Genetic Risk Factors Research Articles

Genome-wide association study of the fatty liver index in the Taiwanese population reveals shared and population-specific genetic risk factors across ethnicities

Background and objectivesAlthough the incidence of fatty liver disease (FLD) is increasing worldwide, the genetic basis of this disease is not fully understood. This study uses the fatty liver index (FLI) to identify and compare genetic variants associated with FLD in Taiwanese and European populations.ResultsIn this study, a total of 145,356 Taiwan Biobank participants were included in the discovery analysis. Subjects with elevated FLI were found to have a significantly greater risk of developing FLD, as confirmed by imaging data (OR: 4.43; 95% CI: 3.88–5.06). Through genome-wide association studies (GWAS), we identified 6 variants previously associated with nonalcoholic fatty liver disease (NAFLD) and validated 50 shared risk variants located in ZPR1 and FTO between the Taiwanese and European populations. Conditional analysis of 423 significant variants from FLI-defined FLD further revealed 16 independent variants within 14 genes. Pathway analysis of GWAS significant genes revealed that lipid metabolism and the peroxisome proliferator-activated receptor (PPAR) signaling pathway are causes of hepatic fat accumulation.ConclusionThis study identified six independent NAFLD-associated variants in GCKR, LPL, TRIB1AL, and FTO and emphasized ZPR1 and FTO as shared risk genes for FLI-defined FLD in both Taiwanese and European populations. These findings support the utility of the FLI for FLD prediction, provide new genetic insights, and reveal the common genetic pathways of FLD across two ethnic groups. This research offers a valuable framework for advancing personalized medicine and therapeutic strategies for FLD.

The impact of apolipoprotein E, type ∊4 allele on Alzheimer's disease pathological biomarkers: a comprehensive post-mortem pilot-analysis.

The apolipoprotein E type ∊4 allele (ApoE4) is known as the strongest genetic risk factor for Alzheimer's Disease (AD). Meanwhile, many aspects of its impact on AD pathology remain underexplored. This study conducts a systematic data analysisof donor data from the Seattle Alzheimer's Disease Brain Cell Atlas. Our investigation delves into the intricate interplay between identified biomarkers and their correlation with ApoE4 across all severities of AD. Employing Pearson R correlation, and one-way and two-way ANOVA tests, we elucidate the pathological changes in biomarkers and the altering effects of ApoE4. Remarkably, the phosphorylation of tau observed in neurofibrillary tangles (NFTs) marked by the AT8 antibody, emerges as the most correlated factor with other pathological biomarkers. This correlation is mediated by both tau and amyloid pathology, suggesting a higher hierarchical role in determining AD pathological effects than other biomarkers. However, non-ApoE4 carriers exhibit a more significant correlation with disease progression severity compared to ApoE4 carriers, though ApoE4 carriers demonstrate significance in exacerbating the effect of accumulating phosphorylated tau and amyloid plaques assessed by AT8 and 6E10 antibodies. Furthermore, our analysis does not observe dramatic neuronal changes in grey matter across the span of AD pathology. Glia activation, measured by Iba1 and GFAP, demonstrates an amyloid-specific correlation. This research marks the first human post-mortem analysis providing a comprehensive examination of prevailing AD biomarkers and their interconnectedness with pathology and ApoE4 genetic factor. Limitations in the study are acknowledged, underscoring the need for further exploration and refinement in future research endeavors.

Clinical, immune and genetic risk factors of malaria-associated acute kidney injury in Zambian children: A study protocol.

