Integrated analysis of clinical and genetic factors on the interindividual variation of warfarin anticoagulation efficacy in clinical practice.

AIM: The anticoagulation effect of warfarin is usually evaluated by percentage of time in therapeutic range (PTTR), which is negatively correlated with the risk of warfarin adverse reactions. This study aimed to explore the effects of genetic and nongenetic factors on anticoagulation efficacy of warfarin during different therapeutic range. METHODS: We conducted an observational retrospective study aiming at evaluating the impact of clinical and genetic factors on PTTR from initial to more than six months treatment. This analysis included patients with heart valve replace (HVR) surgery who underwent long-term or life-long time treatment with standard-dose warfarin for anticoagulation control in Second Xiangya Hospital. All patients were followed for at least 6 months. We genotyped single nucleotide polymorphisms in VKORC1 and CYP2C9 associated with altered warfarin dose requirements and tested their associations with PTTR. RESULTS: A total of 629 patients with intact clinical data and available genotype data were enrolled in this study, and only 38.63% patients achieved good anticoagulation control (PTTR > 0.6). Clinical factors, including male gender, older age, overweight, AVR surgery and stroke history, were associated with higher PTTR. Patients with VKORC1 -1639AA genotype had significantly higher PTTR level compared with GA/GG genotype carriers only in the first month of treatment. Patients with CYP2C9*3 allele had higher PTTR compared with CYP2C9*1*1 carriers. Moreover, compared with VKORC1 -1639 AG/GG carriers, INR > 4 was more likely to be present in patients with AA genotype. The frequency of CYP2C9*1*3 in patients with INR > 4 was significantly higher than these without INR > 4. CONCLUSION: We confirmed the relevant factors of warfarin anticoagulation control, including genetic factors (VKORC1 -1639G > A and CYP2C9*3 polymorphisms) and clinical factors (male gender, older age, overweight, AVR surgery and stroke history), which could be helpful to individualize warfarin dosage and improve warfarin anticoagulation control during different treatment period.

TRIB3 promoter 33 bp VNTR is associated with the risk of cerebrovascular disease in type 2 diabetic patients.

Previous studies have demonstrated that TRIB3 is closely related to insulin resistance, metabolic disorders and vascular diseases. Recently, it was reported that a 33 bp variable number of tandem repeats (VNTR) located in the TRIB3 promoter could considerably alter its transcriptional activity. Nonetheless, whether the shift of TRIB3 transcriptional activity has the effect of inducing diabetic vascular complications is still unclear. Therefore, in our study, we aimed to explore the relationship between the TRIB3 33bp VNTR and diabetic vascular complications. The TRIB3 33bp VNTR polymorphisms were determined by PCR and Sanger sequencing, a total of 798 eligible Chinese patients with type 2 diabetes (T2DM) were included in our study and then evaluated with clinical data. After adjusting for age, gender, BMI, smoking history, drinking history and duration of diabetes, we found that the high number of 33 bp tandem repeats (repeats>8) was significantly associated with an increase in the risk of cerebrovascular diseases compared with the low number of 33 bp tandem repeats (repeats≤6) in patients with T2DM(OR 2.66, 95% CI 1.29-5.47, p = 0.008). The intermediate number of 33bp tandem repeats (6 < repeat≤8) was markedly associated with a decreased risk of diabetic retinopathy compared with the low number of tandem repeats (OR 0.65, 95% CI 0.46-0.91, p = 0.012). Adjusting for gender, age and BMI, there was a significant difference in DBP levels among patients with the number of different 33 bp tandem repeats (Low vs. Intermediate vs. High, 81.6 ± 12.8 vs. 79.8 ± 12.4 vs. 78.7 ± 12.6 mmHg; p = 0.045). Subgroup analysis found that TRIB3 VNTR was significantly correlated with the difference in systolic blood pressure (SBP) in T2DM patients taking ACEI/ARB drugs (Low vs. Intermediate vs. High, 146.27 ± 18.23 vs. 140.01 ± 19.91 vs. 140.77 ± 18.64 mmHg; p = 0.018). Our results indicated that TRIB3 promoter 33bp VNTR is related to vascular diseases in T2DM patients, and may serve as a new biomarker for individualized prevention and therapy of T2DM.

Comparative effectiveness of glycyrrhizic acid preparations aimed at preventing and treating anti-tuberculosis drug-induced liver injury: A network meta-analysis of 97 randomized controlled trials.

