Increased prevalence of the null allele of the p.Arg577Ter variant in the ACTN3 gene in Brazilian long-distance athletes: A retrospective study.

INTRODUCTION: The phenotypic consequences of the p.Arg577Ter variant in the α-actinin-3 (ACTN3) gene are suggestive of a trade-off between performance traits for speed and endurance sports. Although there is a consistent association of the c.1729C allele (aka R allele) with strength/power traits, there is still a debate on whether the null allele (c.1729T allele; aka X allele) influences endurance performance. The present study aimed to test the association of the ACTN3 p.Arg577Ter variant with long-distance endurance athlete status, using previously published data with the Brazilian population. METHODS: Genotypic data from 203 long-distance athletes and 1724 controls were analysed in a case-control approach. RESULTS: The frequency of the X allele was significantly higher in long-distance athletes than in the control group (51.5% vs. 41.4%; p = 0.000095). The R/X and X/X genotypes were overrepresented in the athlete group. Individuals with the R/X genotype instead of the R/R genotype had a 1.6 increase in the odds of being a long-distance athlete (p = 0.012), whereas individuals with the X/X genotype instead of the R/R genotype had a 2.2 increase in the odds of being a long-distance athlete (p = 0.00017). CONCLUSION: The X allele, mainly the X/X genotype, was associated with long-distance athlete status in Brazilians.

Genetic polymorphisms associated with developmental defects of enamel: A systematic review.

BACKGROUND: Polymorphisms in genes related to enamel formation and mineralization may increase the risk of developmental defects of enamel (DDE). AIM: To evaluate the existing literature on genetic polymorphisms associated with DDE. DESIGN: This systematic review was registered in the PROSPERO (CRD42018115270). The literature search was performed in PubMed, Scopus, Web of Science, LILACS, BBO, Cochrane Library, and in the gray literature. Observational studies assessing the association between DDE and genetic polymorphism were included. The Newcastle-Ottawa Scale was used to assess the risk of bias. RESULTS: One thousand one hundred and forty-six articles were identified, and 28 met the inclusion criteria. Five studies presented a low risk of bias. Ninety-two genes related to enamel development, craniofacial patterning morphogenesis, immune response, and hormone transcription/reception were included. Molar-incisor hypomineralization (MIH) and/or hypomineralization of primary second molars (HPSM) were associated with 80 polymorphisms of genes responsible for enamel development, immune response, morphogenesis, and xenobiotic detoxication. A significant association was found between the different clinical manifestations of dental fluorosis (DF) with nine polymorphisms of genes responsible for enamel development, craniofacial development, hormonal transcription/reception, and oxidative stress. Hypoplasia was associated with polymorphisms located in intronic regions. CONCLUSION: MIH, HPSM, DF, and hypoplasia reported as having a complex etiology are significantly associated with genetic polymorphisms of several genes.

Investigating the role of killer cell immunoglobulin-like receptors and human leukocyte antigen genetic variants in hepatitis C virus infection.

The genetic diversity of killer cell immunoglobulin-like receptors (KIRs) and human leukocyte antigen (HLA) genes influences the host's immune response to viral pathogens. This study aims to explore the impact of five single nucleotide polymorphisms (SNPs) in KIR3DL2 and HLA-A genes on hepatitis C virus (HCV) infection. A total of 2251 individuals were included in the case-control study. SNPs including KIR3DL2 rs11672983, rs3745902, rs1654644, and HLA-A rs3869062, rs12202296 were genotyped. By controlling various confounding factors using a modified logistic regression model, as well as incorporating stratified analysis, joint effects analysis, and multidimensional bioinformatics analysis, we analyzed the relationship between SNPs and HCV infection. The logistic regression analysis showed a correlation between KIR3DL2 rs11672983 AA, KIR3DL2 rs3745902 TT, and increased HCV susceptibility (p < 0.01). Stratified analysis indicated that KIR3DL2 rs1654644 and HLA-A rs3869062 also heightened HCV susceptibility in certain subgroups. A linear trend of rising HCV infection rates was observed when combining KIR3DL2 rs11672983 AA and KIR3DL2 rs3745902 TT (ptrend = 0.007). Bioinformatics analysis suggested these SNPs' regulatory potential and their role in altering messenger RNA secondary structure, implying their functional relevance in HCV susceptibility. Our findings indicate that KIR3DL2 rs11672983 AA and KIR3DL2 rs3745902 TT are significantly associated with increased susceptibility to HCV infection.