Acute kidney injury (AKI) affects nearly half of children with severe malaria and increases the risk of adverse outcomes such as death and poor cognitive function. The pathogenesis and predictors of malaria-associated acute kidney injury (MAKI) are not fully described. This study aims to determine the clinical, immune, and genetic correlates of risk to AKI in Zambian children admitted with malaria. In addition, we intend to assess a modified renal angina index (mRAI), kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), and soluble urokinase receptor (suPAR), when done on the first day of admission, for the ability to predict AKI two days later (day 3) in children admitted with malaria. This is an unmatched case-control study with a nested prospective observational study. A case-to-control ratio of 1:1 is used and 380 children with malaria and aged less than 16 years are being recruited from two hospitals in Zambia. Eligible children are recruited after obtaining written informed consent. Recruitment occurs during the malaria season and began on 6th March 2024 and will continue until July 2025. AKI is defined using the 2012 KIDGO AKI creatinine criteria, and cases are defined as children admitted with malaria who develop AKI within 72 hours of admission, while controls are children admitted with malaria but with no AKI. Serum creatinine is collected on Day 1 within 24 hours of admission, on Day 3 and then again on discharge or day 7, whichever comes sooner. Baseline biomarker concentrations will be determined using the Luminex multiplex Elisa system or high-sensitivity ELISA. SPSS version 29 will be used for data analysis. Descriptive statistics and inferential statistical tests will be run as appropriate. A p ≤ 0.05 will be considered as significant. The sensitivity, specificity, and estimates of the area under the curve (AUC) for the renal angina score will be determined.

Selenium and Episodic Memory: The Moderating Role of Apolipoprotein E ε4

Background: Selenium (Se), a vital trace element, plays a neuroprotective role by mitigating oxidative stress through selenoproteins and regulating metal balance. The apolipoprotein E ε4 allele (APOE4), a significant genetic risk factor for Alzheimer’s disease (AD), has been linked to reduced Se levels and weakened antioxidant capacity. This research explores the association between serum Se concentrations and cognitive performance, with an emphasis on how APOE4 status influences this relationship. Methods: This study included 196 older adults from community and memory clinic settings, who underwent assessments for episodic memory, global cognition, and non-memory functions using the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) neuropsychological battery, with serum selenium levels analyzed via inductively coupled plasma–mass spectrometry (ICP-MS) and APOE genotyping conducted to determine allele status. Results: Higher serum Se levels were associated with better episodic memory score (EMS) (B = 0.065, 95% CI = 0.020–0.110, p = 0.005) and CERAD total score (TS) (B = 0.119, 95% CI = 0.046–0.193, p = 0.002). However, the interaction between Se and APOE4 status significantly affected EMS (B = −0.074, 95% CI = −0.109 to −0.039, p < 0.001), with significant benefits observed in APOE4-negative participants. Conclusions: This study highlights the genotype-specific impact of Se on cognitive health, emphasizing the need for personalized nutritional interventions targeting Se levels, particularly for APOE4-negative individuals. Future research should further elucidate the mechanisms of Se’s effects and assess its therapeutic potential in aging populations.

Breast cancer risk assessment based on a predictive model: evaluation of risk factors among Japanese women

BackgroundEach breast cancer (BC) risk factor has different effects on different populations. However, there are no well-studied and validated BC risk prediction models for Japanese women. We developed accessible predictive models for Japanese women with optimal variables to evaluate risk factors for use by both medical institutions and women for primary BC prevention and to increase the BC screening rate. We evaluated the characteristics and distribution diversity of risk factors in this population.MethodsThis retrospective case–control study of 2,494 Japanese women included data from an original, paper-based questionnaire. The logistic regression models included 18 variables from 6 risk factors based on menopausal status (PRE, premenopausal; PERI, perimenopausal; and POST, postmenopausal). Models were evaluated based on the Akaike Information Criterion, area under the receiver operating characteristic curve (AUC), and internal validation. Bootstrap methods for bias correction in discrimination and calibration and standard deviations were calculated by the modified case–control ratio.ResultsWe created and evaluated 432 candidate models for each group. Notably, BMI, parity, FHx, and smoking history were found to increase risk in all groups. Risk-reducing factors included breastfeeding duration in the PRE and PERI models and regular alcohol consumption in the PERI and POST models. Age reduced risk in the PERI model but increased risk in the POST model. Differences were observed between PRE and PERI versus POST with respect to variable selection in parity and FHx. Our models had moderate discriminatory accuracy. AUCs (confidence intervals) of the PRE, PERI, and POST models were 0.669 (0.625–0.715), 0.669 (0.632–0.702), and 0.659 (0.627–0.693), respectively. Bias-corrected AUCs (standard deviations) were 0.697 (0.041) for PRE, 0.684 (0.033) for PERI, and 0.674 (0.031) for POST, respectively. Our models were well-calibrated after bias correction.ConclusionOur widely available, simple, and cost-effective models with optimal variables could indicate the characteristics of certain genetic and environmental risk factors for BC in Japanese women.

