QT length during methadone maintenance treatment: gene × dose interaction

Methadone is known to be a risk factor for sudden death by enlarging ECG QT corrected (QTc) interval. For other medical conditions, QTc lengthening has been described as the result of interactions between pharmacological treatments and genetic factors. Former heroin‐dependent subjects under methadone maintenance treatment in remission for at last 3 months were recruited. We studied the association between QTc length (Bazett formula) and 126 SNPs located on five genes (KCNE1, KCNQ1, KCNH2, NOS1AP and SCN5A) previously associated with drug‐induced QT prolongation. Both SNP‐based and gene‐based approaches were used, and we tested also the interaction of the top SNP with methadone dosage to predict the QTc length. In our sample of 154 patients, current methadone daily dose was associated with QTc length (r_Pearson = 0.26; P = 10^?3). Only one SNP, rs11911509 on KCNE1, remained significantly associated with QT length after correction for multiple testing (P = 3.84 × 10^?4; p_corrected = 0.049). Using a gene‐based approach, KCNE1 was also significantly associated with QTc length (p_empirical = 0.02). We found a significant interaction between methadone dosage and rs11911509 minor allele count (allele A vs. C; P = 0.01). Stratified analysis revealed that the correlation between QTc length and methadone dosage was restricted only to AA carriers of this top SNP. Patients’ genetic background should be taken into account in the case of clinically relevant QT enlargement during methadone maintenance treatment.     

HLA‐DQB1*03 genotype and perioperative blood transfusion are not conducive to the prognosis of patients with gastric cancer

Background

Gastric cancer (GC) is a disease associated with a higher incidence and mortality, and some host genetic polymorphisms have been reported as potential factors contributing to the development of GC. In view of this, the study was conducted to investigate the effects of HLA‐DQB1 gene polymorphisms and perioperative blood transfusion on prognosis of patients with gastric cancer (GC).

Methods

A total of 142 patients with GC (case group) and 150 healthy controls (control group) were enrolled. Relationship between HLA‐DQB1 gene polymorphisms, perioperative blood transfusion, and clinical pathological parameters of patients with GC after operation was analyzed. Kaplan‐Meier curve was applied for analyzing survival rate of patients with GC, and Cox multivariate regression analysis for prognostic factors of patients with GC.

Results

The frequency of HLA‐DQB1*03 gene was increased in patients with GC. Patients with GC with HLA‐DQB1*03 genotype had higher number of tumor size >6 cm, deeper depth of infiltration, higher LNM rate, and later stage of disease. Patients with HLA‐DQB1*03 genotype had lower survival rate compared with other genotypes. Anemia before operation, depth of infiltration in T3 stage and T4 stage, LNM in N1 stage and N2 stage, and HLA‐DQB1*03 genotype were regarded as independent risk factors for patients with GC.

Conclusion

These results demonstrate that HLA‐DQB1*03 genotype and perioperative blood transfusion are not conducive to the prognosis of patients with GC, which could provide a reference for the treatment of GC.

     

A population analysis of the DGAT1 inhibitor GSK3008356 and its effect on endogenous and meal‐induced triglyceride turnover in healthy subjects

Non‐alcoholic steatohepatitis (NASH) is a liver disease in which fatty infiltration is accompanied by liver inflammation. GSK3008356 is under development as a selective inhibitor of diacylglycerol acyltransferase 1 (DGAT1), a key enzyme involved in the formation of triglyceride (TG). Decreased DGAT1 activity can reduce circulating TG and liver TG, and therefore could potentially prevent or treat NASH. The aim of the current study was to develop a population pharmacokinetic–pharmacodynamic (PKPD) model that characterizes the PK disposition of GSK3008356 and its relation to the changes in blood TG. Drug concentrations were measured in 104 healthy adults receiving various single (SD) and repeat doses (RD) in a first time in human (FiH) study. A 30% fat meal was given at hour 2 postdose, and blood postprandial TG concentrations were measured at various time points. The population PKPD model consists of several parts including a PK model, drug effect model, meal effect model, and a turnover model. The pharmacokinetic data were described using a 3‐compartment model. Drug effect was described by an inhibitory sigmoidal Emax model. Since TG levels change with the introduction of a meal, a bi‐exponential meal effect model was utilized. The total change in TG was fitted using a turnover model with drug and meal effects on the TG production rate. The current analysis presents a PKPD modeling strategy of time‐varying TG data coming from both endogenous and exogenous sources. In general, the presented model could be utilized in the model‐based drug development of drugs that influence TG levels in blood.     

Silencing of the DNA methyltransferase 1 associated protein 1 (DMAP1) gene in the invasive ladybird Harmonia axyridis implies a role of the DNA methyltransferase 1‐DMAP1 complex in female fecundity

The invasive harlequin ladybird Harmonia axyridis is a textbook example of polymorphism and polyphenism as the temperature during egg development determines the frequency of melanic morphs and the number and size of black spots in nonmelanic morphs. Recent concepts in evolutionary biology suggest that epigenetic mechanisms can translate environmental stimuli into heritable phenotypic changes. To investigate whether epigenetic mechanisms influence the penetrance and expressivity of colour morphs in H. axyridis, we used RNA interference to silence key enzymes required for DNA methylation and histone modification. We found that neither of these epigenetic mechanisms affected the frequency of different morphs, but there was a significant impact on life‐history traits such as longevity and fecundity. Strikingly, we found that silencing the gene encoding for DNA methyltransferase 1 associated protein 1 (DMAP1) severely reduced female fecundity, which correlated with an abundance of degenerated ovaries in DMAP1‐knockdown female beetles. Finally, we observed significant differences in DMAP1 expression when we compared native and invasive H. axyridis populations with a biocontrol strain differing in egg‐laying capacity, suggesting that the DNA methyltransferase 1‐DMAP1 complex may influence the invasive performance of this ladybird.