Search Results (108)

The aim of this study was to assess the effect of sertraline on the gene expression of placental transporters for hormones, folates, nutrients and drugs over the course of pregnancy in rats. The studies were conducted on gestational days (GDs) 16 and 20 following oral treatment with 10 mg/kg/day sertraline or the vehicle, administered from weaning onward. The weight and area of the fetuses and placentas were analyzed, and maternal plasma sertraline concentrations were measured. Gene expression of ATP-binding cassette transporter b1a and b1b (Abcb1a and Abcb1b), organic anion-transporting polypeptide 4a1(Slco4A1/Oatp4a1), folate receptor-α (Folr1), reduced folate carrier (Slc19A1/Rfc), and L-type amino acid transporter (Slc7A5/Lat1) was evaluated in the placenta. Sertraline reduced fetal weight (p < 0.001) and fetal area (p < 0.01) at GD 16, while no significant differences were observed in placental weight or area between exposed and unexposed groups. Sertraline concentration was significantly lower at GD20 than at GD16 (p < 0.001). At GD 16, sertraline reduced the expression of Abcb1a (p = 0.027), Abcb1b (p < 0.01), and Oatp4a1 (p = 0.037) compared with controls. Conversely, sertraline induced Folr1 expression in both GDs and increased Rfc expression at GD 20, while Lat1 was not affected. These findings indicate that sertraline alters placental drug transporter gene expression and may impair nutrient transfer to the fetus. Full article

Although ombitasvir/paritaprevir/ritonavir plus dasabuvir (OPrD) therapy is highly effective for chronic hepatitis C (CHC), clinicians frequently encounter transient hyperbilirubinemia, which can be misidentified as hepatotoxicity. This study investigated the role of SLCO1B1 (OATP1B1) and SLCO1B3 (OATP1B3) genetic polymorphisms in predicting bilirubin spikes and distinguishing transporter-mediated interference from hepatocellular injury. In this prospective study of 65 patients with HCV genotype 1, genotyping for OATP1B1 (c.388A>G, c.521T>C) and OATP1B3 (c.334T>G, c.699G>A) was performed using PCR-RFLP and capillary electrophoresis (QIAxcel Advanced System). Clinical and biochemical parameters were monitored over a 12-week treatment period. Hyperbilirubinemia (total bilirubin >1.1 mg/dL) developed in 18.5% of the cohort, typically within the first month. A distinct ‘AST-dominant’ biochemical signature, elevated bilirubin and AST paired with stable ALT, was identified, suggesting transporter-specific interference rather than hepatocyte damage. Statistical analysis pinpointed the OATP1B3 c.699G>A (rs7311358) variant as the sole genetic driver (p = 0.007). Carriers of the c.699G>A allele faced a 6.3-fold higher risk of developing hyperbilirubinemia (OR: 6.30, 95% CI: 1.48–26.80, p = 0.032), while no significant associations were found for OATP1B1 variants. We conclude that OATP1B3 c.699G>A is a potent predictor of OPrD-induced hyperbilirubinemia. Identifying this genotype pre-treatment allows clinicians to anticipate transient, benign bilirubin elevations and prevent unnecessary drug discontinuation, thereby mitigating therapeutic inertia and ensuring treatment continuity for CHC patients. Full article

Tuberculosis (TB) remains a major public health challenge in Peru, where interindividual variability in treatment response and drug-induced hepatotoxicity may be influenced by host genetic background. This study aimed to characterize clinically relevant polymorphisms in NAT2, CYP2E1, and SLCO1B1 in a cohort of TB patients from Southern Peru, a genetically underrepresented Andean population. Thirty-five adults receiving first-line therapy (isoniazid and rifampicin) underwent targeted Sanger sequencing of key functional variants among these three genes. NAT2 acetylator phenotypes were predominantly intermediate (68.6%), followed by rapid (20%) and slow (11.4%) profiles, with high minor allele frequencies for rs1041983 and rs1801280. CYP2E1 functional promoter variants were infrequent, whereas SLCO1B1 exhibited notable allelic heterogeneity, suggesting potential variability in rifampicin transport. Comparative analysis with previously reported Peruvian data revealed regional differences in acetylator distribution, supporting population-specific pharmacogenomic stratification. Although clinical toxicity outcomes were not evaluated, the high prevalence of reduced acetylation genotypes suggests a substantial proportion of patients may benefit from genotype-informed isoniazid dosing strategies. These findings provide foundational data for implementing precision medicine approaches using affordable and targeted technologies in TB management within Andean populations and support the integration of pharmacogenomics into national TB control programs. Full article

