Polymorphic Enzyme Research Articles

Genetic variants and clinical factors affecting the response to 5-fluorouracil–based treatment in Chilean patients with advanced colorectal cancer.

114 Background: Colorectal cancer (CRC) ranks as the second most common cancer in Chile, affecting both men and women. Late diagnosis results in approximately 25% of patients presenting with metastatic disease, with a five-year survival rate of about 14%. Standard treatment includes tumor resection followed by adjuvant chemotherapy, commonly involving 5-fluorouracil (5-FU) combined with drugs like oxaliplatin or irinotecan. However, patient responses to 5-FU vary greatly due to genetic polymorphisms in enzymes like thymidylate synthase (TYMS) and dihydropyrimidine dehydrogenase (DPD), which affect the drug's pharmacokinetics and pharmacodynamics. Polymorphisms in genes related to oxaliplatin elimination and efficacy, such as glutathione-S-transferases (GSTs) and DNA repair enzymes, also play a role. However, the relationship between genetic variants and treatment outcomes remains unclear, often varying by population and cancer stage. Although predictive models for treatment response and risk exist for various diseases, no comprehensive model combining genetic and clinical variables to predict chemotherapy safety in Chilean CRC patients has been developed. Objective: This study aimed to identify relevant genetic variants in the genes TYMS , TYMP , DPYD , GSTP1 , MTHFR , ERCC2 , ABCB1 , ABCC2 , ABCC4 , and ABCG2 , which, along with clinical variables, could help create a predictive model for the safety of 5-FU-based chemotherapy in advanced CRC patients. Methods: A retrospective nested case-control study was conducted on 82 advanced CRC patients. Sixteen genetic variants were analyzed to assess their influence on adverse reactions (ADRs) and their severity, using logistic regression to identify potential associations. Multivariate models were developed to predict chemotherapy safety. Results: Among the 16 variants analyzed in 82 patients, several key findings emerged: The G allele of GSTP1 (rs1695) was found to be protective against neuropathy (OR = 0.147; p = 0.012) but increased the risk of mucositis (OR = 2.27; p = 0.036). The C allele of DPYD (rs1801265) was associated with an elevated risk of neuropathy (OR = 4.50; p = 0.05). The TYMS deletion (rs151264360) provided protection against cutaneous (OR = 0.029; p < 0.0001) and hematological ADRs (OR = 0.098; p = 0.005). Additionally, TYMS deletion was protective against severe toxic ADRs (OR = 0.098; p = 0.005). Two multivariate models were created to predict anemia (p = 0.027) and pain (p = 0.01) development. Conclusions: This study represents an initial step toward developing predictive models for ADRs related to 5-FU, such as neuropathy, mucositis, and hematological and skin toxicities. In the future, these findings may contribute to pharmacogenetic-based dose adjustment models aimed at reducing ADRs in Chilean CRC patients undergoing 5-FU-based treatment.

Model-Informed Recommendation of Mavacamten Posology for Chinese Adults With Obstructive Hypertrophic Cardiomyopathy.

Mavacamten is a cardiac myosin inhibitor for adults with obstructive hypertrophic cardiomyopathy (HCM). Dose optimization is performed 4 weeks after starting mavacamten, guided by periodic echo measurements of Valsalva left ventricular outflow tract gradient (VLVOTg) and left ventricular ejection fraction (LVEF). Previously, a population pharmacokinetic (PPK) model was developed and exposure-response (E-R) of VLVOTg (efficacy) and LVEF (safety) was used to identify the mavacamten titration regimen with the optimal benefit/risk ratio, now included in the US prescribing information. Mavacamten is metabolized primarily by cytochrome P450 2C19 (CYP2C19) (74%), a highly polymorphic enzyme. China has a higher prevalence of poor CYP2C19 metabolizer phenotype compared with the global population; therefore, a previous model was adapted to include Chinese patients with obstructive HCM to identify the optimal dosing regimen for this population. Data from a phase I (healthy Chinese volunteers) and a phase III (EXPLORER-CN, NCT05174416; Chinese patients with obstructive HCM) trial of mavacamten were added to the previous PPK and E-R models, and the observed VLVOTg and LVEF from EXPLORER-CN were successfully simulated. Next, five echocardiography-guided titration regimens (plus the EXPLORER-CN regimen) using representative or equal CYP2C19 phenotypes were simulated. The final simulated regimen recommended with an optimal benefit/risk profile across CYP2C19 phenotypes included: down-titration at Week 4 (if VLVOTg < 20 mmHg), restart at Week 12, and up-titration at Week 12 (for VLVOTg ≥ 30 mmHg and LVEF ≥ 55%), and every 12 weeks thereafter. This supports the previously recommended regimen for Chinese patients with obstructive HCM, now approved by the National Medicinal Products Administration.