BACKGROUND AND OBJECTIVES: Clinical guidelines and expert consensus do not yet recommend glycyrrhizic acid (GA) preparations, such as compound glycyrrhizin, diammonium glycyrrhizin, magnesium isoglycyrrhizinate (MGIG), et al., for the prevention of anti-tuberculosis(anti-TB) drug-induced liver injury (DILI) due to insufficient evidence. Although these GA preparations are recommended for the treatment of anti-TB DILI, which one performs best is unclear. Previous conventional meta-analyses did not summarize the results of simultaneous comparisons of different glycyrrhizinate preparations. Therefore, we aimed to compare and rank different GA preparations on preventing and treating the anti-TB DILI by network meta-analysis (NMA). METHODS: A systematic search on PubMed, Web of Science, Embase, the Cochrane Library, China National Knowledge Infrastructure, SinoMed, Chongqing VIP and, the Wanfang Database was performed up to December 19, 2020. The literature was screened according to predefined inclusion and exclusion criteria to extract important information. The outcomes were the incidence of liver injury (prevention section) and treatment response rate (treatment section). The NMA was conducted with a random-effects model under the Bayesian framework to calculate risk ratios (RRs) with 95% credible intervals (95% CrIs) using R software (version 3.6.1). RESULTS: From 1,411 publications, we included 97 relevant randomized clinical trials (RCTs) (10,923 participants). In terms of preventing anti-TB DILI (33 RCTs, comprising 5,762 patients), CGC, DGC, DGEC, and DGI, but not CGI, significantly reduced the incidence of liver injury than control group (RRs ranged from 0.26 to 0.58); CGC and DGEC were superior to DGC (RRs = 0.50 and 0.58, respectively). In terms of treating anti-TB DILI (64 RCTs, comprising 5,161 patients), MGIG was most effective among all regimens (RRs ranged from 1.15 to 1.72) while DGC ranked last (RRs ranged from 0.58 to 0.83). CONCLUSIONS: All GA preparations except for CGI were effective in preventing the incidence of anti-TB DILI and CGC was superior to DGC. MGIG seems to be the best choice among all GA preparations for the treatment of anti-TB DILI. Future clinical practice guidelines should factor in these novel findings to improve patient outcomes; however, further high-quality trials are needed to validate these results.

GRB10 rs1800504 Polymorphism Is Associated With the Risk of Coronary Heart Disease in Patients With Type 2 Diabetes Mellitus.

Diabetic vascular complications are one of the main causes of death and disability. Previous studies have reported that genetic variation is associated with diabetic vascular complications. In this study, we aimed to investigate the association between GRB10 polymorphisms and susceptibility to type 2 diabetes mellitus (T2DM) vascular complications. Eight single nucleotide polymorphisms (SNPs) in the GRB10 gene were genotyped by MassARRAY system and 934 patients with type 2 diabetes mellitus (T2DM) were included for investigation. We found that GRB10 rs1800504 CC+CT genotypes were significantly associated with increased risk of coronary heart disease (CHD) compared with TT genotype (OR = 2.24; 95%CI: 1.36-3.70, p = 0.002). Consistently, levels of cholesterol (CHOL) (CC+CT vs. TT, 4.44 ± 1.25 vs. 4.10 ± 1.00 mmol/L; p = 0.009) and low density lipoprotein cholesterin (LDL-CH) (CC+CT vs. TT, 2.81 ± 1.07 vs. 2.53 ± 0.82 mmol/L; p = 0.01) in T2DM patients with TT genotype were significant lower than those of CC+CT genotypes. We further validated in MIHA cell that the total cholesterol (TC) level in GRB10-Mut was significantly reduced compared with GRB10-WT; p = 0.0005. Likewise, the reversed palmitic acid (PA) induced lipid droplet formation in GRB10-Mut was more effective than in GRB10-WT. These results suggest that rs1800504 of GRB10 variant may be associated with the blood lipids and then may also related to the risk of CHD in patients with T2DM.

