, 1.060–13.071; P = 0.040), in particular with acute kidney injury (AG vs AA genotype: OR = 5.273; 95% CI, 1.093–25.451; P = 0.038; GG vs AA genotype: OR = 7.533; 95% CI, 1.275–44.522; P = 0.026). There was no SNP-SNP interaction found among the 3 SNPs with multifactor dimensionality reduction analysis. ImplicationThe ADRB2 rs1042713 polymorphism might be related to prognosis of patients undergoing cardiac surgery. Patients carrying the G allele of ADRB2 rs1042713 had a higher risk of developing MACCEs, especially acute kidney injury. chictr.org.com identifier: ChiCTR1800015105.