LRP1 and APOA1 Polymorphisms: Impact on Warfarin International Normalized Ratio-Related Phenotypes.

Warfarin international normalized ratio (INR)-related phenotypes such as the percentage of INR time in the therapeutic range (PTTR) and INR variability are associated with warfarin adverse reactions. However, INR-related phenotypes greatly vary among patients, and the underlying mechanism remains unclear. As a key cofactor for coagulation proteins, vitamin K can affect warfarin INR values. The aim of this study was to address the influence of vitamin K-related single-nucleotide polymorphisms (SNPs) on warfarin INR-related phenotypes. A total of 262 patients who were new recipients of warfarin therapy and followed up for 3 months were enrolled. Twenty-nine SNPs were genotyped by matrix-assisted laser desorption/ionization time-of-flight mass array. Sixteen warfarin INR-related phenotypes were observed. After association analysis, 11 SNPs were significantly associated with at least one INR-related phenotype, and 6 SNPs were associated with at least 2 INR-related phenotypes (P < 0.05). In these SNPs, rs1800139, rs1800154, rs1800141, and rs486020 were the most representative. rs1800139, rs1800154, and rs1800141 locate in LRP1 and were found to be correlated with 1-month and 2-month INR variability (P < 0.05). Besides, the APOA1 rs486020 was significantly associated with the first month PTTR (P = 0.009), and patients with C-allele had higher PTTR than those with G-alleles almost during the entire monitoring period. In conclusion, the study revealed that the polymorphisms of LRP1 and APOA1 gene may play important roles in the variation of warfarin INR-related phenotypes. Our results provide new information for improving warfarin anticoagulation management.

Relationship between polymorphisms of the lipid metabolism-related gene PLA2G16 and risk of colorectal cancer in the Chinese population.

This study aimed to investigate the relationship between polymorphisms in the lipid metabolism-related gene PLA2G16 encoding Group XVI phospholipase A2 and the risk of colorectal cancer (CRC) in the Chinese population. A total of 185 patients with CRC and 313 healthy controls were enrolled. Thirteen single nucleotide polymorphisms (SNPs) of PLA2G16 were genotyped with SNPscan™. Linkage disequilibrium and haplotypes were analysed using Haploview software. Multivariate logistic regression was used to determine the association between the various genotypes and CRC risk. We identified five PLA2G16 SNPs (rs11600655, rs3809072, rs3809073, rs640908 and rs66475048) that were associated with CRC risk after adjusting for age, sex and body mass index. Two haplotypes (CTC and GGA) of rs11600655, rs3809073 and rs3809072, were relevant to CRC risk. The rs11600655 polymorphism was also associated with lymph node metastasis and CRC staging, while rs3809073 and rs3809072 may affect transcriptional regulation of PLA2G16 by altering transcription factor binding. These findings suggest that PLA2G16 polymorphisms-especially CTC and GGA haplotypes-increase CRC susceptibility. Importantly, we showed that the rs11600655 CC, rs640908 CT and rs66475048 GA genotypes are independent risk factors for CRC in the Chinese population.

IL-3 and CTLA4 gene polymorphisms may influence the tacrolimus dose requirement in Chinese kidney transplant recipients.

The highly variable pharmacokinetics and narrow therapeutic window of tacrolimus (TAC) has hampered its clinical use. Genetic polymorphisms may contribute to the variable response, but the evidence is not compelling, and the explanation is unclear. In this study we attempted to find previously unknown genetic factors that may influence the TAC dose requirements. The association of 105 pathway-related single nucleotide polymorphisms (SNPs) with TAC dose-adjusted concentrations (C0/D) was examined at 7, 30 and 90 d post-operation in 382 Chinese kidney transplant recipients. In CYP3A5 non-expressers, the patients carrying the IL-3 rs181781 AA genotype showed a significantly higher TAC logC0/D than those with the AG genotype at 30 and 90 d post-operation (AA vs AG, 2.21±0.06 vs 2.01±0.03, P=0.004; and 2.17±0.06 vs 2.03±0.03, P=0.033, respectively), and than those with the GG genotype at 30 d (AA vs GG, 2.21±0.06 vs 2.04±0.03, P =0.011). At 30 d, the TAC logC0/D in the grouped AG+GG genotypes of CTLA4 rs4553808 was significantly lower than that in the AA genotype (P =0.041) in CYP3A5 expressers, but it was higher (P=0.008) in the non-expressers. We further validated the influence of CYP3A5 rs776746, CYP3A4 rs2242480 and rs4646437 on the TAC C0/D; other candidate SNPs were not associated with the differences in TAC C0/D. In conclusion, genetic polymorphisms in the immune genes IL-3 rs181781 and CTLA4 rs4553808 may influence the TAC C0/D. They may, together with CYP3A5 rs776746, CYP3A4 rs2242480 and rs4646437, contribute to the variation in TAC dose requirements. When conducting individualized therapy with tacrolimus, these genetic factors should be taken into account.