Peripheral Blood Markers Associated with Immune-Related Adverse Effects in Patients Who Had Advanced Non-Small Cell Lung Cancer Treated with PD-1 Inhibitors.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have transformed the treatment landscape for patients with advanced non-small-cell lung cancer (aNSCLC), but immune-related adverse events (irAEs) have been evidenced curtailed the clinical use of them. PURPOSE: The aim of this study was to research the influences of inflammation-related peripheral blood markers, including neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) levels, on anti-PD-1 inhibitor-induced irAEs. PATIENTS AND METHODS: A retrospective analysis was conducted of patients treated with PD-1 inhibitors for stage III-IV NSCLC at a single center from 2017 to 2020 were included. Clinical characteristics, peripheral blood markers at the baseline and before subsequent treatment cycles were collected. NLR and PLR were calculated by division of neutrophil and platelet by lymphocyte measured in peripheral blood. The development of irAEs was evaluated and monitored from the therapy start based on CTCAE V4.03. RESULTS: A total of 150 patients were included. Fifty-seven patients had occurred at least one irAEs during follow-up, and mainly grade 1-2 (73.68%). Pruritus, rash and thyroiditis were the most commonly irAEs. Low NLR, PLR and neutrophil at baseline were significantly associated with the development of severe irAEs (P-values were 0.023, 0.0016 and 0.009). The levels of neutrophil, NLR and PLR also significantly decreased when occurred irAEs compared with baseline (P-values were 0.0069, 0.017 and 1.18E-5, respectively). CONCLUSION: The levels of NLR, PLR and neutrophil were associated with the increased risk of severe irAEs when baseline levels were low. NLR, PLR, and neutrophil are simple and available biomarkers that can be used to help predict severe adverse effects in NSCLC patients treated with anti-PD-1 inhibitors.

Prognostic value of liver and kidney function parameters and their correlation with the ratio of urine-to-plasma paraquat in patients with paraquat poisoning.

Acute paraquat poisoning resulting from multiple organ failure usually has a high mortality rate. Liver and kidney, as the key oranges of paraquat detoxification and elimination, their injuries may suppress toxin excretion and enhance the toxicity of paraquat in other organs and worsen the prognosis. Therefore, we intended to explore the prognostic value of liver and kidney function parameters, and further evaluate their correlation with a more stable index urine-to-plasma paraquat (urine paraquat concentrations/plasma paraquat concentrations) instead of considering paraquat concentrations in plasma or urine alone. The study included 33 patients with acute paraquat poisoning admitted to four centres in China from January 2018 to December 2019. Seventeen patients (10 male/7 female) survived, whereas 16 patients (7 male/9 female, 48.48%) died from paraquat poisoning. Alanine aminotransferase (ALT) and the blood urea nitrogen (BUN) represent liver and kidney function parameters, respectively. The ratio of urine-to-plasma paraquat is negatively correlated with ALT (r = -0.94, P = 0 .02) and BUN (r = -0.82, P = 0.03). For receiver operating characteristic curve (ROC) analysis, ALT, BUN and urine-to-plasma paraquat have an AUC over 0.80. The study shows that the functional indexes of liver and kidney, as well as the ratio of urine-to-plasma paraquat, could be considered for evaluating the extent of organ injury and excretion rate of paraquat.

Pharmacomicrobiomics: Exploiting the Drug-Microbiota Interactions in Antihypertensive Treatment.

Hypertension is a leading risk factor for cardiovascular diseases and can reduce life expectancy. Owing to the widespread use of antihypertensive drugs, patients with hypertension have improved blood pressure control over the past few decades. However, for a considerable part of the population, these drugs still cannot significantly improve their symptoms. In order to explore the reasons behind, pharmacomicrobiomics provide unique insights into the drug treatment of hypertension by investigating the effect of bidirectional interaction between gut microbiota and antihypertensive drugs. This review discusses the relationship between antihypertensive drugs and the gut microbiome, including changes in drug pharmacokinetics and gut microbiota composition. In addition, we highlight how our current knowledge of antihypertensive drug-microbiota interactions to develop gut microbiota-based personalized ways for disease management, including antihypertensive response biomarker, microbial-targeted therapies, probiotics therapy. Ultimately, a better understanding of the impact of pharmacomicrobiomics in the treatment of hypertension will provide important information for guiding rational clinical use and individualized use.

Slow-Release H2S Donor Anethole Dithiolethione Protects Liver From Lipotoxicity by Improving Fatty Acid Metabolism.