Personalized statin therapy: Targeting metabolic processes to modulate the therapeutic and adverse effects of statins.

Statins are widely used for treating lipid disorders and cardiovascular diseases. However, the therapeutic efficiency and adverse effects of statins vary among different patients, which numerous clinical and epidemiological studies have attributed to genetic polymorphisms in statin-metabolizing enzymes and transport proteins. The metabolic processes of statins are relatively complex, involving spontaneous or enzyme-catalyzed interconversion between more toxic lactone metabolites and active acid forms in the liver and bloodstream, influenced by multiple factors, including the expression levels of many metabolic enzymes and transporters. Addressing the variable statin therapeutic outcomes is a pressing clinical challenge. Transcription factors and epigenetic modifications regulate the metabolic enzymes and transporters involved in statin metabolism and disposition and, therefore, hold promise as 'personalized' targets for achieving optimized statin therapy. In this review, we explore the potential for customizing therapy by targeting the metabolism of statin medications. The biochemical bases of adverse reactions to statin drugs and their correlation with polymorphisms in metabolic enzymes and transporters are summarized. Next, we mainly focus on the regulatory roles of transcription factors and epigenetic modifications in regulating the gene expression of statin biochemical machinery. The recommendations for future therapies are finally proposed by targeting the central regulatory factors of statin metabolism.

Associations between (pharmaco-)genetic markers and postoperative pain after inguinal hernia repair – a prospective study protocol

BackgroundPostoperative pain is a common complication following surgery, with severity and duration varying between patients. Chronic postoperative pain after inguinal hernia surgery has an incidence rate of approximately 10%. Risk factors for acute and chronic pain following hernia surgery include age, sex, psychosocial factors, and demographic background. Additionally, genetic polymorphisms in enzymes involved in pain mechanisms, as well as the metabolism of analgesics might influence pain perception, pain development, and response to pain medications. Key enzymes include the catechol-o-methyltransferase (COMT), the µ-opioid receptor 1 (OPRM1), and the cytochrome P450 2D6 (CYP2D6).CYP2D6 plays a crucial role in metabolizing analgesics such as tramadol, codeine, and oxycodone. It is also suspected to be involved in the synthesis of catecholamines and endogenous morphines suggesting a potential role in pathophysiology of pain. We hypothesize that the CYP2D6 activity influences the development of postoperative pain after hernia surgery.MethodsThis study is a prospective, observational, multicenter association study investigating adult patients scheduled for inguinal hernia surgery using a robotic-assisted (rTAPP) approach. Patients are enrolled during the preoperative surgical consultation. A buccal swab is collected for genetic testing at this time. Pain at the site of the hernia is assessed using the validated EuraHSQoL score preoperatively and at 2, 4, and 6 weeks postoperatively. Additionally, information on co-medication and details of the surgery will be collected. The planned number of participants is 350 patients. The primary objective is to analyze the association between different genotype-predicted CYP2D6 phenotypes and patient-reported pain intensity 6 weeks after surgery. Secondary objectives include the association between further genetic variants, such as the COMT rs4680 and OPRM1 rs1799971 genotype, and pain severity. Additionally, the potential of pharmacogenetic panel testing to optimize analgesic therapy in hernia surgery patients will be explored.DiscussionThe findings of this study are expected to provide valuable insights into identifying patients at higher risk for postoperative pain before surgery. This knowledge could pave the way for tailored interventions during and after surgery for these specific patients.Trial registrationDeutsches Register Klinischer Studien https://www.drks.de/DRKS00034796 Registered on August 07, 2024.