DNA methylation perspectives in the pathogenesis of autoimmune diseases.

DNA methylation is now widely recognized as being critical to maintain the function of immune cells. Recent studies suggest that aberrant DNA methylation levels not only can result in immune cells autoreactivity in vitro, but also are related to autoimmunity in vivo. Environmental factors and genetic polymorphisms cause abnormal methylation, which affects the expression of certain immune-related genes, being becoming hot spot of explaining the mechanism of autoimmune diseases. This paper reviews the importance of abnormal methylation during the development of common autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis and type 1 diabetes, aiming at a better understanding of the pathogenesis of autoimmune diseases and providing new ideas for the treatment of these diseases.

Rs495828 polymorphism of the ABO gene is a predictor of enalapril-induced cough in Chinese patients with essential hypertension.

OBJECTIVE: ABO genetic polymorphisms have recently been associated with angiotensin-converting enzyme (ACE) activity and inflammation, which play a critical role in the pathogenic mechanism of ACE inhibitor-induced cough. Therefore, the current study determined the association of ABO genetic polymorphisms with enalapril-induced cough in Chinese patients with essential hypertension. METHODS: A total of 450 essential hypertensive patients treated with 10 mg of enalapril maleate were genotyped for ABO genetic polymorphisms using the PCR-direct sequencing method. Cough was recorded when patients were bothered by cough and respiratory symptoms during enalapril treatment without an identifiable cause. RESULTS: The distribution of rs8176740 and rs495828 was different between the coughers and the controls [P=0.039; odds ratio (OR)=0.70, P=0.018; OR=1.41]. The risk of enalapril-induced cough in the rs495828 TT carriers was increased (P=0.008; OR=2.69), which remained significant after false discovery rate correction. The results for the rs8176740 polymorphism were significant in the female subgroup (P=0.027; OR=0.22). Haplotype analysis of the four ABO polymorphisms (rs8176746/rs8176740/rs495828/rs12683493) showed that the frequency of the GATC haplotype was higher in the coughers than those in the controls (26.6 vs. 18.8%, P=0.033; OR=1.43). CONCLUSION: The rs495828 polymorphism was associated with enalapril-induced cough and may serve as a useful pharmacogenomics marker of the safety of enalapril in Chinese patients with essential hypertension. The mechanism for the associations may involve the effects of the ABO gene or ABO blood type on ACE activity and inflammation.

Blood Group Antigen A Carriers Exhibit an Extended Progression-Free Survival with no more Immune-Related Adverse Events.

Extensive investigations have been conducted regarding the potential correlation between blood type and the immune system, as well as cancer risk in the Southern Chinese population. However, the prognostic value of the blood group and its genetic determinants in the context of immune checkpoint inhibitor (ICI) treatment remains unclear. Therefore, the associations between the ABO blood group and its single nucleotide polymorphisms (SNPs) were examined in relation to ICI treatment outcomes in 370 eligible patients with cancer. This approach allowed us to derive the blood group from the SNPs responsible for blood group determination. In the discovery cohort (N = 168), antigen A carriers (blood types A and AB) exhibited an extended progression-free survival (PFS; hazard ratio (HR) = 0.58, 95% confidence interval (CI) = 0.34-0.98). The association results from the SNP-derived blood were consistent with those from the measured blood group. In the validation cohort (N = 202), Cox regression analysis revealed that the antigen A carriers (rs507666 AA+GA genotype carriers) experienced significantly extended PFS compared with the non-antigen A carriers (HR = 0.61, 95% CI = 0.40-0.93). Therefore, a longer PFS was observed in antigen A carriers (P value = 0.003, HR = 0.60, 95% CI = 0.44-0.84). Furthermore, haplotype 2 carriers (rs507666 GA and rs659104 GG) demonstrated both extended PFS and improved overall survival. Notably, the presence of antigen A was not associated with the occurrence of overall immune-related adverse events (irAEs) or organ-specific toxicity. In summary, our findings revealed that antigen A carriers did not experience a higher incidence of irAEs while exhibiting better immunotherapy efficacy.