"Lipotoxicity" induced by free fatty acids (FAs) plays a central role in the pathogenesis of many metabolic diseases, with few treatment options available today. Hydrogen sulfide (H2S), a novel gaseous signaling molecule, has been reported to have a variety of pharmacological properties, but its effect on FAs metabolism remains unclear. The purpose of this study was to investigate the effect and mechanisms of anethole dithiolethione (ADT, a sustained-release H2S donor) on hepatic FAs metabolism. ADT was administered daily for 4 weeks in male Syrian golden hamsters fed a high fat diet (HFD), and FAs profiles of liver tissues were analyzed using GC-MS. The results showed that in HFD-fed hamsters, ADT treatment significantly reduced the accumulation of toxic saturated and monounsaturated fatty acids (C16:0, C18:0, C16:1, and C18:1n9), while increased the content of n-6 and n-3 series polyunsaturated fatty acids (C20:3n6, C20:4n6, and C22:6n3). Mechanistically, ADT obviously inhibited the overexpression of acetyl-CoA carboxylase1 (ACC1), fatty acid synthase (FAS), and stearoyl-CoA desaturase1 (SCD1), and up-regulated the levels of fatty acid transport proteins (FATPs), liver fatty acid binding protein (L-FABP), carnitine palmitoyltransferase 1α (CPT1α), fatty acid desaturase (FADS)1 and FADS2. Notably, ADT administration significantly promoted Mitofusin1-mediated mitochondrial fusion and fatty acid ß-oxidation. These findings suggest that ADT plays a beneficial role by regulating the synthesis, desaturation, ß-oxidation, uptake, binding/isolation, and transport of FAs. In conclusion, ADT is effective in improving FAs metabolic disorders and liver injuries caused by HFD, which renders ADT a candidate drug for lipotoxicity-induced diseases.

TRIB3 rs6037475 is a potential biomarker for predicting felodipine drug response in Chinese patients with hypertension.

BACKGROUND: Our previous studies have found that single nucleotide polymorphisms (SNPs) of tribbles homolog 3 (TRIB3) are related to the hypotensive effects of calcium-channel blockers (CCBs) and angiotensin-converting enzyme (ACE) inhibitors. In this study, we aimed at exploring and validating the effect of TRIB3 polymorphism on antihypertensive drugs responses. METHODS: A total of 830 hypertensive patients, who were administered with open-labeled hydrochlorothiazide (12.5 mg once daily) and randomly assigned to off-labeled felodipine (5 mg) or a matched placebo combination treatment (1:1), were selected from the Felodipine Event Reduction (FEVER) study. A strategy of screening 259 samples and validating the remaining 531 samples was implemented. Four functional SNPs were selected (rs2295490, rs11470129, rs4815567 and rs6037475 in TRIB3). A mixed linear model was performed to analyze the effects of TRIB3 SNPs on antihypertensive drugs responses. RESULTS: We found that TRIB3 rs6037475 CC genotype was associated with a reduction of diastolic blood pressure (DBP) (P=6.3×10-3) in the felodipine treatment group of screening set, and was also associated with a reduction of systolic blood pressure (SBP) (P=0.021), DBP (P=6.0×10-3) and mean arterial pressure (MAP) (P=0.021) in the felodipine treatment group of the validation set. As for the reductions influenced by the rs2295490, rs11470129 and rs4815567 genetic variations, however, the adjusted P-value did not reach statistical significance. Combined screening and validation set analysis found that patients with TRIB3 rs6037475 CC genotype had a significant higher mean SBP, DBP and MAP than those with TT genotype in the felodipine treatment group (CC vs. TT -10.2±0.74 vs. -17.8±0.21, P=7.8×10-3; -4.6±0.50 vs. -10.2±0.23, P=3.0×10-4; -6.5±0.54 vs. -12.7±0.14, P=3.0×10-4, respectively). CONCLUSIONS: These results suggest that TRIB3 rs6037475 genetic variation can be useful as a bio-marker for predicting felodipine drug response in Chinese patients with hypertension.

Population Pharmacokinetics and Dosage Optimization of Linezolid in Patients with Liver Dysfunction.