Determination of Prothrombin Gene G20210A Mutation in Deep Venous Thrombosis among Sudanese Patients - Khartoum State

Background: Deep vein throm¬bosis (DVT) is serious disorders contributing to increased morbidity and mortality worldwide. However, there is, little genetic data from Africa including Sudan. So this study was conducted to investigate the relationship between genetic mutations G20210A in the prothrombin coagulation factor and deep venous thrombosis in Sudanese patients. Methods: This is a cross-sectional study design was carried out in Khartoum state in the period from December 2014 to May 2018. One hundred of patient group and fifty healthy one were enrolled in this study. Mutation was detected using conventional PCR depending on restriction enzyme polymorphism technique. Results: The mutant allele (G/G) was found in 4 (4%) of patients nevertheless, there is no mutant allele was present in control group (P.value=0.152). Moreover, the mixed allele (G/A) was not detected in patients and healthy control. Exclusively, the control group showed only the wild type (A/A). Conclusion: This study noted a few mutant alleles in patients group and only the wild type (A/A) in control one. However, carrying out a genome-wide associated study is recommended to determine relationship between prothrombin gene mutation and frequency of deep vein throm¬bosis in Sudanese population.

The effects of extracellular matrix-degrading enzymes polymorphisms on intervertebral disc degeneration.

The objective of the current study was to investigate the correlation between polymorphisms in extracellular matrix-degrading enzymes and the risk of intervertebral disc degeneration (IDD) diseases. The databases PubMed, Embase, and Cochrane Database were systematically queried from the inception until March 2023 to ascertain studies that meet the eligibility criteria. Utilizing a standardized data collection form to extract data from individual studies. The data were quantified using odds ratio (OR) along with its corresponding 95% confidence interval (95% CI), following an allelic model of inheritance. The study included a total of nine studies and indicated that the presence of rs17576 in the MMP9 gene was significantly associated with an increased risk of IDD diseases (GG: 1.30, 95% CI [1.09-1.55], p = 0.004). The presence of other polymorphisms in extracellular matrix-degrading enzymes did not exhibit a significant association with the susceptibility to IDD. The current study demonstrated a noteworthy correlation between the GG genotype of MMP-9 rs17576 and susceptibility to IDD. The available evidence is insufficient to substantiate the correlation between other extracellular matrix-degrading enzymes and susceptibility to IDD. The constraints of this analysis necessitate further research involving larger sample sizes across diverse ethnicities to provide a comprehensive understanding of the true impact of these polymorphisms on susceptibility to IDD.

The effect of caffeine dose on caffeine and paraxanthine changes in serum and saliva and CYP1A2 enzyme activity in athletes: a randomized placebo-controlled crossover trial

BackgroundAlthough caffeine (CAF) supplementation has been shown to improve exercise performance, its dose-dependent effect on CAF metabolism has not been sufficiently investigated. The aim of this study was to evaluate the effects of 3, 6 and 9 mg of CAF/kgBM on changes of CAF and paraxanthine (PRX) in the serum and saliva at four time-points.MethodsIn a randomized, double-blind, placebo-controlled crossover design, acute pre-exercise supplementation in 26 moderately-trained athletes, participating in high-intensity functional training (HIFT), was examined. The study protocol involved CAF/PRX biochemical analyses of serum and saliva with respect to CYP1A2 polymorphism and CYP1A2 enzyme activity.ResultsDespite significant differences between the serum and saliva levels of CAF and PRX, there was no difference in the PRX/CAF ratio. The interaction effect of dose and time-points for PRX concentration was revealed. The main effects of dose were observed for CAF and the PRX/CAF ratio. The main effect of time-points was registered only for serum CAF.ConclusionsDose- and time-dependent effect of CAF supplementation on CAF and PRX in the serum and saliva of athletes was confirmed, but there was no effect of the CAF dose on CYP1A2 enzyme activity, nor was there an interaction of CYP1A2 with enzyme inducibility. The CAF/PRX correlation indicated the possibility of interchangeable use of serum and/or saliva analyses in exercise studies.Clinical trial registrationThis trial was registered prospectively at ClinicalTrials.gov (NCT03822663, registration date: 30/01/2019).