Multidimensional evaluation of teaching strategies for pharmacology based on a comprehensive analysis involving 21,269 students.

Background: Given the limitations of traditional pharmacology pedagogical method, diverse novel teaching methods have been widely explored. In this study, we performed a network meta-analysis (NMA) to evaluate the effects of different strategies in pharmacology education. Methods: Literature databases were searched from their inception to November 2022, and the studies were screened according to predefined inclusion and exclusion criteria to extract important information. Outcomes, including theoretical test scores, experimental test scores, subjective test scores, satisfaction scores, and the proportion of satisfaction, were analyzed using R software (version 3.6.1) and STATA (version 15). The NMA was conducted with a random-effects model under the Bayesian framework to calculate odds ratios (ORs) or mean differences (MDs) with associated 95% credible intervals (95% CIs). Surface under the cumulative ranking curve (SUCRA) probability values were calculated to rank the teaching methods examined. Results: A total of 150 studies involving 21,269 students were included. This NMA systematically evaluated 24 teaching strategies, such as problem-based learning (PBL), team-based learning (TBL), case-based learning (CBL) and flipped classrooms (FC), etc., The results of the NMA showed that, PBL combined with CBL was most likely to improve students' theoretical and subjective test scores (SUCRA = 75.49 and 98.19%, respectively), TBL was most likely to improve the experimental test score (SUCRA = 92.38%) and the satisfaction score (SUCRA = 88.37%), while FC had the highest probability of being the best option for improving the proportion of satisfaction (SUCRA = 84.45%). Conclusion: The current evidence indicates that TBL, PBL combined with CBL, and FC might be optimal strategies for pharmacology education since they have a more beneficial effect on students.

Gut microbial structural variation associates with immune checkpoint inhibitor response.

The gut microbiota may have an effect on the therapeutic resistance and toxicity of immune checkpoint inhibitors (ICIs). However, the associations between the highly variable genomes of gut bacteria and the effectiveness of ICIs remain unclear, despite the fact that merely a few gene mutations between similar bacterial strains may cause significant phenotypic variations. Here, using datasets from the gut microbiome of 996 patients from seven clinical trials, we systematically identify microbial genomic structural variants (SVs) using SGV-Finder. The associations between SVs and response, progression-free survival, overall survival, and immune-related adverse events are systematically explored by metagenome-wide association analysis and replicated in different cohorts. Associated SVs are located in multiple species, including Akkermansia muciniphila, Dorea formicigenerans, and Bacteroides caccae. We find genes that encode enzymes that participate in glucose metabolism be harbored in these associated regions. This work uncovers a nascent layer of gut microbiome heterogeneity that is correlated with hosts' prognosis following ICI treatment and represents an advance in our knowledge of the intricate relationships between microbiota and tumor immunotherapy.

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.

Evaluating the role of GSTP1 genetic polymorphism (rs1695, 313A>G) as a predictor in cyclophosphamide-induced toxicities.

ABSTRACT: The association between Glutathione S-transferase Pi 1(GSTP1) genetic polymorphism (rs1695, 313A>G) and cyclophosphamide-induced toxicities has been widely investigated in previous studies, however, the results were inconsistent. This study was performed to further elucidate the association.A comprehensive search was conducted in PubMed, Embase, Web of Science, China National Knowledge Infrastructure, and Wan Fang database up to January 5, 2020. Risk ratios (RRs) and 95% confidence intervals (95% CIs) were used to estimate the association between GSTP1 rs1695 polymorphism and cyclophosphamide-induced hemotoxicity, gastrointestinal toxicity, infection, and neurotoxicity.A total of 13 studies were eventually included. Compared with the GSTP1 rs1695 AA genotype carriers, patients with AG and GG genotypes had an increased risk of cyclophosphamide-induced gastrointestinal toxicity (RR, 1.61; 95% CI, 1.18-2.19; P = .003) and infection (RR, 1.57; 95% CI, 1.00-2.48; P = .05) in the overall population. In the subgroup analyses, there were significant associations between GSTP1 rs1695 polymorphism and the risk of cyclophosphamide-induced myelosuppression (RR, 2.10; 95% CI, 1.60-2.76; P < .00001), gastrointestinal toxicity (RR, 1.77; 95%CI, 1.25-2.53; P = .001), and infection (RR, 2.01; 95% CI, 1.14-3.54; P = .02) in systemic lupus erythematosus (SLE) or lupus nephritis syndrome patients, but not in cancer patients.Our results confirmed an essential role for the GSTP1 rs1695 polymorphism in the prediction of cyclophosphamide-induced myelosuppression, gastrointestinal toxicity, and infection in SLE or lupus nephritis syndrome patients. More studies are necessary to validate our findings in the future.

