Genetic Susceptibility Factors Research Articles

Direct and indirect regulation of β-glucocerebrosidase by the transcription factors USF2 and ONECUT2

Mutations in GBA1 encoding the lysosomal enzyme β-glucocerebrosidase (GCase) are among the most prevalent genetic susceptibility factors for Parkinson’s disease (PD), with 10–30% of carriers developing the disease. To identify genetic modifiers contributing to the incomplete penetrance, we examined the effect of 1634 human transcription factors (TFs) on GCase activity in lysates of an engineered human glioblastoma line homozygous for the pathogenic GBA1 L444P variant. Using an arrayed CRISPR activation library, we uncovered 11 TFs as regulators of GCase activity. Among these, activation of MITF and TFEC increased lysosomal GCase activity in live cells, while activation of ONECUT2 and USF2 decreased it. While MITF, TFEC, and USF2 affected GBA1 transcription, ONECUT2 might control GCase trafficking. The effects of MITF, TFEC, and USF2 on lysosomal GCase activity were reproducible in iPSC-derived neurons from PD patients. Our study provides a systematic approach to identifying modulators of GCase activity and deepens our understanding of the mechanisms regulating GCase.

VDR gene polymorphism in susceptibility to urolithiasis among the Asian population: A systematic review and meta-analysis

Urolithiasis is one of the most prevalent urinary diseases worldwide. Several studies have reported VDR gene polymorphisms to have a contributing genetic factor in susceptibility to urolithiasis and suggested its possibility of being a good candidate marker for urolithiasis. However, results across numerous studies centred on the relationship between the VDR gene polymorphism and urolithiasis have been inconclusive. To perform a meta-analysis concerning the association between the risk of urolithiasis and VDR gene polymorphismsviz., ApaI, BsmI, FokI, and TaqI among the Asian population. A comprehensive electronic search was conducted to identify published studies that investigates the relationship between four polymorphisms (ApaI, BsmI, FokI and TaqI) in the VDR gene and the risk of urinary stone disease using electronic databases. VDR ApaI and FokI polymorphisms were found to be associated with urolithiasis risk. Results from pooled analysis indicated ApaI aa genotype to be associated with urolithiasis compared to AA or Aa genotypes. In addition, the minor f allele of FokI variant was identified to be the risk allele in susceptibility to urolithiasis while F allele to be protective. Moreover, from the subgroup analysis, the ff genotype of FokI and aa genotype of ApaI were associated with higher risk of urolithiasis among the East Asian but not among the Southwest Asians.

Genetic Aspects of Glaucoma: An Updated Review.

Glaucoma is a group of diverse diseases characterized by cupping of the optic nerve head due to the loss of retinal ganglion cells. It is the most common cause of irreversible blindness throughout the word; therefore, its timely diagnosis and early detection through an ophthalmological examination are very important. We, herein, present the information on the epidemiology, pathophysiology, clinical diagnosis, and treatment of glaucoma. We also emphasize the investigations of the last decades that have allowed identifying numerous genes and susceptible genetic factors. We have also described in detail the genes whose mutations cause or contribute to the development of the disease.

Whole Exome Sequencing Identifies Epithelial and Immune Dysfunction-Related Biomarkers in Food Protein-Induced Enterocolitis Syndrome.