Linezolid is the first synthetic oxazolidone agent to treat infections caused by Gram-positive pathogens. Infected patients with liver dysfunction (LD) are more likely to suffer from adverse reactions, such as thrombocytopenia, when standard-dose linezolid is used than patients with LD who did not use linezolid. Currently, pharmacokinetics data of linezolid in patients with LD are limited. This study aimed to characterize pharmacokinetics parameters of linezolid in patients with LD, identify the factors influencing the pharmacokinetics, and propose an optimal dosage regimen. We conducted a prospective study and established a population pharmacokinetics model with the Phoenix NLME software. The final model was evaluated by goodness-of-fit plots, bootstrap analysis, and prediction corrected-visual predictive check. A total of 163 concentration samples from 45 patients with LD were adequately described by a one-compartment model with first-order elimination along with prothrombin activity (PTA) and creatinine clearance as significant covariates. Linezolid clearance (CL) was 2.68 liters/h (95% confidence interval [CI], 2.34 to 3.03 liters/h); the volume of distribution (V) was 58.34 liters (95% CI, 48.00 to 68.68 liters). Model-based simulation indicated that the conventional dose was at risk for overexposure in patients with LD or severe renal dysfunction; reduced dosage (300 mg/12 h) would be appropriate to achieve safe (minimum steady-state concentration [Cmin,ss] at 2 to 8 µg/ml) and effective targets (the ratio of area under the concentration-time curve from 0 to 24 h [AUC0-24] at steady state to MIC, 80 to 100). In addition, for patients with severe LD (PTA, ≤20%), the dosage (400 mg/24 h) was sufficient at an MIC of ≤2 µg/ml. This study recommended therapeutic drug monitoring for patients with LD. (This study has been registered in the Chinese Clinical Trial Registry under no. ChiCTR1900022118.).

Pleiotropic Effects of Metformin on the Antitumor Efficiency of Immune Checkpoint Inhibitors.

Cancer is an important threat to public health because of its high morbidity and mortality. In recent decades, immune checkpoint inhibitors (ICIs) have ushered a new therapeutic era in clinical oncology. The rapid development of immune checkpoint therapy is due to its inspiring clinical efficacy in a group of cancer types. Metformin, an effective agent for the management of type 2 diabetes mellitus (T2DM), has shown beneficial effects on cancer prevention and cancer treatment. Emerging studies have suggested that metformin in combination with ICI treatment could improve the anticancer effects of ICIs. Hence, we conducted a review to summarize the effects of metformin on ICI therapy. We also review the pleiotropic mechanisms of metformin combined with ICIs in cancer therapy, including its direct and indirect effects on the host immune system.

In vivo pharmacodynamic and pharmacokinetic effects of metformin mediated by the gut microbiota in rats.

AIMS: The gut microbiota plays a crucial role in the efficacy of metformin in T2DM treatment. We evaluated whether the pharmacodynamics and pharmacokinetics of metformin are mediated by gut microbiota. MAIN METHODS: We used conventional diabetic and pseudo-germ-free rats. After 6 weeks of metformin treatment, pharmacodynamic indexes were determined. Metformin concentrations were measured with a validated HPLC-MS/MS method after the first oral administration. KEY FINDINGS: Most endpoints were similar between vehicle-treated diabetic and vehicle-treated pseudo-germ-free diabetic rats. However, after 6 weeks of metformin treatment, compared with conventional diabetic rats, pseudo-germ-free diabetic rats exhibited significantly increased FBG, decreased oral glucose, reduced GSP, worsened insulin resistance, increased hyperlipidemia, and increased hepatic steatosis severity. Moreover, the Cmax of pseudo-germ-free rats increased significantly, while the t1/2α decreased significantly. These pharmacodynamic and pharmacokinetic changes were probably due to a decrease in Oct1 expression in the liver, resulting in altered hepatic uptake of metformin in vivo. SIGNIFICANCE: These results implied that the gut microbiota may play an important role in the pharmacodynamics and pharmacokinetics of metformin and that the changes in these properties are probably due to Oct1 downregulation in the livers of pseudo-germ-free rats.

Incorporation of Gene-Environment Interaction Terms Improved the Predictive Accuracy of Tacrolimus Stable Dose Algorithms in Chinese Adult Renal Transplant Recipients.