Background: Statins are central to primary and secondary prevention of atherosclerotic cardiovascular disease but are often underutilized due to myopathy and intolerance. While individual pharmacogenetic (PGx) variants, particularly in SLCO1B1, are linked to statin-associated muscle symptoms, the real-world impact of both clinical and cumulative PGx burden on regimen modification and adverse outcomes remains unclear. We aimed to evaluate the existing uncertainty regarding whether combined PGx scores can effectively guide statin dose titration and regimen modification, thereby filling a key clinical gap. Methods: A retrospective cohort study of 911 statin-treated patients with coronary artery disease was conducted from the Qatar Cardiovascular Biorepository with available whole-genome sequencing data. Variants in SLCO1B1, ABCG2, and CYP2C9 were combined into a functional PGx burden score, and their associations with statin regimen modification, intolerance, myopathy, liver injury, adherence, and composite adverse events were evaluated. The composite adverse events were defined as the occurrence of any statin-related adverse event, including statin-associated myopathy, liver injury, or poor medication adherence, during the follow-up period. Patients were classified as having experienced the composite outcome if at least one of these events occurred. Results: Over 12 months following statin initiation, 10.2% of patients underwent dose escalation, 11.4% de-escalation, and 78.4% remained on the same regimen. PGx burden is not statistically significantly associated with statin intolerance (OR 1.14; 95% CI: 0.73–1.76), composite adverse outcome (OR 1.08; 95% CI 0.82–1.42), or time to regimen change (HR 1.02; 95% CI 0.77–1.35). However, higher PGx burden showed a directional tendency toward dose de-escalation (RRR 1.18, 95% CI 0.76–1.84) and lower likelihood of escalation (RRR 0.93, 95% CI 0.56–1.54). Conclusions: Clinical factors, particularly statin intensity and myopathy, were the primary determinants of regimen modification. The PGx burden contributes to vulnerability to statin-related adverse effects in a context-dependent manner but does not independently drive statin regimen modification in routine clinical practice. Prospective studies are warranted to assess the clinical utility of PGx-guided workflows in statin therapy. Full article

Background: Nonalcoholic fatty liver disease (NAFLD) is common in rheumatoid arthritis (RA), and methotrexate (MTX) use raises concern about hepatotoxicity. We evaluated whether HLA-DRB1, PNPLA3, SLCO1B1, and MTHFR variants are associated with NAFLD, liver fibrosis, or MTX toxicity/pharmacokinetics in RA, after accounting for clinical covariates. Methods: In a cross-sectional cohort of 159 patients with RA, NAFLD, and fibrosis were assessed by FibroScan (CAP ≥ 275 dB/m; LSM > 8 kPa). We compared baseline characteristics by NAFLD status and fitted multivariable models for NAFLD, fibrosis, ALT elevation, and MTX toxicity; MTX pharmacokinetics were analyzed in 111 MTX-treated patients. Multiple testing was controlled using the Benjamini–Hochberg method. Results: The prevalence of NAFLD was 36%, and that of fibrosis was 11%. NAFLD patients had higher CAP and LSM, and markedly greater adiposity indices (body weight, BMI, waist and hip circumference, WC). BMI and WC were independently associated with NAFLD (BMI OR 1.27 per kg/m², 95% CI 1.16–1.40; WC OR 1.06 per cm, 95% CI 1.01–1.12). No HLA-DRB1, PNPLA3, SLCO1B1, or MTHFR variant showed an association that survived multiple-comparison correction. Among MTX users, 21/111 (19%) experienced toxicity. SLCO1B1 and MTHFR variants did not influence MTX pharmacokinetics; age was associated with lower dose-normalized MTX exposure, and cumulative dose was positively associated with exposure. Conclusions: In RA, adiposity—not the tested candidate pharmacogenes—drives NAFLD risk, and SLCO1B1/MTHFR variants do not support MTX dose adjustment. The findings emphasize routine clinical risk factors over single-gene testing for NAFLD and MTX hepatotoxicity in this setting. Full article

