Genetics
Abstract
A large inter-individual variability in weight loss outcomes following bariatric surgery is reported. To ensure optimal patient management, it is crucial to accurately identify those most likely to benefit from the intervention. Since genetic variants largely contribute to surgery response, polygenic scores (PGS) derived from genome-wide association studies (GWAS) could constitute valuable tools for clinical decision making. We developed and evaluated PGS to predict the weight loss response in 540 patients with body mass index (BMI) ≥35kg/m2 who underwent biliopancreatic diversion with duodenal switch. Summary statistics derived from BMI-derived GWAS, together with summary statistics from previously published GWAS of BMI and adiposity features, were used to construct, evaluate, and benchmark weight-loss PGS. The full-adjusted BMI PGS model built in the entire cohort explained 39.6% of the mean-over-time excessive body weight loss (%EBWL), while the BMI-PGS built in the training dataset explained 38.9%. All benchmarked PGS based on BMI showed a significant relationship with mean-over-time %EBWL. These findings highlight the potential of BMI PGS in predicting weight loss after bariatric surgery and support their use as promising tools to improve the effectiveness of future anti-obesity treatments. Funding: Canadian Institutes of Health Research (PJT-168876).
Authors
Bastien Vallée Marcotte, Juan de Toro-Martín, André Tchernof, Louis Pérusse, Simon Marceau, Marie-Claude Vohl
Abstract
Cutaneous radiation injury is an unintended consequence of radiotherapy for many common cancers and can progress to debilitating radiation-induced skin fibrosis (RISF). Existing radiation injury models do not fully capture the skin toxicities observed in patients, contributing to the lack of efficacious therapies to mitigate RISF. To address this, we developed an ex vivo human skin model that recapitulates the temporal radiation injury and RISF response. Human skin explants (N=12) subjected to ionizing radiation demonstrated DNA double-strand breaks and robust p53-driven transcriptional programming of cell cycle arrest, apoptosis, and senescence compared to non-irradiated controls. Irradiated skin also exhibited induction of pro-inflammatory cytokines, epithelial-mesenchymal transition, pro-fibrotic TGF-beta1 (TGFB1)-mediated signaling, and thickened collagen over time. P53 regulators murine double minute 2 (MDM2) and microRNA (miR)-34a were induced post-irradiation and may be leveraged to modulate injury response. Notably, RNA-sequencing of breast skin from mastectomy patients post-radiotherapy showed similar p53, inflammatory, and TGFB1 signatures as the ex vivo model, supporting its translational relevance. Together, this model provides a platform for identifying biomarkers and testing therapies to prevent or mitigate cutaneous radiation toxicities. Targeting the dynamic p53-driven pro-fibrotic radiation response represents a new therapeutic avenue to improve post-radiotherapy quality of life for cancer survivors.
Authors
Caroline Dodson, Sophie M. Bilik, Gabrielle DiBartolomeo, Hannah Pachalis, Lindsey G. Siegfried, Jordan A. K. Johnson, Seth R. Thaller, Irena Pastar, Marjana Tomic-Canic, Anthony J. Griswold, Rivka C. Stone
Abstract
Myotonic Dystrophy Type 1 (DM1) is caused by an expanded CTG repeat in the DMPK gene, resulting in mutant transcripts that form expanded CUG (CUGexp) RNA foci and sequester muscleblind-like (MBNL) RNA-binding proteins. DM1 is multisystemic with progressive worsening of disease manifestations in affected tissues. Disease progression is attributed to somatic expansion of the CTG repeats with age, resulting in production of CUGexp RNA with enhanced intrinsic toxicity due to increased MBNL sequestration. To determine the degree to which cardiac disease progression can occur independently of repeat expansion, we used a transgenic DM1 mouse model with inducible heart-specific expression of a stable, interrupted 960-CUG repeat RNA. Sustained CUGexp RNA expression caused progressive cardiac enlargement, contractile dysfunction, conduction delay, myocardial fibrosis, and reduced survival, while MBNL-dependent splicing defects remained static, consistent with the stable repeat length. We also determined the degree of reversibility after different periods of CUGexp RNA expression by shutting off the repeat-containing transgene. Suppression of CUGexp RNA expression rescued cardiac abnormalities, but reversibility declined with longer exposure to the toxic RNA. These findings demonstrate that prolonged expression of stable CUGexp RNA drives progressive cardiac pathology, revealing a mechanism of disease progression in DM1 in addition to somatic expansion.