Epigenome-Wide Association Study of Asthma Exacerbations in Europeans.

Asthma exacerbations (AEs) represent the major contributor to the global asthma burden. Although genetic and environmental factors have been associated with AEs, the role of epigenetics remains uncovered. This study aimed to identify whole blood DNA methylation (DNAm) markers associated with AEs in Europeans. DNAm was assessed in 406 blood samples from Spanish individuals using the Infinium MethylationEPIC microarray (Illumina). An epigenome-wide association study was conducted to test the association of DNAm with AEs at differentially methylated positions, regions, and epigenetic modules. CpGs suggestively associated with AEs(false discovery rate [FDR] < 0.1) were followed up for replication in 222 European individuals, and the genome-wide significance (p < 9 × 10-8) was declared after meta-analyzing the discovery and replication samples. Additional assessment was performed using nasal tissue DNAm data from 155 Spanish individuals. The effects of genetic variation on DNAm were assessed through cis-methylation quantitative trait loci (meQTL) analysis. Enrichment analyses of previous EWAS signals were conducted. Four CpGs were associated with AEs, and two were replicated and reached genomic significance in the meta-analysis (annotated to ZBTB16 and BAIAP2). Of those, CpG cg25345365 (ZBTB16) was cross-tissue validated in nasal epithelium (p= 0.003) and associated with five independent meQTLs (FDR < 0.05). Additionally, four differentially methylated regions and one module were significantly associated with AEs. Enrichment analyses revealed an overrepresentation of prior epigenetic associations with prenatal and environmental exposures, immune-mediated diseases, and mortality. DNAm in whole blood and nasal samples may contribute to AEs in Europeans, capturing genetic and environmental risk factors.

Sex-specific influences of APOEε4 genotype on hippocampal neurogenesis and progenitor cells in middle-aged rats

Alzheimer's disease (AD) disproportionately and uniquely affects females, and these sex differences are further exacerbated by the presence of Apolipoprotein (APOE) ε4 alleles, the top genetic risk factor for late-onset AD. To expand our understanding about how late-onset AD risk might differentially influence males and females, this study explores how APOEε4 affects hippocampal neurogenesis and microglia, key neuroplastic markers involved in AD pathogenesis, differently by sex in middle-aged rats. A rat model expressing the humanized (h) APOEε4 allele was characterized to examine markers of adult neurogenesis (neural progenitor cells and new-born neurons) and immune cells (microglia) in the dentate gyrus of the hippocampus in 13 month-old male and female rats. We observed basal sex differences in neurogenesis at middle age, as wildtype male rats had greater densities of neural progenitor cells and new-born neurons in the dentate gyrus than wildtype female rats. Male hAPOEε4 rats exhibited fewer neural progenitor cells, fewer new-born neurons, and more microglia than male wildtype rats. On the other hand, female hAPOEε4 rats exhibited more new-born neurons than female wildtype rats. Interestingly, females had more microglia than males regardless of genotype. Correlations were conducted to further elucidate any sex differences in the relationships between these biomarkers. Notably, there was a significant positive correlation between neural progenitor cells and new-born neurons, and a significant negative correlation between new-born neurons and microglia, but only in male rats. In contrast to the clear pattern of effects of the hAPOEε4 risk factor on hippocampal neurogenesis in males, females had unaltered levels of neural progenitor cells and increased density of new-born neurons. Furthermore, relationships between neurogenesis and microglia were significantly correlated within males, and not females. This suggests that females may be presenting a compensatory response to the hAPOEε4 genotype at middle age. Collectively, these results exemplify the importance of thoroughly examining influences of sex on AD endophenotypes, as it may reveal sex-specific pathways and protective mechanisms relevant to AD.

Contributions of Genetic Variation in Astrocytes to Cell and Molecular Mechanisms of Risk and Resilience to Late-Onset Alzheimer's Disease.