Background: Interindividual differences in statin efficacy and tolerability are partly determined by genetic and metabolic factors. The SLCO1B1 c.521T>C polymorphism affects hepatic statin transport, while vitamin D deficiency may influence lipid metabolism and muscular tolerance. This study aimed to assess the impact of SLCO1B1 genotype and vitamin D status on lipid-lowering response and adverse events in postmenopausal women treated with atorvastatin or rosuvastatin. Methods: A total of 145 Croatian postmenopausal women were prospectively followed for 16 weeks. Participants received atorvastatin or rosuvastatin with dose titration to achieve low-density lipoprotein cholesterol (LDL-C) targets. Serum lipids, liver enzymes, and creatine kinase were monitored monthly. Serum levels of 25-hydroxyvitamin D were quantified by LC–MS/MS, while SLCO1B1 c.521T>C genotyping was performed using real-time PCR. Results: Rosuvastatin achieved a higher LDL-C target attainment rate compared with atorvastatin (81.1% vs. 67.6%, p = 0.02). The SLCO1B1 genotype was not associated with lipid response but was significantly associated with adverse effects. In multivariable regression analysis, patients with the T/C genotype had a significantly higher risk of developing adverse effects compared with those with the T/T genotype (OR 7.4, 95% Cl 2.1–26.7, p = 0.002). Vitamin D status showed no significant association with lipid outcomes or adverse events, although participants with severe deficiency exhibited a weaker LDL-C response. Conclusions: Rosuvastatin demonstrated superior lipid-lowering efficacy and tolerability compared with atorvastatin in postmenopausal women. The SLCO1B1 c.521T>C variant primarily affected safety rather than efficacy, while severe vitamin D deficiency might contribute to diminished statin response. Integrating pharmacogenetic and endocrine profiling could enhance individualized statin therapy and cardiovascular prevention in women. Full article

Background: Pharmacogenetic markers associated with the need to switch patients from methotrexate (MTX) to biologic agents in moderate-to-severe psoriasis remain insufficiently studied. The pharmacokinetics of MTX depend on the individual characteristics of the patient, as well as on the function of specific transporters and enzymes involved in its absorption, distribution, metabolism, and elimination; therefore, polymorphisms in genes encoding these proteins may be considered pharmacogenetic predictors of MTX intolerance or insufficient efficacy. This study aimed to investigate genetic variants associated with MTX intolerance or insufficient efficacy leading to therapy switch. Methods: A total of 80 patients with moderate-to-severe psoriasis were included: 43 who required switching from MTX to biologics and 37 who continued MTX therapy. Twelve polymorphisms in transporter and metabolism-related genes (ABCB1 (rs1045642), MTHFR (rs1801133), ABCB1 (rs1128503), ABCC2 (rs3740066), ABCC2 (rs717620), ABCG2 (rs2231137), GSTP1 (rs1695), SLC19A1 (rs1051266), COL18A1 (rs9977268), SLCO1B1 (rs2306283), SLCO1B1 (rs4149056), and ABCB1 (rs2229109)) were analyzed using next-generation sequencing. Results: Significant differences in genotype frequencies were observed for SLC19A1 rs1051266 (p = 0.03) and COL18A1 rs9977268 (p = 0.02). Carriers of the T allele in both genes were more frequent among patients requiring biologic therapy, suggesting a possible association with MTX intolerance or reduced efficacy. Conclusions: The study revealed an association between polymorphisms in the SLC19A1 rs1051266 and COL18A1 rs9977268 genes and the need to switch from MTX to biologic therapy in patients with moderate-to-severe psoriasis. These findings suggest that carriers of the C allele in these genes may have an increased risk of methotrexate intolerance. Full article

