Associations between Serum Betaine, Methyl-Metabolizing Genetic Polymorphisms and Risk of Incident Type 2 Diabetes: A Prospective Cohort Study in Community-Dwelling Chinese Adults

Previous studies have explored associations between betaine and diabetes, but few have considered the effects of genes on them. We aimed to examine associations between serum betaine, methyl-metabolizing genetic polymorphisms and the risk of type 2 diabetes in Chinese adults. This prospective study comprised 1565 subjects aged 40–75 without type 2 diabetes at baseline. Serum betaine was measured by high-performance liquid chromatography tandem mass spectrometry. Genotyping of methyl-metabolizing genes was detected by Illumina ASA-750K arrays. Cox proportional hazards model was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). During a median of 8.9 years of follow-up, 213 participants developed type 2 diabetes. Compared with participants in the lowest quartile of serum betaine, those in the highest quartile had lower risk of type 2 diabetes, adjusted HRs (95%CIs) was 0.46 (0.31, 0.69). For methylenetetrahydrofolate reductase (MTHFR) G1793A (rs2274976) and MTHFR A1298C (rs1801131), participants carrying 1793GA + AA and 1298AC + CC had lower risk of type 2 diabetes. Interactions of serum betaine and genotype of MTHFR G1793A and MTHFR A1298C could be found influencing type 2 diabetes risk. Our findings indicate that higher serum betaine, mutations of MTHFR G1793A and A1298C, as well as the joint effects of them, are associated with lower risk of type 2 diabetes.

Effects of Host Genetic Polymorphisms on the Efficacy of the Radical Cure Malaria Drug Primaquine

Malaria is a major cause of death in low-income countries. Malaria relapses are caused by Plasmodium vivax–induced latent liver stage hypnozoites, and relapses contribute significantly to the total disease burden. The goal of malaria elimination is threatened in countries where P. vivax is endemic and relapses remain a key aspect of concern. Targeting of the hypnozoites is crucial for radical cure and this is achieved by primaquine (PQ). In addition to its anti-hypnozoite effects, PQ also possesses gametocidal activity against all malaria causing Plasmodium species and is hence a useful tool to curtail malaria transmission. It is well known that host glucose-6-phosphate dehydrogenase (G6PD) deficiency is associated with hemolysis after treatment with PQ. Multiple other host polymorphisms impact on PQ metabolism, potentially affecting drug efficacy. Being a prodrug, PQ requires host factors cytochrome P450 2D6 (CYP2D6), cytochrome P450 NADPH: oxidoreductase (CPR) and monoamine oxidase (MAO) for its metabolism and conversion to active form. The efficacy of PQ in the host is therefore dependent on genetic polymorphisms of these three host genes. The efficacy of PQ is important for clearing reservoirs of P. vivax infection. Here, we have analyzed the known spectrum of genetic polymorphisms for host genes that enable PQ metabolism. It is vital to delineate the polymorphisms that determine the ultimate efficacy of PQ for formulating better malaria elimination strategies in countries with severe malaria burden. Thus population-based studies of these gene variants will provide new insights into the role of host genetics on PQ treatment outcomes.

Influence of calcineurin inhibitors and genetic polymorphism of transporters on enterohepatic circulation and exposure of mycophenolic acid in Chinese adult renal allograft recipients