Reactive astrocytes are associated with Alzheimer's disease (AD), and several AD genetic risk variants are associated with genes highly expressed in astrocytes. However, the contribution of genetic risk within astrocytes to cellular processes relevant to the pathogenesis of AD remains ill-defined. Here, we present a resource for studying AD genetic risk in astrocytes using a large collection of induced pluripotent stem cell (iPSC) lines from deeply phenotyped individuals with a range of neuropathological and cognitive outcomes. IPSC lines from 44 individuals were differentiated into astrocytes followed by unbiased molecular profiling using RNA sequencing and tandem mass tag-mass spectrometry. We demonstrate the utility of this resource in examining gene- and pathway-level associations with clinical and neuropathological traits, as well as in analyzing genetic risk and resilience factors through parallel analyses of iPSC-astrocytes and brain tissue from the same individuals. Our analyses reveal that genes and pathways altered in iPSC-derived astrocytes from individuals with AD are concordantly dysregulated in AD brain tissue. This includes increased levels of prefoldin proteins, extracellular matrix factors, COPI-mediated trafficking components and reduced levels of proteins involved in cellular respiration and fatty acid oxidation. Additionally, iPSC-derived astrocytes from individuals resilient to high AD neuropathology show elevated basal levels of interferon response proteins and increased secretion of interferon gamma. Correspondingly, higher polygenic risk scores for AD are associated with lower levels of interferon response proteins in astrocytes. This study establishes an experimental system that integrates genetic information with a matched iPSC lines and brain tissue data from a large cohort of individuals to identify genetic contributions to molecular pathways affecting AD risk and resilience.

Overview of the etiology of childhood cancer and future directions.

We provide an overview of the etiology of childhood cancer, the state of the literature, and highlight some opportunities for future research, including technological advancements that could be applied to etiologic studies of childhood cancer to accelerate our understanding. Risk factors of childhood cancer were summarized based on demographics and perinatal factors, environmental risk factors, and genetic risk factors. Overall, demographics and perinatal factors are the most well studied in relation to childhood cancer. While environmental risk factors have been implicated, more work is needed to pinpoint specific exposures, identify window(s) of susceptibility, and understand mechanisms. With genome-wide association studies (GWAS), genetic risk factors of eight childhood cancers have emerged, and opportunities remain to conduct GWAS for other cancer types and determine whether risk variants are inherited or de novo. Technological advancements that can shed light into the susceptibility of childhood cancer include metabolomics, using primary teeth as an exposure matrix, and long-read sequencing. The development of childhood cancer remains largely not well understood. Collaboration to increase sample size to conduct analyses by histology and/or molecular subtype and application of novel technologies will accelerate our understanding of childhood cancer.

Modifiable lifestyle factors and risk of intracranial aneurysm: A univariate and multivariate Mendelian randomisation study.

The aim of this study was to assess the potential causal relationship between lifestyle factors and intracranial aneurysms (IAs) using a two-sample Mendelian randomization (MR) approach. The study used a pooled dataset from a genome-wide association study that covered information on 24 lifestyle factors, intracranial aneurysm cases, subarachnoid hemorrhage, and unruptured aneurysms. Five MR methods were applied for analysis by selecting single nucleotide polymorphisms as instrumental variables, with the inverse variance weighting method as the main method. To ensure the stability of the results, horizontal multiple validity tests, sensitivity analyses, and inverse MR were performed, and genetically determined exposure factors were adjusted by multivariate MR. Several lifestyle factors were found to have a significant genetic causal effect on the occurrence and development of intracranial aneurysms. For example, lamb intake, smoking initiation, number of cigarettes smoked per day, length of television viewing, and fatigue were identified as genetic risk factors and strongly associated with aneurysm rupture, whereas red wine intake showed some genetic protection against intracranial aneurysms and similarly affected aneurysm rupture. Sensitivity analyses and inverse MR verified the robustness of these results. After adjusting for exposure factors, multivariate MR confirmed daily smoking and smoking initiation as risk factors for intracranial aneurysms, unruptured aneurysms, and subarachnoid hemorrhage, whereas red wine intake was a genetically protective factor against intracranial aneurysms and subarachnoid hemorrhage. This MR analysis revealed a genetic causal link between specific lifestyle factors and intracranial aneurysms, emphasizing the need for further studies to confirm these findings and explore their mechanisms.