LRP1 polymorphisms associated with warfarin stable dose in Chinese patients: a stepwise conditional analysis.

Aim: The aim of this study was to investigate whether variability in warfarin stable dose (WSD) could be influenced by vitamin K-related polymorphisms in patients with heart valve replacement. Patients & methods: Twenty-nine vitamin K-related SNPs in 208 patients who initially took warfarin and achieved WSD were genotyped. Results: After conducting conditional analysis for both VKORC1 -1639G>A and CYP2C9*3, LRP1 rs1800139 and LRP1 rs1800154 were significantly associated with WSD (p = 0.007 and p = 0.015, respectively). Multivariate analysis showed that LRP1 rs1800139 accounted for 5.9% WSD variability. Conclusion: Our results suggest that a novel vitamin K-related gene, LRP1, exerts a relevant influence on WSD, independent of VKORC1 -1639G>A and CYP2C9*3.

Association between polymorphisms in SLC15A1 and PLA2G16 genes and development of obesity in Chinese subjects.

INTRODUCTION: The small peptide transporter 1 (PepT-1) and adipose phospholipase A2 (AdPLA) play a key role in the development of obesity. However, there are no data assessing the impact of PepT-1 (SLC15A1) and AdPLA (PLA2G16) variants on obesity susceptibility. Therefore, we assessed the contribution of 9 single-nucleotide polymorphisms (SNPs) between these two genes on obesity susceptibility in Chinese subjects. MATERIALS AND METHODS: A total of 611 participants were enrolled in the study, and 9 SNPs in the SLC15A1 and PLA2G16 genes were selected. Blood samples were collected for genotyping. Overweight and obesity were established by body mass index. Regression analyses were performed to test for any association of genetic polymorphisms with weight abnormality. RESULTS: The genotype frequencies (P=0.04 for rs9557029, P=0.027 for rs1289389) were significantly different between obese or overweight subjects and healthy controls. However, no significant difference in allele was found between these three groups (P>0.05). Further logistic regression analyses adjusted for age and sex also failed to reveal significant associations between overweight, obesity, and the selected SNPs (P>0.05). CONCLUSION: Data indicate that the selected 9 SNPs in SLC15A1 and PLA2G16 genes were not related to obesity susceptibility in the Han Chinese population.

Value of bilirubin oxidase and its mutants in the diagnosis of hyperbilirubinemia.

OBJECTIVE: To elucidate the significance of the coordination amino acid residues in bilirubin oxidase (BO) and their kinetic characteristics, and evaluate whether BO mutants may serve as better diagnostic agent for hyperbilirubinemia. METHODS: The BO mutants I402G and C457S were obtained by site-directed mutagenesis and confirmed by amino acid sequence analysis. Ru-incorporated C457S mutant was obtained by direct incubation of ruthenium compounds with the mutant. The electron paramagnetic resonance (EPR) spectra of the recombinant BO and the mutants were investigated, and the enzyme kinetics of the recombinant BO and I402G mutant were measured with bilirubin as the substrate at 25 degrees C. RESULTS: The BO mutants were expressed and purified successfully. The mutant I402G showed low enzyme activity, and had C457S virtually no enzyme activity. Nevertheless Ru-incorporation conferred higher enzyme activity to C457S mutant. The enzyme kinetic investigations revealed that the kinetic parameter k(cat) of the recombinant BO and I402G mutant was 235.8 min(-1) and 6.9 min(-1), respectively, suggesting higher enzyme activity of the recombinant BO. CONCLUSIONS: The coordinating amino acids have important significance in maintaining the integrity of active centers and enzyme activities of recombinant BO and its mutants. The enzyme activities of the mutants I402G and C457S are much lower than those of recombinant BO, therefore they are not appropriate for diagnostic purpose. Ru-incorporation facilitates the formation of a new intact active center in C457S mutant, which therefore acquires enzyme activity.