Aim: Study the influence of calcineurin inhibitors (CNI) and genetic polymorphisms of transporters on enterohepatic circulation (EHC) of mycophenolic acid (MPA) in Chinese adult renal allograft recipients and estimate the effect of various covariates on prediction performance of MPA AUC0-12h. Method: MPA concentrations of 125 Chinese patients were collected 0-12 hours after administration. Genotypes of transporters were determined in 64 patients. The influence of type of CNI and genetic polymorphisms on MPA exposure was studied. Shapley additive explanations method was used to study the impact of sampling times and covariates related to EHC on AUC0-12h. Extreme gradient boosting (XGboost) machine learning-based model was established to predict AUC0-12h. Results: Dn-AUC6-12h was significantly lower in patients co-administered with CsA (P<0.05). When co-administered with TAC, for SLCO1B1 T521C or ABCC C-24T, patients with wild-type genotype had significantly higher dn-AUC6-12h (P <0.05). Patients with SLCO1B3 334T/699G alleles had significantly lower dn-AUC6-12h than homozygotes (P=0.004). No significant difference was found in CsA subgroup. For estimating AUC0-12h, C0h, C2h, C8h, type of CNI, transporters genotypes and the difference between C0h and C2h were retained in the final model, which had good prediction performance (r2=0.9739). Conclusion: Patients co-administered with CsA had lower MPA EHC than those who received TAC. MPA EHC is affected by ABCC2 C-24T, SLCO1B3 T334G/G699A, and SLCO1B1 T521C genotypes in patients treated with TAC. Type of CNI and genetic polymorphisms of transporters can improve prediction performance of MPA AUC0-12h estimating model, developed using XGboost machine learning method.

Genetic Regulatory Networks of Apolipoproteins and Associated Medical Risks

Apolipoproteins (APO proteins) are the lipoprotein family proteins that play key roles in transporting lipoproteins all over the body. There are nearly more than twenty members reported in the APO protein family, among which the A, B, C, E, and L play major roles in contributing genetic risks to several disorders. Among these genetic risks, the single nucleotide polymorphisms (SNPs), involving the variation of single nucleotide base pairs, and their contributing polymorphisms play crucial roles in the apolipoprotein family and its concordant disease heterogeneity that have predominantly recurred through the years. In this review, we have contributed a handful of information on such genetic polymorphisms that include APOE, ApoA1/B ratio, and A1/C3/A4/A5 gene cluster-based population genetic studies carried throughout the world, to elaborately discuss the effects of various genetic polymorphisms in imparting various medical conditions, such as obesity, cardiovascular, stroke, Alzheimer's disease, diabetes, vascular complications, and other associated risks.

Association of ZFHX3 Genetic Polymorphisms and Extra-Pulmonary Vein Triggers in Patients With Atrial Fibrillation Who Underwent Catheter Ablation

Background: The ZFHX3 gene (16q22) is the second most highly associated gene with atrial fibrillation (AF) and is related to inflammation and fibrosis. We hypothesized that ZFHX3 is associated with extra-pulmonary vein (PV) triggers, left atrial (LA) structural remodeling, and poor rhythm outcomes of AF catheter ablation (AFCA).Methods: We included 1,782 patients who underwent a de novo AFCA (73.5% male, 59.4 ± 10.8 years old, 65.9% paroxysmal AF) and genome-wide association study and divided them into discovery (n = 891) and replication cohorts (n = 891). All included patients underwent isoproterenol provocation tests and LA voltage mapping. We analyzed the ZFHX3, extra-PV trigger-related factors, and rhythm outcomes.Result: Among 14 single-nucleotide polymorphisms (SNPs) of ZFHX3, rs13336412, rs61208973, rs2106259, rs12927436, and rs1858801 were associated with extra-PV triggers. In the overall patient group, extra-PV triggers were independently associated with the ZFHX3 polygenic risk score (PRS) (OR 1.65 [1.22–2.22], p = 0.001, model 1) and a low LA voltage (OR 0.74 [0.56–0.97], p = 0.029, model 2). During 49.9 ± 40.3 months of follow-up, clinical recurrence of AF was significantly higher in patients with extra-PV triggers (Log-rank p &lt; 0.001, HR 1.89 [1.49–2.39], p &lt; 0.001, model 1), large LA dimensions (Log-rank p &lt; 0.001, HR 1.03 [1.01–1.05], p = 0.002, model 2), and low LA voltages (Log-rank p &lt; 0.001, HR 0.73 [0.61–0.86], p &lt; 0.001, model 2) but not the ZFHX3 PRS (Log-rank p = 0.819).Conclusion: The extra-PV triggers had significant associations with both ZFHX3 genetic polymorphisms and acquired LA remodeling. Although extra-PV triggers were an independent predictor of AF recurrence after AFCA, the studied AF risk SNPs intronic in ZFHX3 were not associated with AF recurrence.