Platelet related gene IQGAP1 contributes to the onset and abnormal immune landscape of ischemic stroke patients.

Ischemic stroke (IS) is a complex illness resulting from a combination of numerous environmental and genetic risk factors. Recent reports have shed light on the vital role that platelets play in the pathophysiology of IS. Here, we aimed to explore the potential platelet-related genes in IS and investigate the effect of platelet-related genes in the immune microenvironment of IS. The data of IS were retrieved from the Gene Expression Omnibus database. Firstly, we screened the platelet-related genes that were correlated with the onset of IS using differential expression analysis, enrichment analyses, and protein-protein interaction (PPI) network. Moreover, we analyzed the clinical value and functional information of platelet-related genes in IS. Finally, we explored the correlation between platelet-related genes and immune cells' infiltration. Ten platelet-related genes that were correlated with the onset of IS were identified, among which IQGAP1 was located at the core of the PPI network. IQGAP1 was found to be expressed in the normal brain tissue and its expression was significantly elevated in IS samples. The area under the curve (AUC) values for IQGAP1 in both the GSE16561 and GSE58294 datasets were close to 1. IQGAP1 knockdown might increase OGD/R‑induced HT22 cell viability. Additionally, FoxO signaling pathway, NOD-like receptor signaling pathway, Phagosome and Platelet activation pathways were significantly activated in IS patients with high IQGAP1 expression compared to those with low IQGAP1 expression. The IS patients in the IQGAP1high and IQGAP1low groups showed dramatically different proportions of immune cells and immune-related functions, and the IQGAP1 expression was correlated with the immune cell' infiltration in IS. In this study, we identified the IQGAP1 might serve as a potential diagnostic marker for IS, and the IQGAP1 expression was very relevant in determining the immune cell' infiltration in IS patients.

Abstract TMP101: Clinical and Genetic Risk Factors Predict Atrial Fibrillation Based on Hypertrophic Cardiomyopathy

Background: Clinical and genetic predispositions are significant in predicting atrial fibrillation (AF); however, their role in patients with hypertrophic cardiomyopathy (HCM) remains unclear. This study aims to elucidate the impact of clinical and genetic risk factors on the development of AF in patients with and without HCM. Methods: This retrospective analysis involved data from the UK Biobank cohort, collected between 2006 and 2010. The cohort comprised 500,543 individuals: 1,361 diagnosed with and 499,182 without HCM. Participants were stratified based on their validated polygenic risk score for AF: the bottom 10% constituted the low-risk genetic group, the top 10% comprised the high-risk genetic group, and the remainder comprised the intermediate-risk genetic group. We assessed the incidence of AF and cardiovascular complications and analyzed its predictors, including genetic risk. Results: We examined 1,180 patients with HCM (mean age 61.1±7.1, 63.0% male) and 476,238 participants without HCM (mean age 57.0±8.1, 45.3% male). During the 11.6-year follow-up period, the age- and sex-adjusted AF incidence rates for the low-, intermediate-, and high-risk genetic groups were 2.4, 3.6, and 5.4 per 100 person-years in patients with HCM and 0.2, 0.5, and 1.0 per 100 person-years in participants without HCM, respectively. Genetic risk was a less significant predictor of AF in HCM groups (HR:2.51, 95%CI:1.59–3.98) than in non-HCM groups (HR:4.77, 95%CI:4.47–5.09) ( P =0.008 for interaction). Clinical risk factors, including male sex, body mass index, hypertension, and previous myocardial infarction, were less significant predictors of AF in patients with HCM than in those without HCM. A high genetic risk was significantly associated with the risk of cardiovascular complications in participants with and without HCM. Conclusions: Genetic predisposition was associated with the development of AF and cardiovascular complications in people with and without HCM; this association was weaker in the HCM group.

Risk factors for isolated congenital heart defects in infants from Western Mexico.