The narrow therapeutic window of tacrolimus necessitates daily monitoring and predictive algorithms based on genetic and nongenetic factors. In this study, we constructed predictive algorithms for tacrolimus stable dose in a retrospective cohort of 1045 Chinese renal transplant recipients. All patients were genotyped for CYP3A4 20230T>C (rs2242480), CYP3A4 T>C (rs4646437), CYP3A5*3 6898A>G (rs776746), ABCB1 129T>C (rs3213619); ABCB1 c.1236C>T (rs01128503), ABCB1 c.2677G>T/A (rs2032582) and ABCB1 c.3435C>T (rs1045642) polymorphisms, and the effects of gene-gene and gene-environment interactions on the predictive accuracy of algorithm were evaluated. In wild-type CYP3A4 rs2242480 (TT) carriers, patients who took calcium channel blockers had lower tacrolimus stable doses than those without the concomitant medications (P < 1 × 10-4 ). In contrast, there was no significant difference in mutant type patients. Similarly, the tacrolimus stable doses in wild-type CYP3A5 rs776746 carriers who had hypertension were higher than those without hypertension (P = 4.10 × 10-3 ). More importantly, dose-predictive algorithms with interaction terms showed higher accuracy and better performance than those without interaction terms. Our finding suggested that wild-type CYP3A4 rs2242480 (TT) carriers should be more cautious to take tacrolimus when they are coadministrated with calcium channel blockers, and CYP3A5 rs776746 (AA) carriers may need higher tacrolimus dosage when they are in combination with hypertension.

MIR4532 gene variant rs60432575 influences the expression of KCNJ11 and the sulfonylureas-stimulated insulin secretion.

PURPOSE: Diabetes mellitus is a major chronic disease and causes over one million deaths. KCNJ11 genetic polymorphisms influence the response of first-line oral antidiabetic agent sulfonylureas. Hsa-miR-4532 correlates with diabetic nephropathy and has a high abundance in urine. MIR4532 rs60452575 G>A variant changes the mature sequence of hsa-miR-4532. We studied whether the genetic polymorphisms of MIR4532 rs60452575 would influence KCNJ11 expression and sulfonylurea-stimulated insulin secretion or not. METHODS: To estimate the influence that rs60452575 G>A variant has on the interaction of hsa-miR-4532 and KCNJ11, we constructed a pmirGLO vector containing 3' UTR of KCNJ11 and co-transfected it with wild-type and mutant hsa-miR-4532 mimics into HEK293 cells; and we overexpressed wild-type and mutant hsa-miR-4532 mimics into HEK293 cells and MIN6 cells to access its effects on KCNJ11 expression and response of sulfonylureas. RESULTS: MIR4532 rs60452575 G>A variant appeared to disrupt the repression of KCNJ11 expression in both cell lines, and reduce the sulfonylurea-stimulated insulin secretion by breaking the binding of the hsa-miR-4532 to 3' UTR of KCNJ11 in MIN6 cells. CONCLUSIONS: Our study indicates that MIR4532 rs60452575 variant influences KCNJ11 expression and sulfonylurea response. It might be a potential predictive factor of sulfonylureas therapy.

Association of PON2 Gene Polymorphisms (Ser311Cys and Ala148Gly) With the Risk of Developing Type 2 Diabetes Mellitus in the Chinese Population.

Background: The association between paraoxonase 2 (PON2) gene polymorphisms and type 2 diabetes mellitus (T2DM) has been extensively investigated in the Chinese population with conflicting results. In this study, we systematically evaluated the association between PON2 Ser311Cys and Ala148Gly polymorphisms and T2DM risk by pooling all relevant studies. Methods: We searched PubMed, Embase, CNKI, and Wanfang databases for the studies. The strength of association was determined by the allelic, homozygous, heterozygous, recessive, and dominant genetic models and measured as odds ratio (OR) and 95% confidence interval (CI), under fixed- or random-effect models. Results: There was no significant association between PON2 Ser311Cys polymorphism and T2DM under any of the genetic models: allelic (OR = 1.06, 95% CI = 0.77-1.45; P = 0.721), heterozygous (OR = 1.13, 95% CI = 0.87-1.45; P = 0.362), dominant (OR = 1.10, 95% CI = 0.80-1.51; P = 0.562), recessive (OR = 0.87, 95% CI = 0.48-1.58; P = 0.648), homozygous (OR = 0.94, 95% CI = 0.47-1.89; P = 0.865). Similarly, no significant association was found in PON2 Arg148Gly polymorphism under any of the models: allelic (OR = 1.17, 95% CI = 0.91-1.50; P = 0.218), heterozygous (OR = 1.28, 95% CI = 0.94-1.74; P = 0.117), dominant (OR = 1.25, 95% CI = 0.93-1.67; P = 0.142), recessive (OR = 0.99, 95% CI = 0.52-1.88; P = 0.973), homozygous (OR = 1.08, 95% CI = 0.57-2.07; P = 0.808). Conclusions: The PON2 Ser311Cys and Ala148Gly polymorphisms were not associated with the risk of developing T2DM in the Chinese population.