Pharmacogenetic testing: current state of the issue

Aim. The purpose of this work is to emphasize the importance and practical benefits of pharmacogenetics in medicine, demonstrating how the integration of pharmacogenetics into clinical practice can improve treatment outcomes and enhance the safety of therapies. Pharmacogenetics is a rapidly developing branch of pharmacology that studies how genetic variation affects an individual’s response to drugs. By understanding these genetic differences, healthcare providers can tailor drug therapy to maximize efficacy and minimize adverse drug reactions. The field aims to move away from the traditional one-size-fits-all approach and instead personalize medical treatment based on a person’s genetic makeup. The ability to predict a person’s response to medication based on their genetic profile has profound implications. For example, pharmacogenetic testing can identify patients at risk for life-threatening adverse drug reactions, such as drug-induced liver injury. This proactive approach can prevent adverse events, improving patient safety and the overall quality of care. In addition, pharmacogenetics aids in the development of new drugs by identifying genetic markers associated with drug responses, optimizing the drug development process, and reducing the time and costs associated with bringing new drugs to market. Key advances in pharmacogenetics include the identification of genetic polymorphisms in enzymes, such as cytochrome P450, that affect drug metabolism, thereby influencing both safety and efficacy. Pharmacogenetic testing allows doctors to predict the best drug and dosage for a patient, improving treatment outcomes and reducing the risk of adverse drug events. Despite its potential, the integration of pharmacogenetics into clinical practice faces challenges, including a lack of reliable clinical evidence, inadequate physician education, and the need for a comprehensive health IT infrastructure to support the use of genetic data. Ethical and legal issues, such as patient privacy and the risk of genetic discrimination, also present significant obstacles. However, continued research, the development of genetic testing technologies, and interdisciplinary collaborations are paving the way for more widespread adoption of pharmacogenetics, which promises to significantly improve patient care and healthcare efficiency. Key resources such as PharmGKB, CPIC, and the NIH provide valuable information and guidance for clinicians, researchers, and students, helping bridge the gap between genetics research and clinical application. Conclusions. Pharmacogenetics represents a significant advancement in personalized medicine, offering the potential to tailor drug therapies to individual genetic profiles. Although the field has made substantial progress, challenges remain in the form of insufficient clinical evidence, implementation barriers, and ethical concerns. Continued research and collaboration among stakeholders are essential to fully realize the benefits of pharmacogenetic testing in clinical practice.

The Association Between Antioxidant Enzyme Polymorphisms with Type 2 Diabetes Mellitus in Jazan Province.

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by persistent hyperglycemia, which results in initiates oxidative stress and disrupts various cellular pathways. In this study, we examined the relationship between polymorphisms in antioxidant enzymes, specifically glutathione peroxidase 1 (GPx1) and catalase (CAT), and the susceptibility to T2DM in a Saudi population from the Jazan Province. A total of 419 participants were evaluated, including 247 T2DM patients and 172 controls. They were genotyped for the GPx1 Pro198Leu and CAT-262C/T polymorphisms by a PCR-based method. The results indicated that individuals with the CAT T/T genotype had a 60% lower likelihood of developing T2DM compared with those harboring the C/C genotype (uOD 0.4; 95% CI 0.2-0.8, p = 0.04); however, no significant association was observed between the GPx1 polymorphism and T2DM. The results suggest that CAT polymorphism may confer a protective effect against T2DM, whereas the GPx1 polymorphism appears not to be a determinant of T2DM susceptibility in this population. Further studies including larger and more diverse cohorts are necessary to validate these results and elucidate the underlying mechanisms. Understanding the genetic factors that contribute to T2DM is essential for developing targeted preventive and therapeutic strategies.

The Role of Pharmacogenetic-Based Pharmacokinetic Analysis in Precise Breast Cancer Treatment.

Given the high prevalence of breast cancer and the diverse genetic backgrounds of patients, a growing body of research emphasizes the importance of pharmacogenetic-based pharmacokinetic analysis in optimizing treatment outcomes. The treatment of breast cancer involves multiple drugs whose metabolism and efficacy are influenced by individual genetic variations. Genetic polymorphisms in drug-metabolizing enzymes and transport proteins are crucial in the regulation of pharmacokinetics. Our review aims to investigate the opportunities and challenges of pharmacogenomic-based pharmacokinetic analysis as a precision medicine tool in breast cancer management.