Congenital heart defects (CHDs) are caused by a complex interaction between numerous genetic and environmental risk factors, some of which may differ between different populations. A case-control study was conducted among 1232 newborns, including 308 patients with isolated CHDs (cases) and 924 infants without birth defects (controls), born all during the period 2009-2023 at the Hospital Civil de Guadalajara "Dr. Juan I. Menchaca" (Guadalajara, Mexico). Potential parental risk factors for CHDs were compared using multivariate logistic regression analysis to evaluate the deviance explained by different variables of interest. Consanguinity [adjusted odds ratio (aOR) = 3.3; 95% confidence interval (CI) 1.3-8.5], relatives with CHD (aOR = 8.5; 95% CI 5.3-13.8), maternal first-trimester exposure to diabetes (aOR = 3.5; 95% CI 2.4-5.1), hypertension (aOR = 2.6; 95% CI 1.5-4.4), alcohol consumption (aOR = 1.5; 95% CI 1.0-2.1), and illicit drug use (aOR = 2.4; 95% CI 1.2-5.3), as well as for the paternal history of alcohol consumption (aOR = 1.4; 95% CI 1.0-1.8) and illicit drug use (aOR = 2.7; 95% CI 1.7-4.1), were associated with CHDs. Contrarily, aOR for maternal age ≤19 years (aOR = 0.6; 95% CI 0.4-0.8) and maternal first-trimester coffee consumption (aOR = 0.7; 95% CI 0.5-0.9) have protective odds. Our results suggest that genetic factors, maternal diseases, environmental exposures, and reproductive factors can increase the occurrence of isolated CHDs in our sample, and they are discussed as clues in its pathogenesis.

No effect of apolipoprotein E polymorphism on MRI brain activity during movie watching.

Apolipoprotein E ε4 is a major genetic risk factor for Alzheimer's disease, and some apolipoprotein E ε4 carriers show Alzheimer's disease-related neuropathology many years before cognitive changes are apparent. Therefore, studying healthy apolipoprotein E genotyped individuals offers an opportunity to investigate the earliest changes in brain measures that may signal the presence of disease-related processes. For example, subtle changes in functional magnetic resonance imaging functional connectivity, particularly within the default mode network, have been described when comparing healthy ε4 carriers to ε3 carriers. Similarly, very mild impairments of episodic memory have also been documented in healthy apolipoprotein E ε4 carriers. Here, we use a naturalistic activity (movie watching), and a marker of episodic memory encoding (transient changes in functional magnetic resonance imaging activity and functional connectivity around so-called 'event boundaries'), to investigate potential phenotype differences associated with the apolipoprotein E ε4 genotype in a large sample of healthy adults. Using Bayes factor analyses, we found strong evidence against existence of differences associated with apolipoprotein E allelic status. Similarly, we did not find apolipoprotein E-associated differences when we ran exploratory analyses examining: functional system segregation across the whole brain, and connectivity within the default mode network. We conclude that apolipoprotein E genotype has little or no effect on how ongoing experiences are processed in healthy adults. The mild phenotype differences observed in some studies may reflect early effects of Alzheimer's disease-related pathology in apolipoprotein E ε4 carriers.

Cutaneous Mastocytosis in Pediatric Patients With Skin of Color: A Retrospective Cohort Study.

Cutaneous mastocytosis (CM) is a rare skin disease with limited data on its prevalence across different racial groups. This retrospective cohort study examines the characteristics of CM at Nationwide Children's Hospital (NCH) from January 2010to June 2022, identifying 192 confirmed cases of CM and further stratifying this cohort to 155 patients with documented Fitzpatrick phototypes. There were two important findings: first, nine (4.7%) of the CM cases were Black and 165 (85.9%) wereWhite, compared to 8502 (23.0%) Black and 21,177 (57.3%) White of the overall NCH dermatology population; second, 85.8% were Fitzpatrick phototypes I-III, and 14.9% were types IV-VI with no significant differences, other thantypes IV-VIbeing more likely to receive treatment (p = 0.01). Our study highlights the need to better understand the genetics and other risk factors of CM, as well as the social determinants of health impacting pediatric patients with skin of color.