Drug-induced hyperglycaemia and diabetes: pharmacogenomics perspectives.

Drug-induced diabetes is widely reported in clinical conditions, and it is becoming a global issue because of its potential to increase the risk of severe cardiovascular complications. However, which drug mechanisms exert their diabetogenic effects and why the effects present significant inter-individual differences remain largely unknown. Pharmacogenomics, which is the study of how genomic variation influences drug responses, provides an explanation for individual differences in drug-induced diabetes. We highlight that pharmacogenomics can be involved in regulating the expression of genes in signaling pathways related to the pharmacokinetics or pharmacodynamics of drugs or the pathogenesis of diabetes, contributing to the differences in drug-induced glucose impairment. The pharmacogenomics studies of the major diabetogenic drugs are reviewed, including calcineurin inhibitors, antipsychotics, hormones, and antihypertensive drugs. We intend to elucidate the genetic basis of drug-induced diabetes and pave the way for the precise use of these drugs in the clinic.

Corrigendum: Application of Machine-Learning Models to Predict Tacrolimus Stable Dose in Renal Transplant Recipients.

This corrects the article DOI: 10.1038/srep42192.

Pharmacokinetics, Pharmacodynamics and Pharmacogenetics of Tacrolimus in Kidney Transplantation.

BACKGROUND: Tacrolimus (Tac, or FK506), a calcineurin inhibitor (CNI), is the first-line immunosuppressant which consists of the footstone as immunosuppressive regimens in kidney transplantation. However, the drug toxicity and the significant differences of pharmacokinetics (PK) and pharmacodynamics (PD) among individuals are hidden troubles for clinical application. Recently, emerging evidences of Tac pharmacogenetics (PG) regarding drug absorption, metabolism, disposition, excretion and response are discovered for better understanding of this drug. METHOD: We reviewed the published articles regarding the Tac PG and its effects on PK and PD in kidney transplantation. In addition, we summarized information on polygenic algorithms. RESULTS: The polymorphism of genes encoding metabolic enzymes and transporters related to Tac were largely investigated, but the results were inconsistent. In addition to CYP3A4, CYP3A5 and P-gp (also known as ABCB1), single nucleotide polymorphisms (SNPs) might also affect the PK and PD parameters of Tac. CONCLUSION: The correlation between Tac PK, PD and PG is very complex. Although many factors need to be verified, it is envisaged that thorough understanding of PG may assist clinicians to predict the optimal starting dosage, help adjust the maintenance regimen, as well as identify high risk patients for adverse effects or drug inefficacy.

European versus Asian differences for the associations between paraoxonase-1 genetic polymorphisms and susceptibility to type 2 diabetes mellitus.

Many studies have examined the associations between paraoxonase-1 (PON1) genetic polymorphisms (Q192R, rs662 and L55M, rs854560) and the susceptibility to type 2 diabetes mellitus (T2DM) across different ethnic populations. However, the evidence for the associations remains inconclusive. In this study, we performed a meta-analysis to clarify the association of the two PON1 variants with T2DM risk. We carried out a systematic search of PubMed, Embase, CNKI and Wanfang databases for studies published before June 2017. The pooled odds ratios (ORs) for the association and their corresponding 95% confidence intervals (CIs) were calculated by a random- or fixed-effect model. A total of 50 eligible studies, including 34 and 16 studies were identified for the PON1 Q192R (rs662) and L55M (rs854560) polymorphism, respectively. As for the PON1 Q192R polymorphism, the 192R allele was a susceptible factor of T2DM in the South or East Asian population (OR > 1, P < 0.05) but represented a protective factor of T2DM in European population (OR = 0.66, 95% CI = 0.45-0.98) under a heterozygous genetic model. With regard to the PON1 L55M polymorphism, significant protective effects of the 55M allele on T2DM under the heterozygous (OR = 0.77, 95% CI = 0.61-0.97) and dominant (OR = 0.80, 95% CI = 0.65-0.99) genetic models were found in the European population, while no significant associations in the Asian populations under all genetic models (P > 0.05). In summary, by a comprehensive meta-analysis, our results firmly indicated that distinct effects of PON1 genetic polymorphisms existed in the risk of T2DM across different ethnic backgrounds.