Authors
Rong-Chi Hu, Mohammadreza Tabary, Xander H.T. Wehrens, Thomas A. Cooper
Abstract
Sleep disturbance is a prevalent yet poorly understood comorbidity in autism spectrum disorders (ASD). Here, we uncover a bidirectional regulatory axis connecting the ASD risk gene POGZ to core circadian mechanisms. We demonstrate that Pogz is widely expressed in the suprachiasmatic nucleus (SCN), the central pacemaker of the circadian rhythms and exhibits circadian oscillations in both the hypothalamus and liver with its transcription directly regulated by the circadian molecule DBP through a D-box element in its proximal enhancer. Pogz-deficient mice exhibited prolonged circadian periodicity, impaired light-induced phase shift, delayed adaption to an 8-hour advance jet-lag, and reduced SCN c-Fos activation in response to light pulses. Mechanistically, POGZ interacts with and enhances the transcription activity of CREB, a key regulator of light-induced phase resetting. Notably, Pogz deletion leads to ASD-related deficits in social novelty and cognition, with cognitive impairments influenced by both photoperiod and behavioral paradigm. Our findings thus reveal a critical, previously unrecognized intersection between an ASD risk gene and circadian clock, offering new insights into the pathogenesis of core ASD symptoms and comorbid sleep disturbances.
Authors
Ting Wu, Jiao He, Chu-Jun Xu, Chi-Yu Li, Pingchuan Zhang, Yanfeng Wang, Shanshan Zhu, Lusi Zhang, Jingtan Zhu, Jing Zhang, Jia-Da Li, Huadie Liu
Abstract
BACKGROUND In chronic alcohol consumers, immune cells may drive the progression from mild liver injury to more severe alcohol-associated liver diseases (ALD), including alcohol-associated hepatitis (AAH) and cancer. Liver macrophages, both resident and infiltrating, express Allograft Inflammatory Factor 1 (AIF1), which is upregulated during inflammation and enhances immune activation. METHODS Using serum and urine samples from 868 individuals classified as having alcohol use disorder or not based on DSM-IV/V criteria, along with serum and liver biopsy tissue from a second cohort of 27 patients diagnosed with AAH, we evaluated the impact of the AIF1 promoter single nucleotide polymorphism (SNP) (rs3132451; C/C, C/G, G/G) on liver function markers and immune cell profiles. RESULTS AIF1 transcript levels were genotype-dependent: C/C homozygotes expressed 5.2% of the levels observed in G/G individuals, while C/G heterozygotes expressed 46%. Unlike most SNPs associated with harmful effects, the G/G genotype is highly prevalent, present in ~70% of patients. Among chronic alcohol users, G/G individuals exhibited elevated markers of liver injury and a more than threefold increase in hepatic immune cells, including infiltrating AIF1⁺ macrophages and neutrophils. Despite similar durations of alcohol misuse, G/G individuals had higher Model for End-Stage Liver Disease scores compared to C/G individuals, indicating a significantly greater 90-day mortality risk. Notably, some immune abnormalities, such as elevated neutrophils, persisted in G/G males even after alcohol abstinence. CONCLUSION These findings suggest that functional genetic variation in AIF1 may contribute to the severity and persistence of ALD. TRIAL REGISTRATION ClinicalTrials.gov NCT02231840. FUNDING Research support was provided from the National Institute on Alcohol Abuse and Alcoholism (NIAAA) of the National Institutes of Health (NIH) under grant 1ZIAAA000440-02 and R24AA025017.
Authors
Priscila C. Antonello, Colin A. Hodgkinson, Dechun Feng, Cheryl Marietta, Baskar Mohana Krishnan, Maria A. Parra, Zhaoli Sun, Bin Gao, David Goldman, Michelle W. Antoine
Abstract
Next-generation sequencing technologies are increasingly used to diagnose genetic disorders, particularly immunological diseases with broad and overlapping immune dysregulation. Cryopyrin-associated periodic syndromes (CAPS) are caused by gain-of-function mutations in NLRP3 and include 3 autoinflammatory diseases spanning a continuum of severity: familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disease (NOMID). Linking NLRP3 variants to protein dysfunction and clinical phenotype remains challenging because of genetic modifiers and environmental factors. We report the generation and phenotyping of 5 mouse lines expressing either the common human NLRP3 allele or 1 of 4 CAPS mutations spanning the disease spectrum from FCAS to NOMID. In these lines, the murine Nlrp3 locus is replaced by syntenic integration of the human NLRP3 locus, yielding 1 line with the common allele and 4 lines each carrying a distinct CAPS mutation. Unlike models in which a human mutation is introduced into the mouse protein, these lines recapitulate the spectrum of disease severity observed in humans. These findings support a model in which evaluation of nonsynonymous mutations in mice is optimized when introduced in the context of the human gene. This suggests that species-specific regulation and/or intramolecular epistasis may impact modeling of disease-associated variants.