The Role of Tissue Persistent Organic Pollutants and Genetic Polymorphisms in Patients with Benign and Malignant Kidney Tumors.

This study aimed to explore whether there is an association between environmental exposure to POPs and kidney tumor induction, and whether blood POP concentrations reflect kidney tissue concentrations. POP derivatives were determined in blood, tumor tissue, tumor surrounding tissue, and perirenal fat tissue samples taken from patients who underwent surgery for renal tumors. A voluntary control group was recruited for blood and urine samples as well. Urinary excretions of o,o'-dityrosine, chlorotyrosine, nitrotyrosine, and 8-OHdG were measured in the same patients. The possible role of genetic polymorphisms in CYP1A1, GST isozymes P, M, and T, and hOGG1 genes on the predisposition to renal cancer was investigated. Some POPs have been found to be associated with kidney cancer, as evidenced by their significantly high ORs. 8-OHdG levels were significantly higher compared to the control group. The GSTT1 null polymorphism can be a risk factor for malignant but not for benign kidney tumors.

Changes in the tissue elements of the gastric mucosa interacting with different strains of Helicobacter pylori, taking into consideration the patient's genotype.

The present study aimed to investigate the peculiarities of adaptation of tissue elements of the gastric mucosa during interaction with Helicobacter pylori, as determined by genetic characteristics of the bacterium and the host. Venous blood and biopsy samples of the mucosa of the antrum and body of the stomach from young patients (18 to 25 years old) were examined. The condition of the gastric mucosa was assessed using stained histological preparations. Venous blood was collected from the patients to ascertain the polymorphisms of the IL-lß and IL-IRN genes. The most pronounced changes were observed in the parameters of reparative regeneration of epithelial differentiation during colonization of the gastric mucosa by H. pylori strains carrying the CagA(+) and BabA2(+) genes. These included an increase in proliferation and apoptosis rates and alterations in epithelial differentiation markers characterized by elevated production of Shh and MUC5AC, as well as a reduction in the production of the protective mucin MUC6 by isthmus gland cells. The presence of the vacAs1 and vacAs2 genes of H. pylori results in a high level of apoptosis in epithelial cells without accelerating proliferation. It was found that after eradication, patients with preserved cellular infiltrates in their gastric mucosa plates were carriers of mainly the IL-1ß*T/IL-1RN*2R haplotypes after 12 months.

The Frequencies distribution of CYP3A5 rs776746 and ABCB1 rs1045642 polymorphisms in the west Algerian population and relationships with pharmacogenetics.

Introduction: Pharmacogenetic markers, such as the ATP Binding Cassette (ABCB1) and cytochrome P450 (CYP) 3A5 enzymes, play a crucial role in personalized medicine by influencing drug efficacy and toxicity based on individuals' or populations' genetic variations.This study aims to investigate the genetic polymorphisms of CYP3A5 (rs776746) and ABCB1 (rs1045642) in the West Algerian population and compare the genotypes and allelic distributions with those of various ethnic groups. Methods: The study involved 472 unrelated healthy subjects from the Western Algerian population. DNA genotyping was performed using TaqMan allelic discrimination assay. The variants in our population were compared to those in other ethnic groups available in the 1000 Genomes Project. Genotype and allele frequencies were calculated using the chi-square test and the Hardy-Weinberg equilibrium (HWE). Results: The minor allele frequencies were found to be 0.21 for CYP3A5 6986A and 0.34 for ABCB1 3435T. These frequencies were similar to those observed in North African populations, while notable differences were observed in comparison to certain Caucasian and African populations. Conclusion: The difference in the allelic and genotypic distribution of these polymorphisms emphasize the need for dose adjustments in drugs metabolized by CYP3A5 and transported by ABCB1 to optimize treatments outcomes.

Analysis of human papillomavirus type 16 E4, E5 and L2 gene variations among women with cervical infection in Xinjiang, China.