Food protein-induced enterocolitis syndrome (FPIES) is a food allergy primarily affecting infants, often leading to vomiting and shock. Due to its poorly understood pathophysiology and lack of specific biomarkers, diagnosis is frequently delayed. Understanding FPIES genetics can shed light on disease susceptibility and pathophysiology-key to developing diagnostic, prognostic, preventive and therapeutic strategies. Using a well-characterised cohort of patients we explored the potential genome-wide susceptibility factors underlying FPIES. Blood samples from 41 patients with oral food challenge-proven FPIES were collected for a comprehensive whole exome sequencing association study. Notable genetic variants, including rs872786 (RBM8A), rs2241880 (ATG16L1) and rs2289477 (ATG16L1), were identified as significant findings in FPIES. A weighted SKAT model identified six other associated genes including DGKZ and SIRPA. DGKZ induces TGF-β signalling, crucial for epithelial barrier integrity and IgA production; RBM8A is associated with thrombocytopenia absent radius syndrome, frequently associated with cow's milk allergy; SIRPA is associated with increased neutrophils/monocytes in inflamed tissues as often observed in FPIES; ATG16L1 is associated with inflammatory bowel disease. Coexpression correlation analysis revealed a functional correlation between RBM8A and filaggrin gene (FLG) in stomach and intestine tissue, with filaggrin being a known key pathogenic and risk factor for IgE-mediated food allergy. A transcriptome-wide association study suggested genetic variability in patients impacted gene expression of RBM8A (stomach and pancreas) and ATG16L1 (transverse colon). This study represents the first case-control exome association study of FPIES patients and marks a crucial step towards unravelling genetic susceptibility factors underpinning the syndrome. Our findings highlight potential factors and pathways contributing to FPIES, including epithelial barrier dysfunction and immune dysregulation. While these results are novel, they are preliminary and need further validation in a second cohort of patients.

Causal association between hyperthyroidism and risk of gastroesophageal reflux or esophageal cancer: a bidirectional Mendelian randomization investigation.

Emerging observational studies indicated an association between hyperthyroidism and gastrointestinal disorders. However, it remains unclear whether this association is causal, particularly in the case of gastroesophageal reflux (GERD) and esophageal cancer. To assess the potential causal relationship between hyperthyroidism and GERD or esophageal cancer, we conducted a bidirectional 2-sample Mendelian randomization study. Independent genetic instruments for hyperthyroidism from the UK Biobank (N case=3,545 and N control=459,388) and public genome-wide association study (GWAS) dataset (N case=3,731 and N control=480,867) were used to investigate the association with esophageal cancer in the UK Biobank study (N case=740 and N control=372,016) and GERD in the public GWAS database (N case=20,381 and N control=464,217). Four different approaches (inverse variance weighted (IVW), weighted mode, MR-Egger, and weighted median regression) were used to ensure that our results more reliable. Additional sensitivity analyses were also performed to validate our results. When hyperthyroidism was considered as the exposure factor, it appeared to act as a protective factor for GERD (ORIVW = 0.88, 95% CI, 0.79-0.99, P = 0.039), while as a risk factor for esophageal cancer (ORIVW = 1.03, 95% CI, 1.01-1.06, P = 0.003). However, there is no evidence supporting a reverse causal relationship between genetic susceptibility to hyperthyroidism and GERD or esophageal cancer. Our findings provided genetic evidence supporting bidirectional causal relationships between hyperthyroidism and GERD or esophageal cancer. These results substantiate certain discoveries from previous observational studies on a causal level and provide insight into relevant genetic susceptibility factors.

Central Serous Chorioretinopathy: Epidemiology, Genetics and Clinical Features.

Central serous chorioretinopathy (CSCR) is the fourth most common medical retinal disease. Moderate vision loss occurs in approximately one-third of patients who have the chronic form of the disease. CSCR has a multifactorial etiology, with acquired risk factors and increasing evidence of genetic susceptibility factors. The detection of new gene variants in CSCR and association of these variants with age-related macular degeneration provide insights into possible disease mechanisms. The contribution of multimodal ocular imaging and associated research studies to the modern-day clinical investigation of CSCR has been significant. This review aims to provide an overview of the most significant epidemiological and genetic studies of CSCR, in addition to describing its clinical and multimodal imaging features. The review also provides an update of the latest evidence from studies investigating pathophysiological mechanisms in CSCR and current opinions on multimodal imaging to better classify this complex retinal disease.

Pharmacological Strategies in Dermatomyositis: Current Treatments and Future Directions.

