Search Results (2,928)

The CD33 rs12459419 (C>T; Ala14Val) single-nucleotide polymorphism (SNP) has been reported to modulate treatment response and survival in pediatric patients with acute myeloid leukemia (AML) receiving gemtuzumab ozogamicin (GO), an anti-CD33 antibody linked to the cytotoxic compound calicheamicin. However, it remains unclear whether this SNP also affects CD33 expression on leukemic blasts. Moreover, its prognostic significance in adult AML patients treated with standard chemotherapy without GO has not been investigated. In this study, we retrospectively genotyped 184 adult AML patients who received standard induction chemotherapy for the CD33 rs12459419 SNP genotype and collected CD33 expression data. The observed genotype distribution was 46% (n = 85) CC, 43% (n = 79) CT, and 11% (n = 20) TT. CD33 expression was detected in significantly higher proportions of leukemic blasts in patients with the CC genotype than those with the TT genotype (p = 0.0009). A similar trend was observed between the CT and TT genotypes (p = 0.06). No significant differences in clinical outcome were detected among the three genotype cohorts. Grouping CC and CT genotypes together based on their similar CD33 expression and comparing them to patients with the TT genotype also revealed no differences in overall survival (OS), event-free survival (EFS), or relapse-free survival (RFS). Using a proportion of 90% CD33-positive blasts to define high versus low expression groups also failed to identify a meaningful impact on OS, EFS, or RFS, either across genotypes or independent of genotype. In conclusion, our findings indicate that the CD33 rs12459419 SNP does not affect outcomes or survival in adult AML patients receiving standard chemotherapy in the absence of GO. Furthermore, no association was seen between CD33 expression and clinical outcomes between the three genotypes. To our knowledge, this is the first study to investigate the prognostic impact of the CD33 rs12459419 SNP per se on outcome and survival in adult AML patients treated with chemotherapy without GO. Validation in larger patient cohorts is required to conclusively rule out a prognostic role of the CD33 rs12459419 SNP in AML. Full article

Taste impairment is a little-known non-motor Parkinson’s disease (PD) feature with potential diagnostic value. However, its biological basis and sex-specific patterns remain unclear. We combined psychophysical taste testing, salivary α synuclein (αsyn) profiling, genotyping of four SNCA polymorphisms, and Supervised Learning (SL) within a unified, sex-aware analytical framework to analyze sensory, molecular, and genetic correlates of gustatory dysfunction in 99 PD patients and 60 healthy controls. Overall taste identification was markedly reduced in PD, independently of sex. However, males and females showed distinct taste quality alterations: females preserved sour recognition, while males showed marked citric acid misidentification. SL modeling achieved high accuracy, revealing that the inability to perceive saltiness was most informative overall, astringency misidentification strongly predicted female PD, and sour misidentification characterized male PD. Salivary oligomeric αsyn showed a significant sex × diagnosis interaction, being elevated only in PD females, specifically those failing to identify astringency. Genotype–phenotype analyses revealed sex-dependent associations between SNCA variants (rs356219, rs181489, and rs2583988) and astringency recognition. These findings demonstrated that sex critically shapes the interplay between taste dysfunction, peripheral αsyn biology, and SNCA genetics in PD, supporting sex-aware chemosensory phenotyping and the development of precision taste-based biomarkers. Full article