Organic anion-transporting polypeptides (OATPs) are key transporters of hepatic uptake for endogenous compounds and xenobiotics. Human OATP1B1 and OATP1B3 are well-studied due to their role in drug–drug interactions. In contrast, data on murine OATP1B2, the rodent orthologue of these transporters, are limited, despite its importance in early drug development. Here, we systematically compared the transport characteristics of mouse and rat OATP1B2 under identical experimental conditions. The K_m values for estrone-3-sulfate (E₁S) and taurocholate (TCA) were 242 and 73 µM for mOATP1B2 and 90 and 16 µM for rOATP1B2. Nine clinically relevant drugs were evaluated for inhibitory effects, showing strong correlation between species. Cyclosporine A, ritonavir, odevixibat, rosuvastatin, and rifampicin markedly inhibited uptake. Rifampicin demonstrated species-specific differences, with higher IC₅₀ values for mOATP1B2 (E₁S: 9.6 µM; TCA: 7.7 µM) than rOATP1B2 (E₁S: 1.1 µM; TCA: 2.4 µM). A comparison of the rodent data with the human orthologues revealed similar inhibition patterns but distinct substrate selectivity: hOATP1B1 showed high affinity for E₁S but negligible TCA uptake, while hOATP1B3 transported TCA weakly but not E₁S. This study provides insights into species-specific differences in OATP-mediated hepatic uptake and is therefore valuable for the interpretation of preclinical studies and their transfer to human pharmacology. Full article

Colorectal cancer (CRC) remains the third leading cause of mortality among cancer patients in developed countries. Each new study in this field can contribute to better detection, diagnosis, and treatment of this disease. Our study aimed to assess transcriptional activity of genes associated with the biotransformation of xenobiotics and endobiotics in all three phases in the CRC adenocarcinoma, including correlations between them, as well as the aromatic hydrocarbon receptor (AhR) pathways. Based on transcriptome analysis (1252 mRNAs) of the CRC tissue and healthy colon, the upregulation or downregulation of 46 significant mRNAs was presented. The study also revealed the downregulation of AKR7A2 and upregulation of SLC5A6 and SLC29A2, previously undistinguished and potentially therapeutically valuable in CRC. The diagnostic potential of ADH1C, GGT5, NQO2, and SLC25A5 was demonstrated. It was stated that the AHR, EPHX1, GSTP1, and SLC25A32 did not correlate in healthy intestinal tissue whereas AHCY, ALDH1A1, NNMT, GSTM4, UGT2B17, and SLCO1B3 did not correlate in CRC. The disturbed transcriptional activity of genes related to the biotransformation process at all stages of CRC suggests that this may be the cause of its occurrence; the genes ought to be taken into account in preventive strategies and the treatment of patients. Full article

Gut microbiota, through both its species composition and its metabolites, impacts expression and activity of intestinal drug transporters. This phenomenon directly affects absorption process of orally administered drugs and contributes to the observed inter-individual variability in pharmacotherapeutic responses. This review summarizes mechanistic evidence from in vitro and animal studies and integrates clinical observations in which alterations in gut microbiota are associated with changes in oral drug exposure, consistent with potential regulation of key intestinal drug transporters—such as P-glycoprotein (P-gp, ABCB1), Breast Cancer Resistance Protein (BCRP, ABCG2), MRP2/3 proteins (ABCC2/3), and selected Organic Anion-Transporting Polypeptides (OATPs, e.g., SLCO1A2, SLCO2B1)—by major bacterial metabolites including short-chain fatty acids (SCFAs), secondary bile acids, and tryptophan-derived indoles. The molecular mechanisms involved include activation of nuclear and membrane receptors (PXR, FXR, AhR, TGR5), modulation of transcriptional and stress-response pathways (Nrf2, AP-1) with simultaneous suppression of pro-inflammatory pathways (NF-κB), and post-translational modifications (e.g., direct inhibition of P-gp ATPase activity by Eggerthella lenta metabolites). The review also highlights the pharmacokinetic implications of, e.g., tacrolimus, digoxin, and metformin. In conclusion, the significance of “drug–transporter–microbiome” interactions for personalized medicine is discussed. Potential therapeutic interventions are also covered (diet, pre-/probiotics, fecal microbiota transplantation, modulation of PXR/FXR/AhR pathways). Considering the microbiota as a “second genome” enables more accurate prediction of drug exposure, reduction in toxicity, and optimization of dosing for orally administered preparations. Full article