Dermatomyositis (DM) is a complex and rare autoimmune disease characterized by muscle weakness and distinctive skin rashes. Its pathogenesis involves a combination of genetic susceptibility, environmental triggers, and immunological factors, with interferon pathways and specific gene upregulations playing crucial roles. Diagnosis is based on clinical presentation, laboratory findings, and imaging, with particular emphasis on myositis-specific antibodies and characteristic muscle and skin changes. The clinical heterogeneity of DM, including variants such as clinically amyopathic DM and DM-associated interstitial lung disease, necessitates a personalized diagnostic and therapeutic approach. Current pharmacological treatments for DM include glucocorticoids, which remain the first-line therapy despite their long-term adverse effects. Immunosuppressants, such as azathioprine, methotrexate, and mycophenolate mofetil, are commonly used in combination with glucocorticoids to enhance efficacy and reduce steroid dependence. Biologics, such as rituximab and intravenous immunoglobulin, have shown effectiveness in refractory cases. Emerging therapies, particularly Janus kinase inhibitors, offer promise for treatment-resistant DM, although they present significant safety concerns, including increased risks of infections and cardiovascular events. Despite significant advancements, managing DM remains challenging due to its rarity and variability. Future research should prioritize the development of precision medicine approaches tailored to individual genetic and pathological features. Additionally, integrated treatment strategies combining pharmacological and non-pharmacological interventions are crucial to improving patient outcomes and quality of life. Understanding the etiology and pathogenesis of DM more deeply will be vital for developing more effective and targeted treatments, ultimately leading to better disease management and prognosis.

Exome Sequencing of a Blastomycosis Case–Control Cohort From Manitoba and Northwestern Ontario, Canada

ABSTRACTBackgroundBlastomycosis is a pulmonary disease caused by Blastomyces spp., a group of pathogenic dimorphic fungi endemic to a number of geographic regions, specifically Manitoba and northwestern Ontario, Canada. Immunosuppression is a major risk factor affecting disease susceptibility, yet host immunity is not well understood. Genetic immunodeficiencies can also influence disease, with variants in IL6, GATA2 and VDBP shown to influence susceptibility. Additional genetic factors in disease susceptibility and severity remain undetected. Our study seeks to identify potential genetic risk factors in a blastomycosis case–control cohort from Manitoba and northwestern Ontario, Canada.MethodsExomes from 18 blastomycosis cases and 9 controls were sequenced, variants were identified and filtered for accuracy and quality. We performed candidate gene prioritisation and variant aggregation to identify genetic associations and explored the full exome dataset.ResultsNinety‐nine genetic variants in 42 candidate genes were identified in the exome dataset. No variants associated with susceptibility were identified in a single‐variant analysis although two non‐synonymous variants in TYK2 were enriched among cases suggesting a possible role in susceptibility. Gene‐based association analysis found variants in TLR1 enriched in controls (p = 0.024) suggesting a possible protective effect. Gene cluster analysis identified genetic variants in genes of chromatin remodelling, proteasome and intraflagellar transport significantly enriched in cases (false discovery rates < 14%).ConclusionsThe findings in this study show novel associations with blastomycosis susceptibility. A better understanding of host immunity and genetic predisposition to Blastomyces infection can help to inform clinical practice for improved outcomes.

Association of the VEGF 2578C>A Polymorphism With Metabolic Syndrome and Erectile Dysfunction.