Notable drug-drug interaction between omeprazole and voriconazole in CYP2C19 *1 and *2 (rs4244285, 681G>A) alleles in vitro

The drug-drug interaction (DDI) and CYP2C19 genetic variation can lead to a high blood concentration of voriconazole. CYP2C19 is a highly genetically polymorphic enzyme, and CYP2C19*2 is more frequent among Asians associated with reduced metabolism of drugs. Clinical study found that co-administration with omeprazole significantly increased voriconazole concentrations and there was an additive effect in CYP2C19*2 allele. CYP2C19 rs4244285 (681G>A) is the key polymorphism of CYP2C19*2 allele. This study aims to describe the in vitro effects of omeprazole on CYP2C19*1 and *2 (681G>A), and determine how CYP2C19 polymorphisms influence the DDI between omeprazole and voriconazole. Using the lentiviral expression system, we successfully generated HepG2-derived cell lines stably expressing CYP2C19*1 and *2 (681G>A). The results showed that the CYP2C19 mRNA level, protein level, and enzymatic activity were lower in HepG2-CYP2C19*2 (681G>A) than HepG2-CYP2C19*1 cells. Our study also showed that the inhibition rates of omeprazole on voriconazole had no significantly differences between CYP2C19*1 and *2 (681G>A). But the IC50 of omeprazole on CYP2C19*1 slightly lower than CYP2C19*2 (681G>A). Moreover, omeprazole inhibited CYP2C19 protein level in cells carrying CYP2C19*1 and CYP2C19*2 (681G>A). Our study demonstrated that omeprazole could inhibit voriconazole metabolism in both CYP2C19*1 and CYP2C19*2 (681G>A).

Association of Angiotensin Converting Enzyme Phenotypes and Polymorphisms with Clinical Outcomes in SARS-CoV2 Patients with Hypertension in an Urban Emergency Department.

The role of Angiotensin-converting enzyme (ACE and ACE2) phenotypes and polymorphisms in modulating severe acute respiratory syndrome coronavirus (SARS-- CoV2) infection in hypertensive patients remains unclear. Our objective was to determine the distribution of ACE and ACE2 receptor phenotypes by patient demographics and correlate ACE and ACE2 levels of activity with SARS-CoV-2 outcomes. Hypertensive patients treated for SARS-CoV-2 at an urban emergency department (ED) were prospectively enrolled in a cohort study between August 2020 and April 2021. Blood samples were collected during ED visits or hospitalization. Outcome measures including hospitalization, intensive care unit (ICU) admission, and 30-day mortality were obtained from electronic health records. Multivariable logistic regression was used. Of the 150 patients enrolled, 60% were Black, 32% Hispanic/Latinx, 4% Non-Hispanic Whites, and 4% others. The mean age was 59 (+/-14) years. The rate of hospitalization was high (86%) and Hispanic/Latinx had a higher likelihood of ICU admission. Patients harboring the rs2285666 genotype TT, AA, and GC alleles were more likely to be admitted to ICU, and those with TT and AA had higher mortality. The ACE level was a significant predictor of hospitalization with a protective effect in both unadjusted and adjusted results. Hispanics/Latinx had a four times higher likelihood of ICU admission compared to all others, and age was significantly associated with 30-day mortality. Our results show that even after adjusting for age, race, and sex, ACE levels remained a predictor of hospitalization. ACE/ACE2 phenotypes and genotypes potentially play an important role in disease progression in SARS-CoV-2 patients.

Relative Age Effect and ACTN3 R577X and ACE I/D Polymorphisms in Brazilian Football Players: An Association Genetic Study

ABSTRACT The Relative Age Effect (RAE) suggests older athletes within an annual cohort have advantages over their younger peers. We hypothesized that younger athletes could overcome these disadvantages through favorable α-actinin-3 (ACTN3) and angiotensin converting enzyme (ACE) polymorphisms. This study aimed to: 1) examine RAE prevalence among Brazilian football players; 2) investigate the distribution of the ACTN3 and ACE polymorphisms; and 3) explore the association between polymorphisms and RAE across competitive levels and positions. The sample included 627 male players from first-division Brazilian teams in four age categories: U15 (n = 172), U17 (n = 166), U20 (n = 161), and Professionals (n = 128). A control group was established using data from the general Brazilian population documented in previous studies Results showed RAE presence across all competitive levels and positions. Players with the ACTN3 R allele, especially the RR genotype, had the strongest associations with football players, particularly among defenders. On the other hand, the distribution of ACE polymorphism was not significantly different between controls and players, except in the U17 category, where the I/I genotype was more common. Relatively older players had higher total genotype scores than younger counterparts in the overall sample and defender subgroups. In conclusion, RAE is prevalent among Brazilian football players, with older athletes benefiting from favorable ACTN3 and ACE polymorphisms, contrary to our initial hypothesis.