BACKGROUND: There is a high incidence of cervical cancer in Xinjiang. Genetic variation in human papillomavirus may increase its ability to invade, spread, and escape host immune response. METHODS: HPV16 genome was sequenced for 90 positive samples of HPV16 infection. Sequences of the E4, E5 and L2 genes were analysed to reveal sequence variation of HPV16 in Xinjiang and the distribution of variation among the positive samples of HPV16 infection. RESULTS: Eighty-one of the 90 samples of HPV16 infection showed variation in HPV16 E4 gene with 18 nucleotide variation sites, of which 8 sites were synonymous variations and 11 missense variations. 90 samples of HPV16 infection showed variation in HPV16 E5 and L2 genes with 16 nucleotide variation sites (6 synonymous, 11 missense variations) in the E5 gene and 100 nucleotide variation sites in L2 gene (37 synonymous, 67 missense variations). The frequency of HPV16 L2 gene missense variations G3377A, G3599A, G3703A, and G3757A was higher in the case groups than in the control groups. CONCLUSIONS: Phylogenetic tree analysis showed that 87 samples were European strains, 3 cases were Asian strains, there were no other variations, and G4181A was related to Asian strains. HPV16 L2 gene missense variations G3377A, G3599A, G3703A, and G3757A were significantly more frequent in the case groups than in the control groups.

Genetic diversity of the PvMSP-3α gene in Plasmodium vivax isolates circulating in the National Capital Region (NCR) of India.

Malaria is still a public health problem in tropical countries like India; major malaria parasite species are Plasmodium falciparum and P. vivax. Of which, P. vivax is responsible for ∼40% of the malaria burden at least in the Indian scenario. Unfortunately, there is limited data on the population structure and genetic diversity of P. vivax parasites in India. In this study, we investigated the genetic diversity of P. vivax strains in the South-west district, Delhi and, Nuh district, Haryana [National Capital Region (NCR)], using a polymorphic marker- P. vivax merozoite surface protein-3α (PvMSP-3α) gene. Dried blood spots from microscopically confirmed P. vivax patients were used for investigation of the PvMSP-3α gene. PCR-RFLP was performed on the PvMSP-3α gene to investigate the genotypes and allelic variability with HhaI and AluI restriction enzymes. In total, 40 successfully PCR amplified PvMSP-3α gene segments were subjected to RFLP analysis. Amplified products showed three different base pair size variations viz. genotype A in 31(77.5%), genotype B in 4(10%) and genotype C in 5(12.5%) P. vivax specimens. RFLP with HhaI and AluI revealed 17 (H1-H17) and 25 (A1-A25) allelic variants, respectively. Interestingly, two similar sub-allelic variants, ie. H8 (with HhaI), and A4 (with AluI) clustered within the rural area of Nuh district, Haryana in two samples. With this study, we propose to commission such type of genetic diversity analysis of P. vivax to investigate the circulating genotypes of the parasites from distinct geographical locations across India, that can have significant implications in understanding the population structures of P. vivax.

The GSTP1 rs1695 Polymorphism Is Associated with Mercury Levels and Neurodevelopmental Delay in Indigenous Munduruku Children from the Brazilian Amazon.

Genetic polymorphisms may influence mercury (Hg) toxicity. The aims of this study were to evaluate individual factors, such as the presence of the GSTP1 rs1695 polymorphism, associated with internal Hg dose and child neurodevelopment in indigenous people from the Brazilian Amazon chronically exposed to Hg. Eighty-two indigenous children were clinically evaluated, hair Hg was measured, and the GSTP1 rs1695 polymorphism was genotyped. The mean age was 4.8 years, the median Hg was 5.5 µg/g, and 93.8% of children exceeded the safe limit (2.0 µg/g). Fish consumption was associated with Hg levels (p = 0.03). The GSTP1 rs1695 A>G polymorphism was in the Hardy-Weinberg equilibrium and the highest prevalence of the GSTP1 AA genotype (80%) was found in Sawré Aboy, which had the highest Hg levels (10 µg/g) among the studied villages. The Hg levels tended to increase over the years in males and in carriers of the GSTP1 AA genotype (0.69 µg/g and 0.86 µg/g, respectively). Nine children failed the neurodevelopmental test, all of whom had Hg > 2.0 µg/g, and 88.9% carried the GSTP1 AA or AG genotypes, previously associated with the highest internal Hg doses and neurocognitive disorders. The genetic counseling of this population is important to identify the individuals at greater risk for neurodevelopmental disorders resulting from chronic Hg exposure.