Accumulating evidence suggests a link between vascular endothelial growth factor (VEGF), erectile dysfunction (ED), and metabolic syndrome (Mets), possibly because VEGF can alter the physiological pathways involved in the regulation of endothelial cell proliferation. This study aimed to investigate the genetic susceptibility of VEGF 2578C>A polymorphism to the development of ED and Mets. Collected data included five-item International Index of Erectile Function (IIEF-5), components of Mets, and VEGF 2578C>A polymorphism. A total of 596 subjects from Kaohsiung with a mean age of 55.5 years were enrolled, data collection was done at our hospital. Individuals carrying the VEGF 2578 A allele (CA+AA genotypes) demonstrated a higher prevalence of ED compared to those with the CC genotype, with an adjusted odds ratio (OR) of 1.582 (95% confidence interval [95% CI] = 1.123-2.227, p value = 0.009) in multivariate binary regression analysis. Similarly, individuals carrying the VEGF 2578 A allele showed a higher prevalence of Mets compared to those with the CC genotype, with an adjusted OR of 2.461 (95% CI = 1.491-4.064, p value < 0.001). Furthermore, A allele carriers had significantly lower IIEF-5 scores and a higher number of Mets components compared to those with the C allele (P value < 0.001, respectively). In conclusion, VEGF 2578 A allele carriers are at a greater risk of both Mets and ED, suggesting that the VEGF 2578C>A polymorphism may serve as a common genetic susceptibility factor in the development of both disorders. Further research is warranted to evaluate the mechanisms underlying this association.

Genetic susceptibility to temporomandibular joint involvement in juvenile idiopathic arthritis.

Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic condition of childhood. Temporomandibular joint (TMJ) is among the most commonly affected joints in JIA patients. When JIA involves the TMJ, it may affect condylar growth in the joint; therefore, JIA patients are at risk of unfavourable long-term outcomes from associated joint damage. If undetected, TMJ involvement can lead to various functional disabilities such as reduced mandibular mobility and disorders of the mastication muscles. Limitations in sagittal and vertical mandibular growth can result in micrognathia and anterior open bite with aesthetic and functional restrictions. Genetic factors may play a role in determining which individuals are more prone to develop TMJ disorders or in predicting the severity of the disease process. Therefore, we applied a GWAS approach to identify loci associated with TMJ involvement in a sample of Estonian patients with JIA. Our aim was to address the potential role of genetic susceptibility factors in TMJ-JIA, a condition not previously studied in this context. The case group consisted of 55 JIA patients with TMJ involvement and 208 patients without TMJ involvement comprised the control group. The entire cohort was genotyped using the Illumina HumanOmniExpress BeadChip arrays. Imputation was performed using a nationwide reference panel obtained of 2240 individuals whose data were obtained from the Estonian Biobank. We identified six loci as being associated with the risk of TMJ-JIA in Estonian JIA patients. The strongest associations were identified at CD6 rs3019551 (P = 3.80 × 10-6), SLC26A8/MAPK14 rs9470191 (P = 6.15 × 10-6), NLRP3 rs2056795 (P = 8.91 × 10-6) and MAP2K4 rs7225328 (P = 1.64 × 10-5). This study provides first insights into the risk-associated loci between JIA and its manifestation in the TMJ. The reported loci are involved in molecular pathways of immunological relevance and likely represent genomic regions that render the TMJ susceptible to involvement by JIA in Estonian patients.

NOD1 and NOD2 genetic variants: Impact on hepatocellular carcinoma susceptibility and progression in Moroccan population