Background: We investigated whether common variants in SCN1A are associated with antiepileptic drug (AED) non-response in Jordanian patients with epilepsy. Methods: We recruited 114 patients (105 successfully genotyped) and Sanger-sequenced five loci spanning rs6432860 and its flanking region of rs1531380, rs1531379, rs1531378, and rs10198801. Genotype–response associations were tested using contingency analyses and multivariable logistic regression adjusting for age at the time of the interview, number of AEDs, and carbamazepine use. Pre-specified secondary analyses included (i) stratification by AED class (voltage-gated sodium channel [VGSC]-acting vs. non-VGSC agents) and (ii) sensitivity analyses using alternative non-response thresholds (seizures > 0/year and ≥4/year). Linkage disequilibrium (LD) and exact Hardy–Weinberg equilibrium (HWE) tests were evaluated. Cohort minor allele frequencies (MAFs) were compared with global population estimates. Results: The four upstream previously cataloged intronic variant SNPs (rs1531380, rs1531379, rs1531378, and rs6432860) were in a complete pattern of LD association in this population (D′ = 1; r^{2 =} 1) whereas each upstream variant with rs10198801 showed D′ = 1 with inverse correlation (r ≈ −0.53). All loci conformed to the exact HWE tests. Upstream variants had novel associations with a non-response in unadjusted analyses and remained significant after adjustment (genotype aOR = 2.8; 95% CI = 1.1–7.2; p value = 0.03), alongside independent effects of carbamazepine use (aOR = 3.3; 95% CI = 1.3–8.0; p value = 0.009) and a number of AEDs (aOR = 0.17; 95% CI = 0.06–0.50; p value = 0.002). In AED-class stratification, upstream additional intronic variants had novel associations with a non-response among VGSC-treated patients (OR = 3.8; 95% CI = 1.1–13.6; p value = 0.03) whereas rs10198801 was associated among non-VGSC patients (OR = 7.9; 95% CI = 0.9–70; p value = 0.04). Findings were robust using a ≥4 seizures/year threshold (recessive model significant) but not using any seizures > 0/year. Cohort MAFs for upstream variants (~48.6%) exceeded European, African, and Asian estimates. Significance: SCN1A upstream intronic variation has a novel association with AED non-response in the Jordanian cohort, shows mechanism-aligned patterns by AED class, persists after covariate adjustment and under a clinically used seizure-frequency threshold, and warrants ancestry-informed replication and functional validation. 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

This case-control study investigated the association between polymorphisms in the dedicator of cytokinesis 2 (DOCK2) gene and susceptibility to COVID-19 in a Mexican population. Methods: Genotyping of five single-nucleotide polymorphisms (SNPs) in the DOCK2 gene (rs9307 A/G, rs1045176 G/T, rs1045168 C/T, rs2112703 A/C, and rs2287727 A/C) was performed using TaqMan assays in 248 COVID-19 patients and 288 healthy controls. Results: No significant differences were observed in the allelic or genotypic distributions of rs1045176 G/T and rs2287727 A/C between cases and controls. However, under multiple genetic inheritance models (co-dominant, dominant, recessive, heterozygous, and additive), the rs9307 A, rs1045168 C, and rs2112703 A alleles were significantly associated with a reduced risk of COVID-19 (p < 0.05). Furthermore, sub-analyses stratified by genotype in COVID-19 patients revealed that the rs9307 AA, rs1045168 CC, and rs2112703 AA genotypes correlated with altered plasma concentrations of lactic acid dehydrogenase (LDH), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and ferritin. Conclusions: The DOCK2 SNPs rs9307 A/G, rs1045168 C/T, and rs2112703 A/C are associated with decreased susceptibility to COVID-19 in this population and influence plasma levels of LDH, ALT, AST, and ferritin, suggesting a potential role in disease pathogenesis and severity. Full article