Association of Interleukin-6 (rs1800795) and Interleukin-10 (rs1800896) Genetic Polymorphisms with the Outcome of COVID-19 Infection: A Single Center Study.

The corona virus disease-2019 (COVID-19) pandemic has affected most of the world with varying degrees of morbidity and mortality. The presence of genetic polymorphisms may be associated with the severity and outcome of COVID-19 infection. This work aimed to evaluate the genetic polymorphisms of interleukin (IL-6) and IL-10 genes with the outcome of COVID-19 infection. This cross-sectional study was conducted on 354 patients who were classified into moderate and severe cases (including alive and deceased cases). All individuals were genotyped for one SNP for IL-6 (rs1800795) and one SNP for IL10 (rs1800896) using allelic discrimination real-time PCR technique. In this study, 198 cases were moderate, and 156 cases were severe. The risk of allele carriage of the minor allele of IL-6 rs1800795 (C) was significantly higher among the severe group when compared with that of the moderate group (p < 0.0001), while there was a mild significant difference of same allele carriage among alive cases when compared to that of deceased one (p < 0.04). Furthermore, the risk of the C allele of IL-10 rs1800896 was significantly increased in severe cases when compared with the moderate group (p < 0.0001), while there was no significant difference of the risk of the C allele in deceased cases when compared with that of alive ones (p > 0.05). In conclusion, the C allele (rs1800795) of IL-6 and the C allele (rs1800896) of IL-10 were highly significant in severe cases than in moderate cases. The C allele carriage of IL-6 showed only a significant difference between alive and deceased patients and not with the C allele of IL-10.

Fatty acid desaturase insertion-deletion polymorphism rs66698963 predicts colorectal polyp prevention by the n-3 fatty acid eicosapentaenoic acid: a secondary analysis of the seAFOod polyp prevention trial.

BACKGROUND: A fatty acid desaturase (FADS) insertion-deletion (Indel) polymorphism (rs66698963) influences the expression of FADS1, which controls the synthesis of n-6 highly unsaturated fatty acid (HUFA) arachidonic acid (AA). The anti-inflammatory activity of the n-3 HUFA eicosapentaenoic acid (EPA) may be explained by competition with AA for proinflammatory lipid mediator synthesis. A precision medicine approach based on stratification by FADS Indel genotype could identify individuals, who benefit from greatest disease risk reduction by n-3 HUFAs. OBJECTIVES: We tested the hypothesis that the FADS insertion (I) allele predicts colorectal polyp risk reduction in a secondary analysis of the randomized, placebo-controlled, 2×2 factorial seAFOod polyp prevention trial of EPA 2000 mg daily and aspirin 300 mg daily for 12 mo (ISRCTN05926847). METHODS: Participant Indel genotype was determined by polymerase chain reaction (PCR) blind to trial outcomes. Colorectal polyp outcomes were included in negative binomial (polyp number) and logistic (polyp detection rate [PDR; percentage with one or more polyps]) regression models comparing each active intervention with its placebo. Presence of ≥1 Indel I allele and an interaction term (I allele × active intervention) were covariates. RESULTS: In 528 participants with colonoscopy and FADS Indel data, EPA use irrespective of Indel genotype, was not associated with reduced colorectal polyp number (incidence rate ratio [IRR]: 0.92; 95% confidence interval: 0.74, 1.16), mirroring original seAFOod trial analysis. However, the presence of ≥1 I allele identified EPA users with a significant reduction in colorectal polyp number (IRR: 0.50 [0.28, 0.90]), unlike aspirin, for which there was no interaction. Similar findings were obtained for the PDR. CONCLUSIONS: The FADS Indel I allele identified individuals, who displayed colorectal polyp prevention by EPA with a similar effect size to aspirin. Assessment of rs66698963 as a biomarker of therapeutic response to n-3 HUFAs in other populations and healthcare settings is warranted. The seAFOod polyp prevention trial and STOP-ADENOMA study were registered at International Standard Randomised Controlled Trial Number registry as ISRCTN05926847.

Polymorphic Loci of Xenobiotic Biotransformation Genes in Accumulated Mercury Pollution Liquidators and in Workers with Chronic Mercury Vapors Exposure.