A retrospective study: Risk factors and clinical presentation of neonatal surgical conditions

Background: Neonatal surgical conditions are a significant cause of morbidity and mortality in neonates. This study analyzed the socio-demographic characteristics, risk factors, types, and clinical presentation of surgical conditions of neonates admitted for surgical interventions. Objectives: To evaluate the clinical presentation of neonatal surgical conditions, assess maternal health and birth risk factors, and identify prevalent surgical diagnoses. Methods: This was a retrospective review of medical records of neonates admitted with surgical conditions at Khartoum Teaching Hospital and Ibrahim Malik Teaching Hospital from January 2020 to August 2022. Data collected included socio-demographic information, maternal health history, birth characteristics, symptom duration, and diagnosis. Results: 114 neonates' medical records were reviewed. The majority (66, 57.9%) presented within the first week of life, with a male-to-female ratio of 1.2:1. Most neonates (87, 76.3%) were born to non-consanguineous couples, and 108 (94.7%) had no family history of similar conditions. Maternal comorbidities were rare 2 (1.8%). Birth weight distribution showed that 94 (82.5%) were of average weight. Congenital surgical conditions constituted 113 (99.1%) of cases, most cases were gastrointestinal 59 (51.8%), followed by CNS cases 23 (20.2%), abdominal wall defects 12 (10.5%), urological defects 8 (7%), respiratory cases 1 (0.9%), and other miscellaneous cases 11 (9.6%). Anorectal malformations constituted the most common gastrointestinal condition, accounting for 16 cases (14%), followed by Hirschsprung disease 13 (11.4%), jejunal atresia 11 (9.6%), and malrotation 9 (7.8%). Conclusions: This study highlights the prevalence of congenital anomalies as the primary cause of neonatal surgical conditions, with gastrointestinal malformations being the most common. Early presentation within the first week of life and the absence of significant maternal or genetic risk factors were notable findings. Addressing the challenges of late diagnosis, inadequate prenatal screening, and resource limitations is essential for improving outcomes in neonatal surgical care.

Exploration of Genetic Variants Associated with Lung Cancer: A Comprehensive Review

Lung cancer (LC) is a widespread and prevalent disease with a high death rate. The occurrence of this terrible disease is greatly influenced by genetic, occupational and environmental risk factors. Therefore, the present review aimed to investigate and accumulate the information regarding the causative gene of lung cancer. The articles included in this study were retrieved from various online sources, including Cochrane Library, Google Scholar, EMBASE, PubMed and Web of Science databases up to October 2024. Data were extracted based on the PRISMA 2020 guidelines. The study recognized several genetic mutations that are accountable for the progression of lung cancer. The most common identified lung cancer associated with genes include XRCC1, XRCC4, KRAS, TP53, EGFR, PI3KCA, ERCC2/XPD MET, ALK1, BRAF, HER2, LTKB-1/STK11, AKT1 and MAP2K1. Additionally, HER2, MAP2K1/MEK1, AKT, NRAS and various combinations of co-occurring mutations were also noted as stimulators of this cancer. These genes instigate lung cancer either by impairing DNA repair efficiency or interacting with various signaling pathways that result in cell proliferation, differentiation, angiogenesis, invasion and metastasis, such as, PI3k/AKT (phosphatidylinositol 3-kinase/protein kinase B) pathway, MAPKs (mitogen-activated protein) pathway, PKC (protein kinase C), JAK/STAT (Janus kinase/signal transducer and activator of transcription) pathway, as well as RAS signaling. Studying epigenetic mechanisms in lung cancer is crucial to understand the genetic variant linked to the disease and identify potential therapeutic targets and molecular targets of drugs. Bangladesh Pharmaceutical Journal 28(1): 114-125, 2025 (January)

APOEε4 alters ApoE and Fabp7 in frontal cortex white matter in prodromal Alzheimer's disease