Background: Gestation is a period of significant biological plasticity where the intrauterine environment influences fetal development via “fetal programming”. This study systematically reviews and meta-analyzes the association between genetic determinants—specifically the NR3C1, FKBP5, and CRHR1 genes, chosen for their pivotal role in the functional regulation and feedback sensitivity of the hypothalamic–pituitary–adrenal (HPA) axis—and stress reactivity during pregnancy. Methods: Following PRISMA guidelines, a systematic search was conducted across PubMed, Scopus, and Web of Science, yielding an initial total of 1430 records. After removing duplicates and screening 669 studies, a total of 34 primary observational studies were included in the systematic review and qualitative synthesis. For the quantitative synthesis, 27 articles provided sufficient data, resulting in k = 39 independent effect sizes analyzed via a mixed-effects model to account for tissue-specific and cohort-specific outcomes. Results: Systematic analysis reveals that maternal psychosocial stress significantly correlates with NR3C1 hypermethylation, acting as a biological mediator for neonatal cortisol dysregulation and hippocampal volume reduction. The FKBP5 rs1360780 polymorphism emerged as a key moderator of structural vulnerability, showing a “double-hit” effect when combined with epigenetic alterations. Furthermore, the study identifies sex-specific susceptibility, with divergent placental trajectories for male and female fetuses. Meta-analytic estimates confirmed the robustness of these associations (Rosenthal Fail-Safe N = 431,000), despite a general trend toward statistical significance (p = 0.079) in heterogeneous cohorts. Conclusions: The findings underscore a stable link between genetic determinants and prenatal stress reactivity. The interaction between molecular predisposition and environmental factors defines the health of the mother–infant dyad. These results advocate for a transition toward Precision Prenatal Medicine, integrating polygenic risk scores and epigenetic monitoring to implement early, targeted preventive interventions. Full article

Background: ADAMTS13 is a protein that cleaves large multimers of von Willebrand factor, thereby limiting platelet aggregation and adhesion and regulating thrombogenesis. Research findings suggest a possible association between low ADAMTS13 levels and an increased risk of cardiovascular events, and its activity may be influenced by polymorphic variants of the ADAMTS13 gene. Methods: The study group included 259 patients diagnosed with coronary artery disease (CAD) and 238 control blood donors. Genotyping of ADAMTS13 polymorphisms (rs2301612, rs2073932, and rs2285489) was performed using TaqMan PCR. Results: ADAMTS13 gene polymorphisms showed no association with CAD risk or patient survival at 5- or 10-year follow-up. However, higher HDL cholesterol levels were observed in carriers of the G alleles (rs2301612 and rs2073932) and the T allele (rs2285489). Additionally, the rs2285489 and rs2301612 polymorphisms were associated with certain proatherogenic lipid indices. In silico analysis indicated that all studied polymorphisms influenced gene expression in certain vascular tissues or blood. Conclusions: ADAMTS13 gene polymorphisms may affect gene expression in specific tissues; however, this effect does not appear sufficient to meaningfully influence CAD onset or patient survival. A significant association between the analyzed polymorphisms and HDL levels or some proatherogenic lipid indices was observed; however, the underlying mechanism requires further investigation. Full article

Serum gamma-glutamyltransferase (GGT) is a biomarker for cardiovascular disease, but the role of its encoding gene family in ischemic stroke (IS) is unknown. This pilot study of 1288 individuals (600 cases and 688 controls) investigated GGT1, GGT5, GGT6, and GGT7 polymorphisms using the MassARRAY-4 system. Conventional single-variant, haplotype, and diplotype analyses were complemented by Model-Based Multifactor Dimensionality Reduction (MB-MDR) with stability assessment and model prioritization. Conventional analysis identified female-specific associations for three GGT5 variants (rs8140505, rs2275984, and rs2267073; P_perm < 0.05). A common GGT5 haplotype was protective in females (P_perm = 0.02). Diplotype analysis revealed joint effects of GGT genotypes on IS risk in females (FDR < 0.05). MB-MDR uncovered complex higher-order interactions (P_perm < 0.0001): in women, 12 models represented second-order interactions between smoking and individual GGT variants. In men, 8 models centered on GGT1 rs5751909 spanning second- to fourth-order interactions with alcohol, smoking, and other GGT family members. All prioritized models passed FDR correction (q < 0.05) and achieved higher weighted composite scores. eQTL data linked these variants to regulatory networks controlling glutathione metabolism, oxidative stress, and inflammation. This study supports a novel hypothesis on the combined involvement of GGT gene family polymorphisms and pro-oxidant environmental factors in ischemic stroke predisposition, demonstrating that disease risk is shaped by sex-specific gene–environment interactions. The pronounced sexual dimorphism highlights the need for sex-specific personalized approaches: smoking cessation may be particularly impactful in women carrying GGT5 risk variants, while alcohol moderation could be prioritized in men with GGT1 risk variants. Full article