BackgroundNucleotide-binding oligomerization domain 1 (NOD1) and NOD2 are involved in carcinogenic processes by recognizing bacterial cell wall components and triggering inflammation. This study explored the association between genetic variations in NOD1 and NOD2 and susceptibility to hepatocellular carcinoma (HCC) and its progression in a Moroccan population. MethodsGenotyping of NOD1 rs2075820 (C>T) and NOD2 rs718226 (A>G) was performed using the TaqMan allelic discrimination assay in 467 Moroccan individuals. The cohort included 156 patients with hepatocellular carcinoma (HCC), 155 patients with liver cirrhosis (LC) diagnosed with HBV, HCV, or MASLD, and 156 controls. ResultsThe NOD1 rs2075820 variant showed no association with HCC susceptibility or progression, which is consistent with in silico predictions. However, the NOD2 rs718226 G allele and GG genotype were more common in the HCC group compared to the cirrhosis and control groups. Individuals with the homozygous G variant had a 2-fold higher risk for HCC (ORad = 2.12; CI=1.01–4.44; Pad = 0.04). Those with the GG genotype also had an increased risk of HCC (GG vs. AG+AA ORad = 2.28; CI=1.15–4.54; Pad = 0.016). Furthermore, GG genotype carriers had a significantly higher risk of HCC progression (ORad = 2.58; CI=1.26–5.31; Pad​ = 0.031). Individuals with the rs718226 minor allele had a significantly elevated risk of progressing from LC to HCC (ORad = 1.50; CI=1.07–2.09; Pad = 0.016). Stratification analysis indicated that men had a higher risk of HCC progression compared to women (ORad = 4.63; CI=1.53–14.00 vs. ORad = 2.73; CI=1.05–7.09). ConclusionThe NOD1 rs2075820 polymorphism does not appear to be a genetic risk factor for susceptibility to HCC. In contrast, the non-coding NOD2 rs718226 variant significantly increases HCC susceptibility and promotes liver cancer progression in the Moroccan population. Further studies involving larger cohorts are warranted to definitively confirm or refute the effects of NOD1 and NOD2 genetic variants on liver cancer susceptibility and progression.

Fighting Fatty Liver Disease: Pathogenesis and Therapeutic Approaches

FLD is a burgeoning international ailment closely associated with the increasing rates of obesity, type II diabetes mellitus and physical inactivity. This review focuses on the various aspects of FLD pathophysiology including genetic susceptibility, metabolic disturbances, inflammation, oxidative stress, and environmental factors. Diagnostic tests can be simple and non-invasive such as imaging and biomarkers and can be relatively invasive, such as liver biopsies. Currently the treatment focus is made on drug and surgical interventions with lifestyle changes, and besides, gene and stem cell therapies remain an experimental method with fewer evidences. The article points to the problems of patient compliance, adequate diagnostics, and effectiveness of the treatment, the necessity of working on the concept of individualized medicine, new therapeutic strategies, and prevention. A statically and working knowledge and a combination and complex strategy are required to approach and decrease the burden of FLD worldwide.

Genetic and Modifiable Risk Factors for Postoperative Complications of Total Joint Arthroplasty: A Genome-Wide Association and Mendelian Randomization Study.

Background: Total joint arthroplasty (TJA) is an orthopedic procedure commonly used to treat damaged joints. Despite the efficacy of TJA, postoperative complications, including aseptic prosthesis loosening and infections, are common. Moreover, the effects of individual genetic susceptibility and modifiable risk factors on these complications are unclear. This study analyzed these effects to enhance patient prognosis and postoperative management. Methods: We conducted an extensive genome-wide association study (GWAS) and Mendelian randomization (MR) study using UK Biobank data. The cohort included 2964 patients with mechanical complications post-TJA, 957 with periprosthetic joint infection (PJI), and a control group of 398,708 individuals. Genetic loci associated with postoperative complications were identified by a GWAS analysis, and the causal relationships of 11 modifiable risk factors with complications were assessed using MR. Results: The GWAS analysis identified nine loci associated with post-TJA complications. Two loci near the PPP1R3B and RBM26 genes were significantly linked to mechanical complications and PJI, respectively. The MR analysis demonstrated that body mass index was positively associated with the risk of mechanical complications (odds ratio [OR]: 1.42; p < 0.001). Higher educational attainment was associated with a decreased risk of mechanical complications (OR: 0.55; p < 0.001) and PJI (OR: 0.43; p = 0.001). Type 2 diabetes was suggestively associated with mechanical complications (OR, 1.18, p = 0.02), and hypertension was suggestively associated with PJI (OR, 1.41, p = 0.008). Other lifestyle factors, including smoking and alcohol consumption, were not causally related to postoperative complications. Conclusions: The genetic loci near PPP1R3B and RBM26 influenced the risk of post-TJA mechanical complications and infections, respectively. The effects of genetic and modifiable risk factors, including body mass index and educational attainment, underscore the need to perform personalized preoperative assessments and the postoperative management of surgical patients. These results indicate that integrating genetic screening and lifestyle interventions into patient care can improve the outcomes of TJA and patient quality of life.