Unveiling the Interplay: Antioxidant Enzyme Polymorphisms and Oxidative Stress in Preterm Neonatal Renal and Hepatic Functions.

To explore the relationship between oxidative stress biomarkers and the occurrence of acute kidney injury (AKI) alongside notable liver function disturbances in preterm neonates. Given the immaturity of kidneys and incomplete liver development in preterm neonates, oxidative stress poses a considerable threat to their renal and hepatic health. To find out the association between various oxidative stress biomarkers and polymorphisms of antioxidant enzymes with renal and live functions. In this cross-sectional study, we gathered umbilical cord blood and peripheral blood samples for assessing oxidative stress biomarkers and identifying single nucleotide polymorphisms (SNPs) in antioxidant enzymes. Utilizing enzyme-linked immunosorbent assay kits, we quantified these oxidative stress biomarkers. Receiver-operating characteristics curve analysis was employed to ascertain the predictive capacity of these biomarkers, denoted by the area-under-the-curve (AUC). Our findings revealed that umbilical cord heat-shock proteins emerged as robust predictors of neonatal AKI (AUC: 0.92; 95% CI: 0.8-1) with a defined cut-off concentration of 1.8 ng/mL. Likewise, umbilical cord 8-hydroxy-2-deoxy guanosine demonstrated significant predictability for liver function alterations (AUC: 0.7; 95% CI: 0.6-0.9) at a cut-off concentration of 2487.6 pg/mL. We observed significant associations between SNPs in endothelial nitric oxide synthase and catalase with both AKI and impaired liver functions. Prospective studies are warranted to validate these findings, with a particular focus on exploring potential antioxidant interventions aimed at mitigating AKI and liver function abnormalities.

Metabolic and genetic basis of liver damage in mechanical jaundice of non-tumor genesis in obstractive cholangitis or biliary pancreatitis

Aim. Establishment of versatile mechanisms behind liver damage in mechanical jaundice of non-tumor genesis combined with acute obstructive cholangitis or acute biliary pancreatitis.Materials and methods. In total, 64 cases of mechanical jaundice developed against the background of cholelithiasis were studied. Group 1 included 30 patients with mechanical jaundice combined with cholangitis; group 2 included 34 patients with acute biliary pancreatitis. Bile duct reconstruction was performed by an open method followed by standardized treatment. The intensity of membrane lipid peroxidation was determined by the level of diene conjugates, malonic dialdehyde, superoxide dismutase activity, and the activity of phospholipase A2. The severity of endotoxemia was estimated; a molecular-genetic test of the polymorphism of antioxidant system genes was performed.Results. The significance of the gene polymorphism of antioxidant enzymes in the formation of systemic alterative phenomena and severity of liver damage in mechanical jaundice complicated by cholangitis or acute pancreatitis was determined by allocation of patient subgroups depending on the presence of mutant allele T in the gene of superoxide dismutase SOD2 (C1147T). The groups of patients with the presence of such polymorphism, regardless of the combined diseases, demonstrated more pronounced and prolonged liver functional disorders and homeostasis disorders after restoration of biliary tract patency.Conclusion. The presence of mutant alleles of the SOD2 gene (C47T) in patients with non-tumor mechanical jaundice combined with acute cholangitis or pancreatitis is associated with an increase in the intensity of damage mechanisms at the systemic level, primarily with membrane lipid peroxidation, which correlates with the severity of liver damage (r = 0.834–0.967; p &lt; 0.05).

Investigation of the association between polymorphisms in DNA repair enzymes and STEMI

STEMI (ST-elevation myocardial infarction), a condition in which DNA damage likely contributes to its pathogenesis, is among the most severe manifestations of coronary artery disease. There are very few publications in this field in the literature. In our study, we examined the association between four polymorphisms in repair enzymes (LIG4 Thr9Ile, XRCC6 promoter C-57G, XPA -4A/G, OGG1 Ser326Cys) involved in three distinct DNA repair mechanisms [NHEJ (non-homologous end joining)], NER (nucleotide excision repair), and BER (base excision repair), and their impact on the risk of STEMI. This study involved 185 patients diagnosed with STEMI and included 155 healthy controls. The genotyping of SNPs was conducted through the PCR-RFLP (Polymerase chain reaction-restriction fragment length polymorphism) method for the following variants: XRCC6 (rs2267437), XPA (rs1800975), LIG4 (rs1805388), and OGG1 (rs1052133). No significant differences were observed in the genotype distributions of the XRCC6 and OGG1 variations between the control and patient groups. On the other hand, our findings indicate that individuals carrying the mutant G allele for XPA polymorphism and the mutant T allele for LIG4 polymorphism are susceptible to STEMI. Our findings demonstrate the significance of NHEJ and NER DNA repair processes in the pathogenesis of STEMI, as evidenced by the observed relationship between LIG4 and XPA polymorphisms.