Alzheimer’s disease (AD), the most common cause of dementia, is characterized by progressive memory and cognitive decline. Conventional genome-wide association studies (GWAS) comparing AD cases and controls may miss genetic influences that act along a continuum of cognitive function. Using data from 3007 participants in the National Institute on Aging Late-Onset Alzheimer’s Disease Family Study (NIA-LOAD GWAS), we conducted a family-based GWAS of eight quantitative cognitive phenotypes encompassing episodic memory (Logical Memory IA and IIA), working memory (Digit Span Forward, Backward, and Ordering), and semantic fluency (Animal, Fruit and Vegetable, and Vegetable Fluency). Family-based association testing in PLINK v1.9 identified numerous single nucleotide polymorphisms (SNPs) associated with cognitive phenotypes at genome-wide significant (p < 5 × 10⁻⁸) levels. Notably, genome-wide significant variants with cognatic functions were localized to genes implicated in synaptic function, neurodevelopment, and neurodegeneration, including TOMM40 (rs2075650), ERBB4 (rs1521543), APLP2 (rs12281267, rs959354), PTPRD (rs1353983, rs970347, rs1392511), NCAM2 (rs2826728), GRM7 (rs6788201), PAX5 (rs2988003, rs2381595), NRG1 (rs16875655), and NRG3 (rs1937957). Furthermore, the TOMM40 (rs2075650) was significantly associated with AD as a binary outcome (p = 4.60 × 10⁻²⁴) and APLP2 (rs12281267, rs959354), APOE (rs405509), PTPRD (rs1353983, rs970347, rs1392511) were associated with AD (p < 0.001). Additionally, several pathways including the ERBB4 signaling pathway (adjusted p = 2.82 × 10⁻³), driven by ERBB4, NRG1, and NRG3 may contribute to cognitive impairments. This study provides a comprehensive resource of cognitive endophenotype associations in AD families, advancing understanding of the genetic architecture underlying memory, executive function, and cognitive aging, and highlights new therapeutic targets for replication and functional follow-up. Full article

Background/Objectives: Understanding the genetic basis of food consumption is a key step toward precision nutrition, viewed as a long-term future perspective. This study aimed to investigate genetic variants associated with grapefruit (Citrus paradisi) intake and to evaluate their potential relationship with obesity risk. Methods: A genome-wide association study (GWAS) was conducted on 19,653 European-ancestry participants from two prospective cohorts, the Nurses’ Health Study (NHS) and the Health Professionals Follow-Up Study (HPFS). We employed a functional annotation strategy to select a suggestive locus for follow-up analysis, and computationally derived molecular docking simulations explored a plausible functional link between grapefruit’s bioactive compounds and the candidate gene product. Results: Although falling short of the conventional threshold for genome-wide significance, a suggestive locus was prioritized on chromosome 14, with the lead single nucleotide polymorphism (SNP), rs2124 (p < 5 × 10⁻⁶), located within the metabolic gene ADCK1 (aarF domain containing kinase 1). Molecular docking simulations supported a plausible mechanistic hypothesis, indicating that key bioactive compounds in grapefruit could bind with high affinity to the ADCK1 protein. Consistent with the GWAS finding, individuals with the CC genotype reported lower mean grapefruit intake. This genotype was also associated with other lifestyle factors, notably, lower physical activity in women. In age- and multivariate-adjusted models, the CC genotype was associated with a modestly increased risk of incident obesity in females, but not in males. Conclusions: Our exploratory findings suggest a prioritized candidate locus associated with grapefruit intake, and its link to obesity risk may be mediated by the metabolic gene ADCK1. However, given the lack of genome-wide significance and independent replication, these findings should be considered preliminary and exploratory. These hypothesis-generating results support the integration of genetics and dietary habits, warranting further mechanistic validation. Full article