Perinatal Risk Factors Contributing to Development of Childhood Asthma

Background: Genetic susceptibility and environmental factors play crucial roles in the development of childhood asthma. It seems that asthma pathology initiates in utero. The purpose of this study was to examine the relationship between various perinatal exposures and events, and the later development of childhood asthma. Method: A total of ninety children, 45 with childhood asthma and with 45 healthy controls, referred to the Allergy Clinic of Azad University Hospitals between January 2020 and January 2021 were enrolled in the study. All caregivers or parents of these children were interviewed to collect sufficient data concerning the patients’ asthma history. Results: Gestational age, gender, low birth weight, delivery mode, maternal pre-eclampsia, maternal smoking during pregnancy, smoking exposure during the neonatal period, antibiotic prescription in the neonatal period, acetaminophen use in the neonatal period, assisted ventilation and oxygen therapy, neonatal icterus, neonatal respiratory infection, chronic pulmonary disease of prematurity, meconium aspiration, birth order as the first-born child and parental history of allergy were assessed. Among these, the use of antibiotics, oxygen therapy, respiratory infections during the neonatal period, meconium aspiration during labor, and history of allergy in first-grade relatives were the most predictable separate factors, demonstrating the key role of the perinatal period in the development of childhood asthma. Conclusion: To conclude, although previous studies mostly suggested the causal effects of modifiable behaviors or exposures on the development of childhood asthma, the risk factors in the present study were mostly genetic influences, postnatal infections or obstetrics events or their management, which were inevitable in the process of labor.

Role of diet in the prevention and development of Crohn's Disease

Crohn's disease (CD) is a chronic recurrent inflammatory bowel disease (IBD) with frequent ileocolic location, although it can affect the entire gastrointestinal tract. It is characterized by the development of skipped lesions and transmural inflammation and its incidence is increasing. The etiology and pathogenesis are related to genetic susceptibility, intestinal microbiota, dysbiosis, immunological abnormalities and environmental factors (tobacco use, NSAIDs, oral contraceptives and diet). Diet may play a key role in the development and prevention of CD. Dietary patterns with high inflammatory potential (high intake of saturated fat, sugars, proteins, salt, as well as low consumption of fruits and vegetables) are associated with a higher risk of CD, while the consumption of a healthy diet, together with the practice of Exercise is a protective factor against relapses in IBD and reduces the risk of CD. Regarding dietary components, the consumption of fiber, as well as dietary polyphenols, has been related to the maintenance of the intestinal barrier by preventing erosion of the mucosal layer. ω-3 fatty acids, in addition to their anti-inflammatory activity, promote the balance of the intestinal microbiota and their supplementation reduces postoperative complications and accelerates recovery in patients with CD. Vitamin D also plays an important role in the integrity of the intestinal barrier by reducing permeability, in addition to having an immunomodulatory and anti-inflammatory effect, being a useful tool in the improvement of patients with CD. Prebiotics and probiotics may be useful in the treatment of IBD patients by stimulating mucus production, reducing inflammation and dysbiosis, and maintaining the integrity of the intestinal barrier.