Background: Diabetic foot ulcers (DFUs) are chronic wounds with high morbidity and mortality. Secretory proteins coordinate intercellular communication and may regulate inflammation, tissue repair and regeneration, but their contributions to DFU pathogenesis remain unclear. Aim: To discover and validate secretory protein–linked biomarkers that distinguish non-healing DFUs and to explore their potential utility for diagnosis and therapy. Methods: We integrated bulk RNA-sequencing datasets (GSE199939 training set; GSE80178 and GSE143735 validation sets) and a single-cell RNA-sequencing dataset (GSE223964). Differentially expressed genes, secretory protein lists, and weighted gene co-expression networks were intersected to select candidates. Functional enrichment, protein interaction networks and support vector machine–recursive feature elimination identified key markers. We visualized their cell-type distribution at single-cell resolution and validated their expression in external cohorts. Pathway enrichment, gene co-expression networks, ceRNA regulatory analysis and qRT-PCR in patient samples were used for further characterization. Results: Among 4803 differentially expressed genes, 743 overlapped with known secretory proteins. WGCNA highlighted modules strongly associated with DFUs, yielding 386 candidates. SVM-RFE combined with protein interaction analysis pinpointed four secretory proteins—LYZ, MPO, SLCO2B1 and TREM2—as putative biomarkers. Single-cell analyses showed that MPO, LYZ, SLCO2B1 and TREM2 transcripts are detectable in multiple skin-resident and immune cell populations, and that the DFU-associated upregulation of MPO and LYZ is most pronounced within keratinocyte clusters, while MPO and TREM2 remained consistently dysregulated in independent bulk cohorts. MPO-associated genes were enriched for immune and inflammatory pathways, whereas TREM2-linked genes implicated cell cycle and cytoskeletal regulation. GeneMANIA and ceRNA analyses revealed extensive interaction networks. qRT-PCR confirmed differential expression of MPO and TREM2 in clinical DFU tissues. Conclusions: Integrated multi-modal analysis identifies secretory proteins, particularly MPO and TREM2, as central determinants of impaired healing in DFUs. These molecules and their regulatory networks represent promising biomarkers and therapeutic targets for precision management of diabetic wounds. Full article

Statin exposure has been associated with a broad spectrum of muscle toxicity, ranging from asymptomatic creatine kinase (CK) elevation to immune-mediated necrotizing myopathy (IMNM) with anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) antibodies. The mechanisms underlying these adverse effects are not fully understood, and genetic predisposition may play a role. This observational study evaluated the association of HLA-DRB1*11 and SLCO1B1 rs4149056 variants with statin-induced muscle toxicity. A total of 62 statin-exposed patients treated at a single tertiary center were included and classified as follows: IMNM with anti-HMGCR antibodies (n = 11), non-immune myotoxicity (n = 20), and statin-exposed controls without myopathy (n = 31). The mean age was 66 ± 7.5 years, and 62% were women. The frequency of the HLA-DRB1*11 allele was significantly higher in patients with anti-HMGCR IMNM compared to those with non-immune myotoxicity (81.0% vs. 25.0%; OR = 13.5, 95% CI 1.73–15.3; p < 0.01) and controls (81.0% vs. 17.2%; OR = 21.6, 95% CI 2.87–23.7; p < 0.01). No significant difference was found between the non-immune myotoxicity and control groups. Likewise, the SLCO1B1 rs4149056 variant showed no association with either IMNM or non-immune muscle toxicity. These findings confirm a strong association between the HLA-DRB1*11 allele and anti-HMGCR IMNM. This genetic marker may help to better distinguish immune-mediated from non-immune forms of statin-related myopathy. Full article