Association of Polymorphic Cytochrome P450 Enzyme Pathways with Falls in Multimedicated Older Adults

ObjectivesDose exposure is considered relevant for drug-associated falls in older adults, pointing to an importance of drug metabolism. Aim was to analyze individual factors altering drug metabolism such as enzyme saturation by drug exposure and pharmacogenetics in the context of drug-associated falls. DesignProspective population-based study (ActiFE-Ulm study). Setting and ParticipantsCommunity-dwelling older adults. MethodsFocus was laid on the metabolism by polymorphic cytochrome P450 (CYP) enzymes CYP2C19, 2C9, and 2D6. Relevant variants of pharmacogenes were analyzed. Logistic binary regression analysis was used to calculate odds ratios (ORs) and 95% CIs for falls observed prospectively over a 1-year period with drug metabolism characteristics. ResultsIn total, 1377 participants were included in the analysis. Although the phenotype predicted by the genotype was not, the use of drugs metabolized by CYP2C19 was associated with falls. Drugs not known as fall risk–increasing drugs (FRIDs; ie, non-FRIDs), but metabolized by CYP2C19, showed an OR of 1.46 (1.11-1.93) in adjusted analysis. Significant effect modification was observed for a reduced CYP2C19 activity phenotype with non-FRIDs metabolized by CYP2C19. Conclusions and ImplicationsThis study suggests an association between the occurrence of falls in older adults and the metabolic capacity of CYP2C19. Thus, an important step toward prevention of falls might be to personalize dosage and treatment length of the main drug classes known to be CYP2C19 substrates, such as many antidepressants, opioids, and sedatives, but also proton pump inhibitors in particular in poor and intermediate metabolizers.

Isometric Fatigue Resistance of Lumbar Extensors and Cardiovascular Strain in Lower Back Pain Patients Are Associated with Angiotensin-Converting Enzyme and Tenascin-C Gene Polymorphisms

Background: We tested whether gene polymorphisms for angiotensin-converting enzyme (ACE, rs1799752) and tenascin-C (TNC, rs2104772) are associated with variability in fatigue resistance and metabolic strain during static lumbar exercise through interactions with chronic nonspecific lower back pain and habitual physical exercise levels (PA). Methods: Forty-eight patients and matched controls performed an isometric endurance test for lumbar extensors. Metabolic strain to longissimus muscle (oxygen saturation, lactate) and cardiovascular system (muscle hemoglobin, blood pressure) and holding time were monitored. Subjects were genotyped for rs1799752 (II, ID, DD) and rs2104772 (AA, AT, TT). Associations of variance with group, genotype, and PA were analyzed under a 5% false discovery rate. Results: The holding time was lower in patients than in controls (150.9 vs. 188.6 s). This difference was associated with both genotypes, as patients with DD-rs1799752-genotype (p = 0.007) and TT-rs2104772-genotype (p = 0.041) showed lower fatigue resistance. Muscle deoxygenation during exercise varied in positive association with the rs2104772-genotype and PA (p = 0.010, η2 = 0.236). Mean arterial blood pressure (p = 0.028, η2 = 0.108) and recovery of hemoglobin concentration (p = 0.003, η2 = 0.907) demonstrated complex group x rs2104772 interactions. Conclusions: Polymorphisms rs1799752 and rs2104772 influence back pain-related variability in lumbar fatigue resistance. rs2104772 was linked to cardiovascular strain during isometric exercise and recovery via muscle perfusion.