The allele and genotype frequencies of the polymorphic loci CYP1A1 (rs1048943), GSTP1 (rs1695 and rs1138272), GSTM1, and GSTT1 genes were studied in 517 men: in 389 accumulated mercury pollution liquidators (207 firefighters of the Ministry of the Russian Federation for Civil Defence, Emergencies and Elimination of Consequences of Natural Disasters and 182 employees of the Federal Environmental Operator) and 128 former workers (82 patients in the delayed period of chronic mercury intoxication and 46 individuals contacted with mercury and had no chronic mercury intoxication). We found differences in the frequencies of AA and AG genotypes in groups of former workers (χ2=6.96, p=0.008) for the polymorphic locus rs1048943, while the AG-CYP1A1 genotype was characterized by a 5.5-fold decrease in the odds ratio for the development of chronic mercury intoxication (OR=0.18, p=0.0041). An unfavorable combination of genotypes of the studied polymorphic loci increases the risk of undesirable health effects.

Tacrolimus Personalized Therapy based on CYP3A5 Genotype in Chinese Patients with Idiopathic Inflammatory Myopathies.

OBJECTIVE: Idiopathic inflammatory myopathies (IIM) are a heterogeneous and life-threatening group of diseases, especially anti-melanoma differentiation-associated gene 5 antibody positive dermatomyositis (MDA5+ DM) is reportedly strongly associated with high mortality rate. Tacrolimus (TAC) provides an excellent therapeutic option, but the trough concentration (Cmin) -outcome relationship remains unexplored. This study was undertaken to identify optimal Cmin and individualized dose based on CYP3A5 genotype for IIM patients. METHODS: 134 IIM patients with 467 Cmin were enrolled. We examined the relationship between TAC Cmin and relapses. The receiver operating characteristic analysis was used to confirm the optimal Cmin. Analyses of factors influencing Cmin were conducted. The dose requirement based on CYP3A5 genotype was confirmed. RESULTS: TAC Cmin is strongly associated with relapses. The optimal cutoff values were 5.30, 5.85, 4.85 and 5.35 ng/ml for acute, subacute, chronic and all phase IIM patients (p = 0.001, 0.013, 0.002, and < 0.001, respectively), as well as 5.35, 5.85, 5.55 and 5.85 ng/ml for acute, subacute, chronic and all phase MDA5+ DM patients (p = 0.007, 0.001, 0.036, and < 0.001, respectively). CYP3A5 genotype was one of the significant factors influencing TAC Cmin. CYP3A5 expressers required 0.059 mg/kg/d to attain the target Cmin, while nonexpressers required 0.046 mg/kg/d (p = 0.019). CONCLUSION: TAC treatment may elicit favorable outcome in patients with IIM and MDA5+ DM when Cmin exceeded 5.35 and 5.85 ng/ml, which is crucial to lower relapse rate. The individualized dose based on the CYP3A5 genotype provides a reference for TAC personalized therapy in IIM.

Intergenic risk variant rs56258221 skews the fate of naive CD4+ T cells via miR4464-BACH2 interplay in primary sclerosing cholangitis.

Primary sclerosing cholangitis (PSC) is an immune-mediated liver disease of unknown pathogenesis, with a high risk to develop cirrhosis and malignancies. Functional dysregulation of T cells and association with genetic polymorphisms in T cell-related genes were previously reported for PSC. Here, we genotyped a representative PSC cohort for several disease-associated risk loci and identified rs56258221 (BACH2/MIR4464) to correlate with not only the peripheral blood T cell immunophenotype but also the functional capacities of naive CD4+ T (CD4+ TN) cells in people with PSC. Mechanistically, rs56258221 leads to an increased expression of miR4464, in turn causing attenuated translation of BACH2, a major gatekeeper of T cell quiescence. Thereby, the fate of CD4+ TN is skewed toward polarization into pro-inflammatory subsets. Clinically, people with PSC carrying rs56258221 show signs of accelerated disease progression. The data presented here highlight the importance of assigning functional outcomes to disease-associated genetic polymorphisms as potential drivers of diseases.

The First Genetic Characterization of the SPRN Gene in Pekin Ducks (Anas platyrhynchos domesticus).

