Precision Medicine Approach Research Articles

Investigating genetic influences on speech and language development is a fairly new field fueled by interprofessional collaborations among investigators trained in genomics, communication sciences and disorders, or, in rare cases, both. The 2024 Research Symposium, titled "Genetics in Communication Sciences and Disorders," aimed to provide updates on cutting-edge research findings in disorders of speech sound production, speech fluency, spoken language, and written language. A second important goal was to make research methods and findings of genetics studies in speech and language disorders accessible to an audience with expertise in communication sciences and disorders. The articles in this forum are based on the symposium presentations. The authors trace the history of investigating genotype-phenotype associations in their areas of specialty and discuss how technological advances have fueled recent insights in large participant samples. In addition, we show how insights from genetic studies of spoken and written language can be leveraged toward novel interventions based on principles of precision medicine, namely personalized and proactive approaches, with the goal of improved outcomes. A disclaimer is that genetic changes reflect only one of many sources of influence on the human capacity of verbal communication; many others-for instance microbiomes and the physical, social, and cultural environments-should also be acknowledged.

Background: Blood lipid levels are among the leading causal risk factors for cardiovascular disease. While genome-wide association studies (GWAS) have identified numerous loci associated with mean lipid levels, genetic contributions to blood lipid variability remain underexplored. To address this, we conducted a multi-population genome-wide variance quantitative trait loci (vQTL) analysis to identify single nucleotide polymorphisms (SNPs) influencing the variability of blood lipid traits. Methods: vQTL analyses were performed on five circulating lipid measures: high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), triglycerides (TG), and lipoprotein(a) (Lp(a)) in the Penn Medicine Biobank (PMBB). Analyses were implemented using QUAIL, which transforms the phenotype into a quantile integrated rank score and employs quantile regression to assess genetic effects on trait variance. Analyses were performed for each population, adjusting for age, sex, and genetic principal components. Genome-wide significance was set at p < 5e-8. Results: vQTL analysis identified 306 genome-wide significant loci associated with lipid variability. Nearby genes identified included CETP, CELSR2, APOA5, LPL, LPA, and PPM1H. Several loci overlapped with known GWAS loci for lipid levels, while others were novel, suggesting unexplored genetic mechanisms regulating variance. Conclusions: These findings provide new insights into the genetic regulation of lipid variability, which may improve risk stratification for cardiovascular disease and inform precision medicine approaches. Future analyses will replicate this work in the other cohorts (MVP, AoU, and UKB) to validate findings and further elucidate the genetic architecture of lipid variability.

Background: Cardiovascular disease (CVD) risk stratification in primary prevention involves risk factor-based calculators. Subclinical atherosclerosis (SA) disease burden represents an individualized signature of cumulative risk factor exposure and may be undervalued in traditional assessment. Research Questions: How do risk calculators perform for predicting SA surrogates in healthy participants? Can a simplified risk score incorporating SA burden compete with conventional risk factor-based calculators? Methods: Asymptomatic participants in the Progression of Early Subclinical Atherosclerosis (PESA) and BioImage cohorts underwent assessment of ultrasound (US) plaque presence/progression and coronary artery calcium (CAC) presence, which were analyzed as binary surrogate outcomes of atherosclerosis. The performance of various calculators was compared using C-statistics in each cohort overall, by sex, and by age tertiles. A simplified novel risk score utilizing age, sex, and US plaque burden was developed in the BioImage cohort for predicting 5-year major adverse cardiovascular events (MACE; all-cause death, stroke, myocardial infarction, or coronary revascularization). Comparisons were drawn with established risk scores using C-statistics. Results: The cohorts had distinct characteristics (PESA n=3588, median age 46 years, 36% female; BioImage n=6011, median age 69 years, 57% female). All scores were moderately accurate for SA presence by US and CAC, though performance diminished with age (see Table). Scores were less accurate for predicting SA progression in either cohort. In the BioImage cohort, 473 MACE were observed at 5 years. Estimates of 5-year risk increased with age, with increasing baseline plaque burden, and with male sex (see Figure). Performance of the novel calculator using only age, sex, and plaque burden was significantly better than traditional risk factor-based scores (C-statistic 0.667, see Table). Conclusion: In two large cohorts of healthy participants with distinct age ranges, risk factor-based calculators predict SA surrogates with similar accuracy to their prediction of cardiovascular outcomes. A novel simplified score derived from 3 variables (age, sex, plaque burden) outperformed several contemporary risk factor-based calculators. Incorporating SA burden may improve a precision medicine approach to the primary prevention of CVD.