Patient resuscitated after cardiopulmonary arrest exhibits abnormally increased phenytoin metabolic rate due to unknown factors: a case report

BackgroundFosphenytoin (FOS) is a prodrug of phenytoin (PHT) with a metabolism that exhibits Michaelis–Menten-type kinetics. Genetic polymorphisms of the metabolic enzymes of PHT make it challenging to predict its plasma concentrations. High plasma PHT concentrations are typically problematic, and several causes have been elucidated. In contrast, cases of patients with low PHT plasma concentrations that did not increase despite the administration of appropriate PHT doses have been reported, and the causes may include changes in plasma protein-binding rates, genetic mutations, and concomitant use of drugs that induce liver enzymes; however, even these factors do not explain the low PHT plasma concentrations in some cases.Case presentationWe encountered the case of a patient with plasma PHT concentrations that were continuously < 0.7 µg/mL after daily use of FOS for seizures that occurred after cardiopulmonary arrest. We analyzed the protein-unbound fraction, urinary metabolites, and related genes to investigate the cause. False negatives due to the measurement method, errors in dosage and administration method, and increased excretion of PHT were excluded. Hepatic metabolic activity of PHT increased to 4.6–6.1 times the normal level. The S/R ratio of 5-(p-hydroxyphenyl)-5-phenylhydantoin-glucuronide, a major PHT metabolite, was normal at 15.2, suggesting increased activities of CYP2C9 and CYP2C19. Furthermore, the protein-unbound fraction of PHT was 5.2–6.9%, CYP2C19*17 was wild type, and there was no concomitant drug use to induce both enzymes.ConclusionsThe low PHT plasma concentration in this patient was found to be caused by increased hepatic metabolic activity that could not be explained by known factors. Careful monitoring is necessary to consider the possibility of increased hepatic metabolic activity in similar cases.

Peripheral pathway gene variants in lifelong premature ejaculation: CYP19A1, CYP1A1, and CYP1A2 enzymes polymorphisms in Chinese Han men

Abstract Background Recent genetic association studies focusing on central pathways have been performed to investigate the correlation between susceptibility alleles and the risk of lifelong premature ejaculation (LPE). However, there remains a dearth of documented genes associated with peripheral pathways. Objective In this study we aimed to investigate the relationship between single nucleotide polymorphisms (SNPs) associated with the peripheral genes CYP19A1, CYP1A1, and CYP1A2 and the risk of LPE. Methods From August 2017 to August 2020, a total of 511 participants (139 LPE patients and 372 controls) were recruited. Trained medical professionals diagnosed LPE according to the standard definition set by the International Society for Sexual Medicine. Nine candidate SNPs were chosen and genotyped using the MassARRAY system. Allele and genotype frequencies of the SNPs among patients and controls were compared using the χ2 test. Logistic regression analysis, adjusted for age, was performed to calculate odds ratios (ORs) and 95% confidence intervals (CIs) using PLINK version 1.9. Haploview software was employed to analyze linkage disequilibrium and haplotype distribution. The interaction among candidate SNPs concerning LPE risk was evaluated using multifactor dimensionality reduction. The relationship between selected polymorphisms and specific features was assessed using analysis of variance. Outcome Heterozygous SNPs located in the CYP19A1 (rs4646, rs17601876), CYP1A1 (rs1048943), and CYP1A2 (rs762551, rs2470890) genes showed significant correlations with the risk of LPE. Results The findings of this study confirmed that heterozygous SNPs in the CYP19A1 (rs4646 AC vs CC: OR, 1.84; CI, 1.10-3.09; rs17601876 AG vs GG: OR, 1.80; CI, 1.06-3.05) and CYP1A1 genes (rs1048943 CT vs TT: OR, 1.71; CI, 1.02-2.87), respectively, can significantly increase the LPE risk. Participant scores for the Premature Ejaculation Diagnostic Tool (P =.002) and International Index of Erectile Function-5 (P =.020) differed significantly by genotype for the different genotypes of CYP1A1-rs1048943. Haplotype analysis revealed strong linkage disequilibrium under CYP1A2_rs762551-rs2470890 (D' = 1.00). Clinical Implications The findings of this and other investigations of genetic determinants and potential pathogenic mechanisms of LPE may advance diagnostic and therapeutic opportunities in LPE patients. Strengths and Limitations In this study of LPE in men with CYP gene variants we addressed a current research gap. However, data on risk factors such as smoking and drinking were incomplete in both the case and control groups. In future studies we will expand the sample size and enhance data on risk factors for more precise assessments. Conclusion In summary, polymorphisms in the peripheral genes CYP19A1, CYP1A1, and CYP1A2 may play a role in LPE among Chinese men of the Han population.