Prion diseases are fatal neurodegenerative disorders characterized by an accumulation of misfolded prion protein (PrPSc) in brain tissues. The shadow of prion protein (Sho) encoded by the shadow of prion protein gene (SPRN) is involved in prion disease progress. The interaction between Sho and PrP accelerates the PrPSc conversion rate while the SPRN gene polymorphisms have been associated with prion disease susceptibility in several species. Until now, the SPRN gene has not been investigated in ducks. We identified the duck SPRN gene sequence and investigated the genetic polymorphisms of 184 Pekin ducks. We compared the duck SPRN nucleotide sequence and the duck Sho protein amino acid sequence with those of several other species. Finally, we predicted the duck Sho protein structure and the effects of non-synonymous single nucleotide polymorphisms (SNPs) using computational programs. We were the first to report the Pekin duck SPRN gene sequence. The duck Sho protein sequence showed 100% identity compared with the chicken Sho protein sequence. We found 27 novel SNPs in the duck SPRN gene. Four amino acid substitutions were predicted to affect the hydrogen bond distribution in the duck Sho protein structure. Although MutPred2 and SNPs&GO predicted that all non-synonymous polymorphisms were neutral or benign, SIFT predicted that four variants, A22T, G49D, A68T, and M105I, were deleterious. To the best of our knowledge, this is the first report about the genetic and structural characteristics of the duck SPRN gene.

Gene detection of VDR BsmI locus and its approteins, genes and growthplication in rational drug use in patients with osteoporosis.

Aim: This paper determines the polymorphism distribution of the VDR BsmI gene in 350 patients and provides medication recommendations for osteoporosis based on detection results. Materials & methods: Chi-square tests compared genotype and allele frequencies with other populations. Results: Genotype frequencies were 91.66 bb, 8.72 Bb and 0.21% BB, with allelic frequencies of 95.43 b and 4.57% B, adhering to Hardy-Weinberg equilibrium. These findings suggest that VDR gene polymorphisms, particularly at the BsmIlocus, play an essential role in bone health and osteoporosis treatment. Genotype-based drug selection reduced adverse reactions from 14 to two cases. Conclusion: These findings improve clinical treatment efficacy and guide rational drug use for osteoporosis patients.

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Inflammation and endothelial function relevant genetic polymorphisms, carotid atherosclerosis, and vascular events in high-risk stroke population.

Aim: To identify the associations of 19 single nucleotide polymorphisms (SNPs) in genes involved in inflammation and endothelial function and carotid atherosclerosis with subsequent ischemic stroke and other vascular events in the high-risk stroke population. Methods: This was a multicenter community-based sectional survey and prospective cohort study in Sichuan, southwestern China. Eight communities were randomly selected, and the residents in each community were surveyed using a structured face-to-face questionnaire. Carotid ultrasonography and DNA information were obtained from 2,377 out of 2,893 individuals belonging to a high-risk stroke population. Genotypes of the 19 SNPs in genes involved in inflammation and endothelial function were measured. All the 2,377 subjects were followed up for 4.7 years after the face-to-face survey. The primary outcome was ischemic stroke, and the secondary outcome was a composite of vascular events. Results: Among the 2,377 subjects, 2,205 (92.8%) completed a 4.7-year follow-up, 947 (42.9%) had carotid atherosclerosis [372 (16.9%) carotid vulnerable plaque, 405 (18.4%) mean IMT > 0.9 mm, 285 (12.0%) carotid stenosis ≥15%]. Outcomes occurred in 158 (7.2%) subjects [92 (4.2%) ischemic stroke, 17 (0.8%) hemorrhagic stroke, 48 (2.2%) myocardial infarction, and 26 (1.2%) death] during follow-up. There was a significant gene-gene interaction among ITGA2 rs1991013, IL1A rs1609682, and HABP2 rs7923349 in the 19 SNPs. The multivariate logistic regression model revealed that carotid atherosclerosis and the high-risk interactive genotypes among the three SNPs were independent with a higher risk for ischemic stroke (OR = 2.67, 95% CI: 1.52-6.78, p = 0.004; and OR = 3.11, 95% CI: 2.12-9.27, p < 0.001, respectively) and composite vascular events (OR = 3.04, 95% CI: 1.46-6.35, p < 0.001; and OR = 3.23, 95% CI: 1.97-8.52, p < 0.001, respectively). Conclusion: The prevalence of carotid atherosclerosis was shown to be very high in the high-risk stroke population. Specific SNPs, interactions among them, and carotid atherosclerosis were independently associated with a higher risk of ischemic stroke and other vascular events.

Association of UGT1A6 gene polymorphisms with sodium valproate-induced tremor in patients with epilepsy.