Background: Hypertension is a leading risk factor for cardiovascular disease and is highly prevalent in Asian populations. However, most genome-wide association studies (GWASs) and transcriptome-wide association studies (TWASs) have primarily focused on individuals of European ancestry, limiting generalizability to other ethnic groups. Hypothesis: We hypothesized that integrating GWAS, TWAS, and expression quantitative trait locus (eQTL) analyses in a large Taiwanese cohort would uncover novel hypertension-associated genetic loci and gene expression profiles relevant to Asian populations. Methods: We performed the first combined GWAS, TWAS, and eQTL analysis of hypertension using data from the Taiwan Biobank, including 10,739 hypertensive patients and 49,668 normotensive controls, with 4,512,191 genome-wide single nucleotide polymorphisms (SNPs). GWAS identified susceptibility loci, TWAS assessed gene-level associations, and eQTL analysis linked significant variants to gene expression changes in whole blood. Results: We identified 14 genetic loci significantly associated with hypertension, including one novel locus at 5p13.1. eQTL analysis revealed that this locus was significantly associated with DAB2 expression in whole blood. TWAS identified 55 hypertension-associated genes, 20 (36%) of which overlapped with GWAS loci. Notably, several genes outside of GWAS-identified loci—such as FBXL15 , KCNIP2 , and CRIP3 —were highly significant in TWAS and are implicated in vascular function and blood pressure regulation. Conclusions: This integrative genomic and transcriptomic study highlights novel genetic contributors to hypertension in an East Asian population. The findings improve our understanding of hypertension biology and may inform future precision medicine approaches for risk prediction and therapeutic development in diverse populations.

Background/Aims: Heart failure (HF) is a leading cause of cardiovascular morbidity and mortality, with notable sex differences. Although the lifetime risk of HF is similar between sexes, HF with preserved ejection fraction (HFpEF) is more common in women, while HF with reduced ejection fraction (HFrEF) predominantly affects men. While genome-wide association studies have identified over 50 loci associated with HF and its subtypes, previous work has focused on autosomes, leaving the X chromosome underexplored despite its biological relevance and clear sex differences in HF. This study presents the first sex-stratified X-chromosome-wide association study (XWAS) of unclassified HF, HFrEF and HFpEF in a multi-ancestry cohort from the Million Veteran Program (MVP). Methods: We analyzed X-chromosome genotype data from 658,582 MVP participants (91.6% male) across four ancestries: European (72.1%), African American (19.5%), Hispanic (7.5%), and Asian (0.9%). Genotyping was performed using Axiom Biobank Array. Sex- and ancestry- stratified XWAS was conducted using XWAS 3.0 using logistical regression models adjusting for age and the top 10 principal components. Multi-ancestry results were meta-analyzed separately for male and females using GWAMA, incorporating a random-effects model to account for heterogeneity across ancestries. Statistical significance was defined using Bonferroni correction. Results: In unclassified HF, a total of 6 loci were identified in males. For HFrEF, 6 loci were identified in males and 1 in females, while no significant loci were identified for HFpEF. (Table 1). Notably, the genomic loci harboring CHRDL1 and ITM2A were significantly associated with both unclassified HF and HFrEF, but only in males. One intergenic locus identified in females with HFrEF indicates a possible female-specific genetic contribution to HF risk. These findings reflect sex-specific genetic pathways potentially involved in cardiac remodeling and immune regulation in HF and its major sub-types. The smaller number of loci identified in females compared to males may be attributable to the predominantly male composition of the MVP cohort. Conclusions: These results emphasize the need to include the X chromosome in HF genetic studies. The discovery of variants with sex- and subtype-specific effects underscores the role of X-linked genes in HF pathophysiology and supports precision medicine approaches tailored by sex and HF subtype.