GWAS-based polygenic risk scoring for predicting cerebral artery dissection in the Chinese population

ObjectiveCerebral artery dissection (CeAD) is a rare but serious disease. Genetic risk assessment for CeAD is lacking in Chinese population. We performed genome-wide association study (GWAS) and computed polygenic risk score (PRS) to explore genetic susceptibility factors and prediction model of CeAD based on patients in Huashan Hospital.MethodsA total of 210 CeAD patients and 280 controls were enrolled from June 2017 to September 2022 in Department of Neurology, Huashan Hospital, Fudan University. We performed GWAS to identify genetic variants associated with CeAD in 140 CeAD patients and 210 control individuals according to a case and control 1:1.5 design rule in the training dataset, while the other 70 patients with CeAD and 70 controls were used as validation. Then Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and Gene Ontology (GO) enrichment analyses were utilized to identify the significant pathways. We constructed a PRS by capturing all independent GWAS SNPs in the analysis and explored the predictivity of PRS, age, and sex for CeAD.ResultsThrough GWAS analysis of the 140 cases and 210 controls in the training dataset, we identified 13 leading SNPs associated with CeAD at a genome-wide significance level of P < 5 × 10− 8. Among them, 10 SNPs were annotated in or near (in the upstream and downstream regions of ± 500Kb) 10 functional genes. rs34508376 (OR2L13) played a suggestive role in CeAD pathophysiology which was in line with previous observations in aortic aneurysms. The other nine genes were first-time associations in CeAD cases. GO enrichment analyses showed that these 10 genes have known roles in 20 important GO terms clustered into two groups: (1) cellular biological processes (BP); (2) molecular function (MF). We used genome-wide association data to compute PRS including 32 independent SNPs and constructed predictive model for CeAD by using age, sex and PRS as predictors both in training and validation test. The area under curve (AUC) of PRS predictive model for CeAD reached 99% and 95% in the training test and validation test respectively, which were significantly larger than the age and sex models of 83% and 86%.ConclusionsOur study showed that ten risk loci were associated with CeAD susceptibility, and annotated functional genes had roles in 20 important GO terms clustered into biological process and molecular function. The PRS derived from risk variants was associated with CeAD incidence after adjusting for age and sex both in training test and validation.

Genetic Susceptibility and Treatment Personalization in Acute Lymphoblastic Leukemia: A Comprehensive Review of Genetic Susceptibility and Targeted Therapies

Abstract Acute lymphoblastic leukemia (ALL) in children is a complicated and heterogeneous disease impacted by various genetic susceptibility factors. The significance of genetic testing in pediatric ALL diagnosis and management, the role of minimal residual disease (MRD) monitoring, and ethical issues and problems in pediatric genetic testing are discussed in this narrative review. It also looks ahead to the future of genetic susceptibility research, focusing on data integration, artificial intelligence-driven insights, and the possible finding of novel treatment targets. We hope to provide a complete view of the current status and hopeful future of precision medicine in pediatric oncology as we traverse these numerous facets of pediatric ALL. Pediatric ALL is a significant problem in the world of pediatric cancer, requiring a detailed understanding of its genetic foundations and the importance of genetic testing. This narrative review investigates the complex world of pediatric ALL, shedding light on the intricate web of genetic susceptibility factors that influence the progression and treatment results. While we investigate the importance of genetic testing, the critical function of MRD monitoring, and the ethical concerns inherent in pediatric genetic testing, we also look forward to the potential horizons of genetic susceptibility research.

Comparison of Asthma Phenotypes in Severe Asthma Cohorts (SARP, U-BIOPRED, ProAR and COREA) From 4 Continents.