Authors
John N. Snouwaert, MyTrang Nguyen, Christopher A. Gabel, Ivona Aksentijevich, Jenny P.-Y. Ting, Beverly H. Koller
Abstract
Improper light focus on the retina, refractive error, is primarily caused by eye size differences and is the leading cause of vision loss worldwide. C-terminal variants in the Myelin Regulatory Factor (MYRF) gene, a retinal pigment epithelium (RPE)-derived transcription factor, lead to isolated nanophthalmos characterized by a small, though structurally sound eye. However, other MYRF loss-of-function variants cause syndromic disease. To address this discrepancy, in vitro and animal studies were performed on a pathogenic C-terminal variant dG-MYRF (p.Gly1126fs30*, c.3376-1G>A). Human RPE-cells or primary RPE transduced with dG-MYRF showed reduced target gene expression, with decreased steady-state levels of the C-terminal cleavage product, but normal cleavage and localization. A homozygous humanized MYRF C-terminal mouse model (MyrfhumdG/humdG) was embryonic lethal by embryonic day (E) 18.5, while wildtype (MyrfhumWT/humWT) mice were viable. Single-cell RNA-seq from E17.5 MyrfhumdG/humdG and knockout RxCre;Myrffl/fl (E15.5 and P0) mice revealed shared differentially expressed genes, with decreased effect size in the MyrfhumdG/humdG eyes. These findings support dG-MYRF as a hypomorphic allele. Additionally, two MYRF splicing variants creating nonfunctional isoforms were found in families with isolated nanophthalmos. Overall, hypomorphic MYRF alleles underlie isolated nanophthalmos, supporting a tissue-specific threshold effect and highlighting unique roles for the MYRF C-terminus in the RPE.
Authors
Gabrielle M. Rozumek, Michelle L. Brinkmeier, Bin Guan, Su Qing Wang, Catherine Tower, Nina T. Yang, Rachel S. Lim, Dejuan Kong, Daniel Soden, Qitao Zhang, John Y.S. Han, Jason M.L. Miller, Lijin Dong, D. Ford Hannum, Sayoko E. Moroi, Julia E. Richards, Robert B. Hufnagel, Lev Prasov
Abstract
With the increasing use of genetic sequencing to investigate inborn errors of immunity, rare variants are frequently identified, yet their clinical relevance often remains uncertain. Establishing pathogenicity requires a multidisciplinary approach that integrates genetic, structural, functional, and clinical data. Here, we used such a strategy to investigate a previously unreported hemizygous missense variant — alanine (A) to threonine (T) at residue 518 — in Toll-like receptor 8 (TLR8), identified in 2 male siblings with recurrent infections and systemic inflammation, characterized by a proinflammatory immune signature and B cell dysregulation. Functional studies showed that the TLR8 A518T variant enhanced NF-κB activation and increased secretion of proinflammatory cytokines compared with WT TLR8 upon stimulation, consistent with a gain-of-function effect. Protein degradation and turnover assays revealed reduced abundance of the mutant TLR8 protein due to faster turnover and increased proteasomal degradation. Computational modeling predicted enhanced structural stabilization of the active TLR8 homodimer interface via additional water-mediated hydrogen bonds introduced by the A518T substitution. Together, these findings integrating structural modeling with functional assays identify a novel TLR8 ligand-specific gain-of-function mutation resulting in complex immunopathology in 2 siblings.