Background: Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiomyopathy. As genomic sequencing becomes more widespread, early identification of at-risk individuals has improved. InterVar, which applies the 2015 ACMG guidelines, often classifies HCM-associated variants as likely pathogenic/pathogenic (LP/P) at frequencies exceeding true disease prevalence. Improved tools are needed to distinguish pathogenic from benign variants and to guide accurate population risk prediction. Hypothesis: HCM-associated variants classified as LP/P by our novel DiscoVari precision medicine tool demonstrate higher disease penetrance than those classified as LP/P by InterVar. Methods: Phenotypic and genotypic data from the UK Biobank (UKBB) and All of Us (AoU) cohorts were analyzed, focusing on missense variants in ClinGen-designated definitive HCM genes. DiscoVari performed signal-to-noise (S:N) analysis to define pathogenic “hotspots” by comparing variant frequencies in disease vs. population cohorts. Variants were reclassified per ACMG guidelines, using S:N hotspots to support PM1 evidence. Penetrance was defined as the proportion of individuals with clinical HCM among those with an HCM-associated variant. DiscoVari S:N and hotspot localization were also compared to variant classifications by Labcorp Genetics. Statistical significance was set at α = 0.05; Kruskal–Wallis tests were used for non-normal continuous data, and Chi-squared or Fisher’s exact tests for categorical data. Results: DiscoVari is key for variant interpretation as current ACMG criteria hinges on PM1 criteria in 26.5% (UKBB) and 21.7% (AoU) of cases. DiscoVari is superior in variant interpretation, reducing LP/P classifications among individuals without HCM (UKBB: 26.1% to 12%; AoU: 22% to 10.5%). DiscoVari LP/P variants were more strongly associated with HCM (UKBB: OR 2.75; AoU: OR 4.7) than InterVar LP/P variants (UKBB: OR 1.74; AoU: OR 4.07). Variants upgraded by DiscoVari had higher penetrance (OR 7.36) than downgraded variants, which showed no significant difference from the overall cohort. DiscoVari can aid in diagnostic variant interpretation as downgraded Labcorp diagnostic variants (n=578) had significantly lower median S:N than upgraded variants (n=313). Conclusions: Current in silico tools may misclassify low-penetrant variants in HCM genes as LP/P. DiscoVari improves interpretation by reducing over-classification of these variants while retaining those truly associated with disease.

Sepsis-induced myocardial dysfunction (SIMD) critically contributes to mortality in systemic inflammatory responses, driven by multifaceted mechanisms including dysregulated inflammation, immunosuppression, oxidative stress, and autonomic dysfunction. Emerging pathways involve m6A RNA methylation (mediated by methyltransferase METTL3), which coordinates inflammation, apoptosis, and ferroptosis through transcriptomic rewiring. Extracellular vesicles (EVs) serve dual roles: propagating injury via microRNA-885-5p/HMBOX1-induced pyroptosis and delivering therapeutic cargo (e.g., microRNA-223) to suppress inflammation. Mitochondrial dysfunction, marked by reactive oxygen species (ROS)-NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome activation and impaired sarco/endoplasmic reticulum calcium ATPase 2a (SERCA2a) stability, exacerbates metabolic disorder. Autonomic neuromodulation strategies, such as electroacupuncture and noninvasive vagus nerve stimulation, attenuate cardiac injury by rebalancing neuroimmune interactions. Complement hyperactivation (C5a-C5a receptor axis) and immune checkpoint inhibitors (e.g., anti-programmed death-ligand 1 [PD-L1] antibodies) show preclinical efficacy. However, challenges persist in addressing immune heterogeneity, dynamic biomarker profiling, and optimal therapeutic timing. This review bridges mechanistic discoveries to clinical innovation, proposing a paradigm shift toward precision therapies. Future research must bridge mechanistic insights with clinical innovation. By harmonizing pathophysiological understanding with precision medicine approaches, this synthesis underscores the potential to transform SIMD management from supportive care to targeted functional recovery.

Myhre syndrome is a rare, multisystemic disorder caused by gain-of-function mutations in the SMAD4 gene, a key component of the TGF-β signaling pathway. These mutations lead to manifestations affecting neurodevelopment, bone and joint development, fibrosis and stenosis, immune responses, reproductive health, and cardiac function. The Myhre Syndrome Foundation (MSF) is a patient-centered organization focused on accelerating drug discovery while supporting patients, prioritizing research targeting fibrosis/stenosis and autism/intellectual and developmental disabilities, the most significant burdens reported by patients. Their short-term strategy involves: (1) Creating and running a preclinical platform to screen potential treatments using patient-derived and animal models. (2) Clinical readiness, addressing challenges associated with low disease incidence and heterogeneity in clinical trial design, by developing multi-domain endpoints, responder index, and biobanks/biomarkers. (3) Target identification investigating SMAD4 pathogenic variants rewiring protein-protein interactions in key signaling pathways. (4) Fostering partnerships with regulatory authorities, industries, and other patient research organizations. The MSF portfolio includes targeting fibrosis with immunotherapy using FAP-CAR-T cells, and a precision medicine approach aimed at restoring normal SMAD4 function through gene editing and small molecules. MSF aims to develop therapies that address both acute and chronic manifestations of this complex disease, improving the quality of life for affected individuals.