Asthma is a clinical syndrome with various underlying pathomechanisms and clinical phenotypes. Genetic, ethnic, and geographic factors may influence the differences in clinical presentation, severity, and prognosis. We compared the characteristics of asthma based on the geographical background by analyzing representative cohorts from the United States, Europe, South America, and Asia using the Severe Asthma Research Program (SARP), Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes (U-BIOPRED), Program for Control of Asthma in Bahia (ProAR), and Cohort for Reality and Evolution of Adult Asthma in Korea (COREA), respectively. The clinical characteristics and medications for the SARP (n = 669), U-BIOPRED (n = 509), ProAR (n = 996), and COREA (n = 3,748) were analyzed. Subgroup analysis was performed for severe asthma. The mean age was highest and lowest in the COREA and SARP, respectively. The asthma onset age was lowest in the ProAR. The mean body mass index was highest and lowest in the SARP and COREA, respectively. Baseline pulmonary function was lowest and highest in the U-BIOPRED and COREA, respectively. The number of patients with acute exacerbation in the previous year was highest in U-BIOPRED. The mean blood eosinophil count was highest in COREA. The total immunoglobulin E was highest in the ProAR. The frequency of atopy was highest in the SARP. The principal component analysis plot revealed differences among all cohorts. The cohorts from 4 different continents exhibited different clinical and physiological characteristics, probably resulting from the interplay between genetic susceptibility and geographical factors.

Systematic Review on Pathology and Drug Efficacy Clinical Trials (1973-2023) for Cognitive Impairment and Alzheimer’s Dementia

Rationale: The systematic review evaluates the results of last fifty years (1973-2023) of clinical trials on pathology and treatment for cognitive impairment including Alzheimer’s dementia (AD dementia). Objectives: Alzheimer’s dementia is a growing public health concern worldwide. The systematic review analyzes the disease confirming pathological findings presented by modern imaging techniques MRI/ PET. In addition, we analyze the success of fifty years of therapeutic advancements of the neurological disabilities and count on the safe drugs to treat clinical conditions of AD dementia. Findings: We followed the PRISMA guidelines to determine the inclusion and exclusion criteria for the selection of clinical records collected from the NCBI databases. We analyzed the drug efficacy results on the three aspects of the AD brain: (a) morphological deformation of the choroid plexus and hippocampus; (b) senile plaques with amyloid beta42 (Abeta42) including hyperintensities of neurons; and (c) inhibitory action of acetylcholinesterase enzyme. The pathological findings include detection of Abeta42 plaques in cerebral cortex and retention ability of trial drugs in cerebrospinal fluid versus blood plasma of AD patients in the context of disease progression and treatment efficacy. The clinical trial records demonstrated evidence of genetic susceptibility factor(s) clustered in European populations. The susceptibility is also found due to mutations in the presenilin-1 gene and expression of the ApoEε-allele among the population. The clinical records demonstrate moderate efficacy of cholinesterase inhibitors Donepezil and Rivastigmine in improving cognition. The antibodies aducanumab, donanemab, and lecanemab show low to moderate success in removing plaques and reducing plasma Abeta burden. Conclusion: The cholinesterase inhibitors demonstrate moderate success in improving cognition. However, the overall efficacy of antibody treatment was poor. The findings suggest a need for new generation drugs which can clear plaques and improve cognition for AD.

Variant ranking pipeline for complex familial disorders

Identifying genetic susceptibility factors for complex disorders remains a challenging task. To analyze collections of small and large pedigrees where genetic heterogeneity is likely, but biological commonalities are plausible, we have developed a weights-based pipeline to prioritize variants and genes. The Weights-based vAriant Ranking in Pedigrees (WARP) pipeline prioritizes variants using 5 weights: disease incidence rate, number of cases in a family, genome fraction shared amongst cases in a family, allele frequency and variant deleteriousness. Weights, except for the population allele frequency weight, are normalized between 0 and 1. Weights are combined multiplicatively to produce family-specific-variant weights that are then averaged across all families in which the variant is observed to generate a multifamily weight. Sorting multifamily weights in descending order creates a ranked list of variants and genes for further investigation. WARP was validated using familial melanoma sequence data from the European Genome-phenome Archive. The pipeline identified variation in known germline melanoma genes POT1, MITF and BAP1 in 4 out of 13 families (31%). Analysis of the other 9 families identified several interesting genes, some of which might have a role in melanoma. WARP provides an approach to identify disease predisposing genes in studies with small and large pedigrees.