Backgrounds: Objective of this study is to conduct a genome-wide association study (GWAS) of first-parity reproductive traits in Suzi pigs to identify significant single-nucleotide polymorphisms (SNPs) or candidate genes influencing these traits. Methods: This research employed technologies including the Zhongxin 50K SNP chip, simplified genome sequencing, resequencing, and the 100K SNP liquid chip to perform genome-wide SNP detection on 898 Suzi sows. Genotype data and phenotypic data were combined to do GWAS, gene annotation, and enrichment analysis. Results: Results showed that this study obtained phenotypes of 33 first-parity reproductive traits from 574 sows. GWAS results indicated there were 10 first-parity reproductive traits significantly associated with SNPs, and these traits were AFS, AFF, NNB, NH, NW, NS, NM, ND, PB, and CCN. These 10 traits were significantly associated with 60 SNPs, with 15 (25%) located on chromosome 2-the highest proportion. The SNPs significantly associated with AFS and AFF were largely identical. Genome-wide variance component analysis revealed that among the 10 traits with significantly associated SNPs in GWAS, there were 5 traits that exhibited genome-wide heritability ≥ 0.01. Trait of NM showed the highest heritability (0.65–0.7). These significantly associated SNPs annotated 20 candidate genes, including ADAMTS19, PROP1, ZNF354B, PCARE, LUZP2, VIRMA, EPHA5, AAAS, SLCO3A1-SV2B, KIF18A-BDNF, SERGEF, DYNLRB2, HNF4G, CATSPERD, HSD11B1L, DICER1, RARG, PCDHAC2, KRT79, and HSD17B2. GO analysis of candidate genes revealed that the top three biological processes were cell adhesion, positive regulation of cell projection organization, and positive regulation of neuron projection development. KEGG results showed the top three pathways were inositol phosphate metabolism, glutamatergic synapse, and phosphatidylinositol signaling system. Conclusions: These findings provide a foundation for the reproductive breeding of Suzi pigs and offer new insights into biological breeding in pigs. Full article

Background: Solute carrier organic anion transporter family member 1B1 (SLCO1B1) mediates statin uptake into hepatocytes, the primary sites of cholesterol production. While the impact of SLCO1B1 variation on statin-associated muscle symptoms (SAMS) is well-documented, its role in LDL-C reduction remains understudied. This single-center, retrospective cohort study evaluated whether SLCO1B1 variation affects statin effectiveness in 213 adults. Methods: The SLCO1B1 variant rs4149056 (NM_006446.5:c.521T>C) was tested to categorize patients by their SLCO1B1 function: normal, decreased, or poor. The primary endpoint was percent change in LDL-C from baseline to follow-up (≥6 weeks post-statin initiation), with secondary endpoints of SAMS occurrence and statin adherence. Results: Overall, the average LDL-C decreased by 32% across all groups. No significant difference in LDL-C reduction was observed between SLCO1B1 phenotypes (p = 0.24). Conclusions: SLCO1B1 variation did not significantly affect LDL-C reduction, SAMS occurrence, or statin adherence. However, the retrospective design and limited adherence data in this study represent important limitations warranting prospective validation studies. Full article

Background: Methotrexate (MTX) remains the most commonly prescribed drug used to treat rheumatoid arthritis (RA). Polymorphisms in solute carrier organic anion transporter family member 1B3 (SLCO1B3) and SLCO1B1 may play a critical role in MTX pharmacokinetics and patient outcomes. However, research on these polymorphisms in Saudi Arabia remains limited. We evaluated the association of SLCO1B3 (rs4149117, rs7311358) and SLCO1B1 (rs2306283, rs4149056) polymorphisms with MTX efficacy and safety in Saudi patients with RA. Methods: This multicenter, case-control study included patients diagnosed with RA in Jeddah and Taif. Demographic and clinical data were collected and analyzed. Genotyping of SLCO1B3 (rs4149117, rs7311358) and SLCO1B1 (rs2306283, rs4149056) polymorphisms was performed using Sanger sequencing. Statistical analyses, including logistic regression and haplotype analysis, were conducted to evaluate associations between these polymorphisms, MTX efficacy, and toxicity. Results: The study cohort comprised 100 patients with RA, with 46 showing a good response to MTX and 54 showing a poor response. Clinical predictors of MTX response were significantly higher in patients with poor response. Both SLCO1B3 polymorphisms (rs4149117, rs7311358) were significantly associated with anemia. Significant associations were found between SLCO1B1 (rs2306283) and gastrointestinal disturbances and anemia. The GAAT haplotype was significantly more prevalent among good responders, while the TGGT haplotype was significantly associated with poor responders. Conclusions: These results highlight the importance of genetic testing in predicting MTX treatment outcomes and tailoring personalized treatment plans for patients with RA to improve efficacy and minimize adverse effects. Full article