Glioblastomas (GB) are the most common and deadly primary malignant brain tumors due to their infiltrative growth and resistance to conventional therapies. GB cell plasticity and differentiation into drug-resistant mesenchymal-like (MES) states protect tumors from conventional treatments. This study introduces a novel precision medicine approach employing heparin-based nanoparticles (HP-NPs) engineered to cross the blood-brain barrier and target MES-like glioma stem cells (GSCs). Encapsulating doxorubicin (DOX) in HP-NPs reduces drug-mediated complement and coagulation cascades, enhancing hemocompatibility in human whole blood. In vitro, HP-NPs demonstrate efficient uptake by patient-derived GSCs. Preclinical evaluations in patient avatars indicate plain HP-NPs outperform DOX-loaded HP-NPs in reducing GB progression. Transcriptomic studies show HP-NPs downregulate heparin-binding epidermal growth factor (HBEGF), shifting MES GSCs into less plastic astroglial-like cells, impairing tumorigenesis. HP-NPs are well-tolerated and safe at therapeutic doses in healthy rats, offering a promising new paradigm in anticancer therapy to overcome GB recurrence and improve therapeutic outcomes.

IntroductionDisease-modifying treatments such as monoclonal antibodies can be highly effective in chronic inflammatory diseases such as COPD, but often fail in clinical trials due to heterogeneity of inflammation and imperfect tools to stratify patients to select optimal therapeutic approaches. Molecular imaging provides the potential to transform precision medicine in this field.MethodsWe developed and tested a novel molecular imaging platform using therapeutic monoclonal antibodies labelled with SPECT-CT detectable markers to quantify in vivo tumour necrosis factor (TNF) involved in chronic lung inflammation in humans. We undertook a proof-of-concept clinical study involving participants with COPD and healthy controls. Participants underwent SPECT-CT imaging at 6- and 24 h following injection of 99mTc-anti-TNF. Segmentation of lung regions and 99mTc-anti-TNF activity quantification was undertaken using novel semi-automated and AI-driven approaches.ResultsA significant increase in normalised activity, representing increased TNF inflammatory activity, was seen between the two time-points in the COPD group (mean±sd: 64.88±31.04%, p=0.029) and not in healthy controls (35.38±34.33%, p=0.110). However, analysis at a single time-point revealed higher normalised activity in the healthy group. We demonstrated that pulmonary blood vessel density and degree of emphysema were strongly correlated with this activity signal and identified as confounding factors, highlighting the need to address differences in target-organ characteristics in COPD. Experimental methods to adjust for these factors were developed for organ-specific signal quantification.ConclusionsWe report novel analysis techniques for molecular imaging of the human lung, presenting a platform which provides new insights into complex inflammatory disease and future precision medicine approaches.

Atopic dermatitis (AD) is a chronic, relapsing skin ailment characterized by intense itching and diverse clinical manifestations. Its pathogenesis is complex, involving genetic, microbial, and immunological factors. Recently, significant therapeutic advancements have been made in AD, including topical phosphodiesterase-4 (PDE-4) inhibitors, Janus kinase (JAK) inhibitors, and biologics targeting cytokines and signaling molecules such as Interleukin-13 (IL-13), Interleukin-31(IL-31), thymic stromal lymphopoietin (TSLP), and OX40/OX40L. This review comprehensively demonstrates the genetic, microbial, and immunological factors underlying AD, with a particular emphasis on the gut-skin axis. Furthermore, it summarizes recently approved drugs and potential therapeutic agents currently under clinical trials. Besides, the review highlights the emerging role of the gut-skin axis in AD pathogenesis and the breakthroughs in novel targeted therapies. These include inhibitors of IL-13 and IL-31, which have shown remarkable efficacy in reducing disease severity and improving quality of life in patients with moderate-to-severe AD. Additionally, the review contains the potential of targeting the OX40/OX40L pathway, which holds promise for future therapeutic development. Based on these advancements, the review provides an outlook on the potential for individualized treatment strategies or precision medicine approaches in AD, aiming to optimize therapeutic outcomes and patient management.

Hyaluronic acid and its role in pancreatic cancer: Mechanisms of tumor progression, drug resistance, and therapeutic targeting.

The perception of pain varies rhythmically across the day. Although early studies showed variations in pain sensitivity, mechanistic studies are only now identifying how clock genes and individual rhythms affect pain outcomes. Core clock genes, including Bmal1 and Cry1, regulate pain through neuroimmune interactions, providing potential biomarkers to understand individual variability. This rhythmicity offers a promising avenue for a precision medicine approach to identify optimal timing for pain therapies and stratification of individuals. Integrating daily rhythmic patterns with digital health tools could significantly enhance treatment strategies, moving beyond the conventional "one-size-fits-all" approach toward personalized pain management.