Effects of stromal interacting molecule 1 gene silencing by short hairpin RNA on the biological behavior of human gastric cancer cells.

Gastric cancer is one of the most common types of cancer worldwide. It has been reported that stromal interacting molecule 1 (STIM1) is associated with tumor progression and metastatic spread, including in cervical cancer, breast carcinoma and prostatic cancer. The present study investigated whether STIM1, an endoplasmic reticulum Ca(2+) sensor and activator of store-operated channel entry, contributed to SGC7901 cell progression. The pGPU6-shSTIM1 recombinant plasmid was constructed, and the effects of downregulation of STIM1 on the proliferation, apoptosis, migration and invasion of SGC7901 cells were examined. Western blot analysis revealed that transfection with the pGPU6-shSTIM1 plasmid successfully inhibited the expression of STIM1. STIM1 silencing in the gastric cancer cells significantly inhibited cell proliferation by arresting the cell cycle at the G0/G1 phase, and increasing the apoptotic rate following treatment of the SGC7901 cells with pGPU6-shSTIM1, indicated using an MTT cell viability assay and flow cytometery, respectively. As expected, STIM1 knock down also reduced the migration and invasion of the SGC7901 cells, demonstrated using a Transwell assay. The possible molecular mechanism involved the regulation of several signaling pathways involved in the biological behavior of cell survival, apoptosis, migration and metastasis. Together, these finding suggested that the expression of STIM1 is crucial for the proliferation and invasion of SGC7901 cells, providing a foundation for the development of novel type­specific diagnostic strategies and treatments for gastric cancer.

Comparison of the predictive abilities of pharmacogenetics-based warfarin dosing algorithms using seven mathematical models in Chinese patients.

AIM: This study is aimed to find the best predictive model for warfarin stable dosage. MATERIALS & METHODS: Seven models, namely multiple linear regression (MLR), artificial neural network, regression tree, boosted regression tree, support vector regression, multivariate adaptive regression spines and random forest regression, as well as the genetic and clinical data of two Chinese samples were employed. RESULTS: The average predicted achievement ratio and mean absolute error of the algorithms were ranging from 52.31 to 58.08% and 4.25 to 4.84 mg/week in validation samples, respectively. The algorithm based on MLR showed the highest predicted achievement ratio and the lowest mean absolute error. CONCLUSION: At present, MLR may be still the best model for warfarin stable dosage prediction in Chinese population. Original submitted 10 November 2014; Revision submitted 18 February 2015.

Pharmacogenomics and herb-drug interactions: merge of future and tradition.

The worldwide using of herb products and the increasing potential herb-drug interaction issue has raised enthusiasm on discovering the underlying mechanisms. Previous review indicated that the interactions may be mediated by metabolism enzymes and transporters in pharmacokinetic pathways. On the other hand, an increasing number of studies found that genetic variations showed some influence on herb-drug interaction effects whereas these genetic factors did not draw much attention in history. We highlight that pharmacogenomics may involve the pharmacokinetic or pharmacodynamic pathways to affect herb-drug interaction. We are here to make an updated review focused on some common herb-drug interactions in association with genetic variations, with the aim to help safe use of herbal medicines in different individuals in the clinic.

Effect of NR3C2 genetic polymorphisms on the blood pressure response to enalapril treatment.

AIM: The mineralocorticoid receptor (MR; also known as NR3C2) plays important roles in the modulation of blood pressure. The effect of NR3C2 polymorphisms on antihypertensive response to enalapril was investigated. PATIENTS & METHODS: Two hundred and seventy nine essential hypertension patients treated with enalapril were genotyped for two NR3C2 tagSNPs, rs5522 and rs2070950, by Sequenom MassArray™ technology. RESULTS: The reductions in diastolic blood pressure (DBP) were significantly greater in AA homozygotes compared with AG+GG genotype carriers for the rs5522 polymorphism (p = 0.009), and the reductions in DBP were greater in GG homozygotes compared with GC+CC genotype carriers for the rs2070950 polymorphism, with marginal significance (p = 0.065). Stepwise multiple regression analysis indicated that significant predictors of DBP reduction were baseline DBP (p < 0.001), waist:hip ratio (p = 0.001) and rs5522 genotype (p = 0.003). CONCLUSION: NR3C2 rs5522 affects blood pressure response to enalapril treatment and may serve as a useful pharmacogenomic marker of antihypertensive response to enalapril in essential hypertension patients.