Inter-individual variability in outcomes following radiotherapy-based treatment remains a major challenge in head and neck squamous cell carcinoma (HNSCC). Osteopontin (OPN) and its receptor CD44 are key mediators of tumor progression, hypoxia-related treatment resistance, and metastatic dissemination. In this exploratory, hypothesis-generating study, we investigated selected functional polymorphisms in OPN (SPP1) and CD44 genes, together with pretreatment plasma OPN levels, in relation to overall survival (OS), locoregional recurrence-free survival (LRFS), and metastasis-free survival (MFS) in 242 HNSCC patients treated with curative-intent radiotherapy alone (RT) or combined with chemotherapy (RT + CT). In individual multivariable models, the OPN rs11730582 C and CD44 rs13347 T variants were associated with improved survival outcomes, while elevated OPN levels correlated with shorter OS. In full multivariable models, rs11730582 C and high OPN levels remained independent predictors of OS in the entire cohort. In the RT + CT subgroup, high OPN independently predicted worse OS, whereas rs13347 T was associated with better MFS. In the RT subset, rs11730582 CC independently predicted longer OS. These findings suggest that both germline variability within the OPN-CD44 signaling axis and circulating OPN levels are associated with treatment outcomes in HNSCC patients receiving radiotherapy-based regimens. Given the exploratory design, further validation in independent cohorts is warranted. Full article

Background: Epilepsy is a chronic disorder with a higher prevalence in low- and middle-income countries. ATP-binding cassette superfamily B1 (ABCB1) not only has a potential influence on the resistance to antiepileptic drugs but also plays a possible role in the occurrence of epilepsy. Purpose: To evaluate the association of ABCB1 polymorphisms, c.1236C>T (rs1128503), c.2677G>T (rs2032582), and c.3435C>T (rs1045642), with epilepsy susceptibility in a Jordanian cohort. Subjects and methods: Eighty-six cases of patients with epilepsy were analyzed using polymerase chain reaction (PCR) for ABCB1 c.1236C>T, c.2677G>T, and c.3435C>T gene variants. The proportions of genotypes and alleles in the epilepsy group were compared with one hundred healthy controls who were previously also analyzed by PCR. Results: The C alleles of the ABCB1 polymorphisms c.1236C>T and c.3435C>T were more prevalent in the epilepsy group than in controls. The patients with epilepsy were less likely to have the TT genotype compared with controls (concerning ABCB1 c.1236C>T) (OR_{TT vs. CC} = 0.42; 95% CI = [0.19–0.91]; p = 0.019). The CC genotype of ABCB1 c.3435C>T was more frequent in epileptics than healthy people (OR_{CC vs. TT} = 4.3; 95% CI = [1.8–9.95]; p = 0.0007). No significant difference in ABCB1 c.2677G>T allelic and genotypic frequencies was observed between epileptic cases and healthy volunteers. Conclusion: Our findings suggest that ABCB1 c.1236C>T and c.3435C>T variants were associated with epilepsy susceptibility in this Jordanian cohort, whereas no significant association was observed for c.2677G>T. These findings should be interpreted cautiously because of the modest sample size and require validation in larger, independent studies. Full article