BACKGROUND: Individual susceptibility to sodium valproate (VPA)-induced tremors may be due to genetic polymorphisms in the gene encoding the uridine diphosphate glucuronosyltransferase (UGT) enzyme, which affec the drug's clinical efficacy and cause toxic side effects. This study aimed to investigate the association between UGT1A6 polymorphisms and VPA-induced tremors in patients with epilepsy. METHODS: In total, 128 patients with epilepsy were enrolled. Patients with epilepsy who received VPA were divided into tremor and non-tremor groups. Polymerase chain reaction-restriction fragment length polymorphism was used to investigate the genotype of UGT1A6 polymorphisms. RESULTS: Carriers of the UGT1A6 A541G mutant genotype conferred a higher risk of tremor than wild-type carriers (odds ratio 2.128, P = 0.045). Logistic regression analysis showed that the A541G mutant genotype was a significant genetic risk factor for VPA-induced tremors. This suggests that individual susceptibility to VPA-induced tremors may result, at least partially, from genetic variation in UGT1A6 A541G. CONCLUSIONS: Patients with epilepsy carrying the UGT1A6 A541G mutant genotype may have VPA-induced tremors, and early detection of this genotype will help guide the clinical individualizsation of VPA treatment.

Association of KLF14 rs4731702 gene polymorphism with metabolic phenotype in young patients with type 1 diabetes.

AIM: To explore the potential association between the KLF14 rs4731702 polymorphism and metabolic syndrome traits among patients diagnosed with type 1 diabetes (T1D). METHODS: The study group included 350 patients with T1D and 250 healthy control subjects. The analysis focused on the genotyping of KLF14 rs4731702 single nucleotide polymorphism (SNP), as well as evaluating serum concentrations of inflammatory markers, blood pressure, lipid profiles, and the quantitative status of CD4 + CD25highFOXP3+ T cells. RESULTS: Patients with T1D carrying the T allele of KLF14 rs4731702 SNP had higher high-density lipoprotein cholesterol, lower low-density lipoprotein cholesterol, as well as lower glycated haemoglobin and serum concentration of proinflammatory markers than C allele carriers. They also developed hypertension less often than carriers of the C allele. The analysis of CD4 + CD25highFOXP3+ regulatory T-cell status based on KLF14 genotype showed that, in T1D patients, those with the TT genotype had the highest frequency of these cells compared to carriers of the CC and CT genotypes. CONCLUSION: Our study suggests that the T allele of the KLF14 rs4731702 SNP might confer a protective effect against the development of obesity, hypertension, dyslipidaemia, and chronic inflammatory state in patients diagnosed with T1D.

The impact of CYP3A4 genetic polymorphism on crizotinib metabolism and drug-drug interactions.

To elucidate the impact of CYP3A4 activity inhibition and genetic polymorphism on the metabolism of crizotinib. Enzymatic incubation systems for crizotinib were established, and Sprague-Dawley rats were utilized for in vivo experiments. Analytes were quantified using LC-MS/MS. Upon screening 122 drugs and natural compounds, proanthocyanidins emerged as inhibitor of crizotinib metabolism, exhibiting a relative inhibition rate of 93.7%. The IC50 values were 24.53 ± 0.32 µM in rat liver microsomes and 18.24 ± 0.12 µM in human liver microsomes. In vivo studies revealed that proanthocyanidins markedly affected the pharmacokinetic parameters of crizotinib. Co-administration led to a significant reduction in the AUC(0-t), Cmax of PF-06260182 (the primary metabolite of crizotinib), and the urinary metabolic ratio. This interaction is attributed to the mixed-type inhibition of liver microsome activity by proanthocyanidins. CYP3A4, being the principal metabolic enzyme for crizotinib, has its genetic polymorphisms significantly influencing crizotinib's pharmacokinetics. Kinetic data showed that the relative metabolic rates of crizotinib across 26 CYP3A4 variants ranged from 13.14% (CYP3A4.12, 13) to 188.57% (CYP3A4.33) when compared to the wild-type CYP3A4.1. Additionally, the inhibitory effects of proanthocyanidins varied between CYP3A4.12 and CYP3A4.33, when compared to the wild type. Our findings indicate that proanthocyanidins coadministration and CYP3A4 genetic polymorphism can significantly influence crizotinib metabolism.