IL-11-mediated macrophage crosstalk drives renal inflammation and fibrosis: A novel therapeutic target in chronic kidney disease.

Targeted therapy in acute myeloid leukemia: Resistance and overcoming strategy.

Targeting DNA damage response pathways in tumor drug resistance: Mechanisms, clinical implications, and future directions.

A nomogram based on radiological features and immunoscore for predicting meningioma recurrence.

Cervical cancer (CC), a leading cause of death in women, is a preventable disease prevalent in low- or middle-income countries due to fewer vaccination strategies against human papillomavirus (HPV). Our review highlights the roles of key signaling cascades in HPV-driven cervical carcinogenesis, including the phosphoinositide 3 kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR), Wnt/β-catenin, Janus kinase/ Signal Transducer and Activator of Transcription (JAK/STAT), C-X-C motif chemokine ligand 12/ C-X-C chemokine receptor type 4, ferroptosis, and Activator Protein-1 pathways. The relationship between HPV E7 and Histone Deacetylases (HDAC) contributes to immune evasion and oncogenesis in CC, underscoring the potential of HDAC inhibitors, including synthetic and natural ones, as targeted treatment alternatives. We further summarize the therapeutic potential and translational obstacles of small-molecule inhibitors (SMIs) that target diverse oncogenic drivers in CC, such as Lysyl oxidase-like 2, HPV oncoproteins, Murine Double Minute X, DNA Methyltransferases, Glutathione Peroxidase 4, JAK/STAT, topoisomerases, etc. There have been promising advances in targeting these molecules, demonstrating their potential to improve tumor growth, apoptosis, and resistance mechanisms. The potential of SMIs to change therapy tactics for advanced CC is highlighted by their inclusion into clinical trials, particularly those targeting B lymphoma Mo-MLV insertion region 1 homolog, Nuclear receptor-binding SET domain protein 2, and angiogenesis. Proteomic signatures, circRNAs, p16, HPV DNA, and DNA methylation patterns are among the emerging molecular biomarkers that are shaping targeted therapy and early detection methods for CC. In addition, this review also discusses bioinformatics and artificial intelligence (AI) approaches, including deep learning algorithms and omics-based analyses, which offer powerful tools for identifying CC biomarkers, facilitating rapid detection, and informing personalized treatment plans. Although resistance and heterogeneity are still problems, emerging precision medicine approaches are reshaping the way CC is controlled. These include the use of SMIs and innovative biomarkers.

Inflammatory bowel diseases (IBDs) encompass Crohn’s disease and ulcerative colitis. They represent idiopathic and chronic inflammatory conditions. Mucosal immune dysfunction and compromised gastrointestinal barrier integrity are implicated in the pathophysiological mechanisms of inflammatory bowel diseases. Recent studies have identified endothelial dysfunction as a pivotal mediator in IBD pathogenesis. Through multiple cellular and molecular interactions, endothelial dysfunction orchestrates inflammatory responses. Objectives: This systematic review examines contemporary evidence (2019–2025), emphasising the role of endothelial dysfunction in intestinal inflammation mechanisms, focusing on vascular-epithelial crosstalk, molecular signalling pathways, and therapeutic implications. Methods and results: A comprehensive literature search was conducted using PubMed, Google Scholar, Europe PMC and DOAJ databases, focusing on peer-reviewed articles published between 2019 and 2025. Following the database search and screening process, a total of 53 studies met the eligible criteria and were included in the final analysis. Keywords included “endothelial dysfunction,” “inflammatory bowel disease,” “gut-vascular barrier,” “nitric oxide,” and “intestinal inflammation.” Contemporary research demonstrates that endothelial dysfunction in IBD manifests through decreased nitric oxide bioavailability, enhanced oxidative stress, aberrant cytokine networks, pathological angiogenesis, and compromised gut-vascular barrier integrity. The emerging concept of dual barrier dysfunction highlights the interdependent relationship between epithelial and endothelial barriers in maintaining intestinal homeostasis. Conclusions: Offering novel therapeutic targets for precision medicine approaches, endothelial dysfunction represents a central driver in the pathophysiological mechanism in IBD. Understanding vascular-epithelial interactions provides fundamental insights for developing targeted interventions to restore intestinal barrier function and resolve chronic inflammation.

Unveiling the regulatory potential of the non-coding genome: Insights from the human genome project to precision medicine.