The ApoE ε4 allele (APOEε4) is a major genetic risk factor for sporadic Alzheimer's disease (AD) and is linked to demyelination and cognitive decline. However, its effects on the lipid transporters apolipoprotein E (ApoE) and fatty acid-binding protein 7 (Fabp7), which are crucial for the maintenance of myelin in white matter (WM) during the progression of AD remain underexplored. To evaluate the effects of APOEε4 on ApoE, Fabp7 and myelin in the WM of the frontal cortex (FC), we examined individuals carrying one ε4 allele that came to autopsy with a premortem clinical diagnosis of no cognitive impairment (NCI), mild cognitive impairment (MCI) and mild to moderate AD compared with non-carrier counterparts. ApoE, Fabp7 and Olig2 immunostaining was used to visualize cells, whereas myelin basic protein (MBP) immunocytochemistry and luxol fast blue (LFB) histochemistry of myelin in the WM of the FC were combined with quantitative morphometry. We observed increased numbers of ApoE-positive astrocytes in the WM of both NCI and MCI APOEε4 carriers compared with non-carriers, whereas Fabp7-positive cells were elevated only in AD. Conversely, Olig2 cell counts and MBP immunostaining decreased in MCI APOEε4 carriers compared to non-carriers, while LFB levels were higher in NCI APOEε4 carriers compared to non-carriers. Although no correlations were found between ApoE, Fabp7, and cognitive status, LFB measurements were positively correlated with perceptual speed, global cognition, and visuospatial scores in APOEε4 carriers across clinical groups. The present findings suggest that the ε4 allele compromises FC myelin homeostasis by disrupting the lipid transporters ApoE, Fabp7 and myelination early in the onset of AD. These data support targeting cellular components related to WM integrity as possible treatments for AD.

Discovery of a MET-driven monogenic cause of steatotic liver disease.

Metabolic dysfunction-associated steatotic liver disease (MASLD) affects about a third of adults worldwide and is projected soon to be the leading cause of cirrhosis. It occurs when fat accumulates in hepatocytes and can progress to metabolic dysfunction-associated steatohepatitis (MASH), liver cirrhosis, and hepatocellular carcinoma. MASLD pathogenesis is believed to involve a combination of genetic and environmental risk factors. Single nucleotide polymorphisms have been implicated but non-syndromic monogenic causes are lacking. We identified a novel genetic variant in a familial case of MASH and performed deep variant functional analysis including protein modeling, dynamics, and cell-based assays to assess molecular mechanisms of dysfunction and altered cellular signaling. We analyzed exome sequencing data of 3,904 individuals with steatotic liver disease (SLD) to identify additional cases and establish the link between specific gene variants and SLD diagnosis. We discovered and functionally validated the NM_000245.4:c.3505A>T; p.(Ile1169Phe) variant in the MET (mesenchymal epithelial transition) kinase domain as a monogenic cause of SLD. Subsequently, we detected additional ultra-rare, previously un-interpreted, and likely deleterious variants in MET from screening sequencing data. Among individuals with confirmed SLD based on electronic record review, 1.1% (45/3,904) had rare predicted deleterious MET variants. Eight of 45 (17.7%) individuals had predicted deleterious variants in the MET kinase domain confirmed to be functionally like the familial case variant. We report the first germline non-malignant rare MET-driven disease, a monogenic form of SLD.

APOE4 and sedentary lifestyle synergistically impair neurovascular function in the visual cortex of awake mice

Reduced cerebral blood flow occurs early in the development of Alzheimer’s disease (AD), but the factors producing this reduction are unknown. Here, we ask whether genetic and lifestyle risk factors for AD—the ε4 allele of the Apolipoprotein (APOE) gene, and physical activity—can together produce this reduction in cerebral blood flow which leads eventually to AD. Using in vivo two-photon microscopy and haemodynamic measures, we record neurovascular function from the visual cortex of physically active or sedentary mice expressing APOE3 and APOE4 in place of murine APOE. Energy supply and demand are mismatched in APOE4 mice, with smaller increases in cerebral blood flow, blood volume and blood oxygenation occurring during neuronal activation as blood vessels frequently fail to dilate. Exercise dose-dependently overall improves neurovascular function, with an increased impact of exercise apparent after longer exposure times. Several haemodynamic measures show a larger beneficial effect of exercise in APOE4 vs. APOE3 mice. Thus, APOE4 genotype in conjunction with sedentary behaviour produces the worst neurovascular function. Promotion of physical activity may therefore be particularly important to improve cerebrovascular function and reduce dementia risk in APOE4 carriers.