Age-related macular degeneration (AMD) is a complex retinal disease influenced by genetic and metabolic factors. Genetic variants impact disease susceptibility, while alterations in amino acid and purine metabolism are involved in AMD development. This study aimed to examine the association between the COL2A1 rs1635529 polymorphism and AMD, as well as its relation to specific metabolites. The study comprised 919 participants: 261 with early AMD, 229 with exudative AMD, and 429 controls. DNA was extracted using the salting-out method, and genotyping was performed using real-time PCR. Metabolite levels were analysed with liquid chromatography–mass spectrometry. Statistical analysis was conducted using IBM SPSS Statistics 27.0. Logistic regression revealed that carriers of the GT + TT genotypes had a 1.63-fold higher risk of early AMD (p = 0.046). The T allele was also linked to a 1.67-fold elevated risk (p = 0.033). No significant associations were observed in exudative AMD. Furthermore, lower leucine levels were noted in exudative AMD patients, and inosine levels were reduced in GT genotype carriers within the early AMD group. The COL2A1 rs1635529 polymorphism showed a nominal association with early AMD, but not exudative AMD. Differences in leucine and inosine levels were observed, suggesting a potential link between genetic variation and metabolic alterations. These findings indicate possible involvement of collagen-related and metabolic pathways in early disease development; however, the results should be interpreted with caution and require validation in larger studies. Full article

Backgrounds: The aim of this pilot study was to evaluate the hierarchical contribution of individual genetic polymorphisms to the variability of autonomic regulation parameters and respiratory function in athletes of different sport specializations using Classification and Regression Tree (CRT) analysis. Methods: The study included athletes divided into two groups: hockey players (n = 48) and martial artists (n = 43). Heart rate variability (LF, HF) parameters and spirometric indices (FEV₁) were assessed. Genetic analysis included 8 single nucleotide polymorphisms (SNPs): IL6 rs1800795, VDR rs731236, KCNJ11 rs5219, ADRB2 rs1042713, ADRB2 rs1042714, TRHR rs16892496, MSTN rs1805086, UCP3 rs1800849. Results: In martial artists, the main predictors were genes responsible for adrenoreceptor sensitivity (ADRB2) and neuroimmune interactions (IL6). In hockey players, the most significant predictors were genes involved in muscle growth (MSTN), energy metabolism (UCP3), and neuroendocrine regulation (TRHR). These findings indicate that similar resting HRV parameters in athletes from different sports may be associated with different genetic polymorphisms, reflecting sport-specific physiological adaptations to training loads. Conclusions: The results highlight the sport-specific nature of genetic determinants of autonomic regulation. In martial artists, genes related to the immuno-adrenergic axis (IL6, ADRB2) appear to play a dominant role, whereas in hockey players neuroendocrine, muscle-metabolic, and mitochondrial factors (TRHR, MSTN, UCP3) demonstrate greater influence. The observed interactions between genotypes and FEV₁ emphasize the importance of transitioning from generalized approaches toward personalized monitoring strategies in sports science. Full article

Basal blood pressure (BP) is partly determined by systemic vascular resistance, which is modulated by vasoactive pathways, including gaseous messengers. Carbon monoxide (CO), continuously generated by the constitutive enzyme heme oxygenase-2 (HO-2) encoded by HMOX2, promotes vascular smooth muscle relaxation and may contribute to interindividual variability in resting BP. The functional single-nucleotide polymorphism rs4786504_T>C has been associated with higher HMOX2 expression in C-allele carriers, providing a plausible biological link between genetic variation in the HO-2/CO pathway and vascular redox signaling. We investigated this association in forty young, healthy, normotensive adults studied under controlled laboratory conditions during a 4-day sleep deprivation protocol, with repeated standardized daytime BP measurements (478 observations). Linear mixed-effects models were adjusted for major physiological and behavioral covariates. T-allele carriers (C/T + T/T) exhibited higher diastolic BP (β = +6.08 mmHg, 95%CI [1.32–10.84], p = 0.017) and mean arterial pressure (β = +5.28 mmHg, 95%CI [0.28–10.29], p = 0.046) than C/C homozygotes, with no effect on systolic BP or heart rate. The association remained consistent across sensitivity and additive genetic models. This hypothesis-generating study provides preliminary evidence in humans, albeit limited by sample size, of a link between a functional HMOX2 variant and resting BP, consistent with a possible contribution of constitutive HO-2 activity to BP regulation. Full article