Authors
Nikolaos T. Skenteris, Elisa Luttermann, Sanjana Nair, Ioannis Evangelakos, Maria Pujantell, Marie Eggers, Fabian Hausmann, Marleen Bérouti, Benedetta Padoan, Felix J. Flomm, Janna M. Claussen, Benjamin Grünhagel, Anika Salfelder, Brigitte Beifuss, Saskia Biskup, Patrick Blümke, Katrin Rading, Heike Hildebrandt, Urte Matschl, Silke Giesemann-Jansen, Jana Hennesen, Viacheslav O. Nikolaev, Michael Kutsche, Christian Kubisch, Friedrich Koch-Nolte, Nicola M. Tomas, Eva Tolosa, Marc Lütgehetmann, Felix R. Stahl, Veit Hornung, Madeleine J. Bunders, Christian Schlein, Maya Topf, Ina Kötter, Marcus Altfeld
Abstract
BACKGROUND. To construct multi-trait polygenic scores (PRS) predicting chronic obstructive pulmonary disease (COPD) and exacerbations, validate their performance in diverse cohorts, and identify PRS-related proteins for potential therapeutic targeting. METHODS. PRSmix+, a multi-trait PRS framework, is used to train a composite PRS (PRSmulti) in COPDGene non-Hispanic white participants (n=6,647). Associations of PRSmulti with COPD status (GOLD 2-4 vs. GOLD 0 or ICD) and exacerbation frequency were tested in COPDGene African American (n=2,466), ECLIPSE (n=1,858), MassGeneral Brigham Biobank (n=15,152), and All of Us (n=118,566). Protein prediction models were applied to GWAS summary statistics from traits contributing to PRSmulti and were validated with proteomic data in COPDGene (n=5,173) and UK Biobank (n=5,012). RESULTS. PRSmix+ selected 7 traits for PRSmulti. In multivariable models, PRSmulti was associated with COPD status (meta-analysis random effects (RE) OR 1.58 [95% CI: 1.28-1.94]) and exacerbation frequency (meta-analysis RE beta 0.21 [95% CI: 0.11-0.31]), with higher effect sizes observed in smoking-enriched cohorts. PRSmulti outperformed traditional single-trait PRS in all tested cohorts. Using protein prediction models, we identified 73 proteins associated with the PRS that were also validated with measured protein levels in COPDGene and UK biobank. Of these proteins, 25 were linked to approved or investigational drugs. Notable targets include RAGE/sRAGE, IL1RL1, and SCARF2, all implicated in COPD pathogenesis and exacerbations. CONCLUSIONS. Multi-trait PRS improves prediction of COPD and exacerbation risk. Integration with proteomic data identifies druggable protein targets, offering a promising avenue for precision medicine in COPD management. TRIAL REGISTRATION. COPDGene: NCT00608764; ECLIPSE: NCT00292552.
Authors
Chengyue Zhang, Iain R. Konigsberg, Yixuan He, Jingzhou Zhang, Tinashe Chikowore, William B. Feldman, Xiaowei Hu, Yi Ding, Bogdan Pasaniuc, Diana Chang, Qingwen Chen, Jessica A. Lasky-Su, Julian Hecker, Martin D. Tobin, Jing Chen, Sean Kalra, Katherine A. Pratte, Hae Kyung Im, Emily S. Wan, Ani Manichaikul, Edwin K. Silverman, Russell P. Bowler, Leslie A. Lange, Victor E. Ortega, Alicia R. Martin, Michael H. Cho, Matthew R. Moll
Abstract
Mutations in MYOC, the most common genetic cause of glaucoma, cause misfolded myocilin to accumulate in the endoplasmic reticulum (ER), leading to trabecular meshwork (TM) dysfunction, elevated intraocular pressure, and progressive vision loss. While gene editing offers curative potential, current delivery methods rely on viral vectors, which are limited by inflammation, off-target effects, and poor translatability. Here, we report a nonviral lipid nanoparticle (LNP) platform that enables selective in vivo delivery of mRNA encoding an adenine base editor and single guide RNA (LNP-ABE) to TM cells. A direct comparison of LNP-mCherry with lentiviral GFP revealed that LNPs outperform viral vectors, achieving markedly higher efficiency and greater selectivity for the TM without inducing ocular inflammation. In a Cre-inducible Tg.CreMYOCY437H glaucoma mouse model, LNP-Cre mRNA selectively induced mutant MYOC expression in the TM, faithfully recapitulating key disease features. A single administration of LNP-ABE achieved efficient on-target editing of mutant MYOC, reducing mutant myocilin protein by approximately 46%, decreasing aggregates, alleviating ER stress, and fully rescuing the glaucomatous phenotype in Tg.CreMYOCY437H mice. Importantly, no off-target editing or ocular toxicity was detected. These findings establish LNP-based mRNA delivery as a safe, efficient, and clinically translatable approach for TM-targeted genome editing with broad therapeutic potential in glaucoma.
Authors
Balasankara Reddy Kaipa, Linya Li, Prakadeeswari Gopalakrishnan, Samuel Du, Jiin Felgner, Krzysztof Palczewski, Philip Felgner, Gulab S. Zode
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