Biology subjects

Cho, M.

Publications and source records attributed to Cho, M..

At least 19 recordsLinked to original sources

bioRxiv2026

The carbon-nitrogen metabolism gene E1OGDH1 influences maize root system architecture and nitrogen plasticity

Synthetic nitrogen fertilizers have greatly increased crop yields, yet much of the applied nitrogen is lost from agroecosystems and contributes to environmental pollution and higher economic costs. Improving nitrogen uptake efficiency (NUpE) benefits from understanding how root system architecture (RSA) governs soil nitrogen capture. Although root traits have seldom been explicit breeding targets, selection for variation in above-ground nitrogen accumulation has also likely shaped differences in RSA. The Illinois Protein Strain Recombinant Inbred population, derived from more than a century of divergent selection for seed protein concentration, offers a powerful resource for dissecting RSA variation. Using multi-year field phenotyping of excavated root crowns and genome-wide association analysis, we identified a quantitative trait locus on chromosome 10 containing E1OGDH1, which encodes the E1 subunit of the 2-oxoglutarate dehydrogenase (OGDH) complex. OGDH performs a key step in the tricarboxylic acid cycle that also modulates 2-oxoglutarate, an important entry point into nitrogen metabolism and a co-factor for enzymes involved in hormone and secondary product synthesis. Long-read sequencing of inbreds derived from the divergent IHP and ILP parental populations revealed promoter polymorphisms defining E1OGDH1 alleles and differed in E1OGDH1 expression in root tissue. Field experiments in IPSRI lines carrying IHP- or ILP-associated E1OGDH1 alleles showed differences in root architectural traits over two years. CRISPR-Cas9 knockout mutants confirmed a functional role for E1OGDH1 in whole-plant performance and nitrogen-responsive root development. Mutants were shorter, had reduced biomass, and exhibited altered architectural responses to soil nitrogen levels. Transcriptome analysis further showed that loss of E1OGDH1 altered basal and nitrogen-responsive expression of genes associated with root development and nitrogen uptake and metabolism. Together, these findings identify E1OGDH1 as a strong candidate quantitative regulator of maize RSA and nitrogen plasticity, suggesting that central carbon-nitrogen metabolic genes can contribute to root developmental responses relevant to NUpE.

plant biology↗

bioRxiv2026

Identification of smoking-enabled blood miRNA regulatory networks

Cigarette smoking induces complex signaling disruptions that contribute to diseases such as COPD and lung cancer, yet the molecular mechanisms underlying these effects remain incompletely understood. To address this gap, we analyzed peripheral blood from 3190 COPDGene participants using LIONESS and PUMA and constructed miRNA-mRNA regulatory networks associated with smoking status. Comparing networks for active versus former smokers uncovered a striking shift in regulatory architecture: active smokers exhibited elevated miRNA targeting of the mitochondrial complex I protein NDUFA12. This finding was validated in lung tissue expression data from the Lung Genomics Research Consortium (LGRC), where we observed that ever-smokers showed consistent dysregulation of Ndufa12-targeting miRNAs compared to never-smokers. This allowed us to identify a set of smoking-defined circulating and tissue-associated miRNAs. To investigate the specific cellular compartment, we analyzed cell-type deconvoluted expression data from COPDGene blood and LTRC (Lung Tissue Research Consortium) lung tissue, as well as lung transcriptomics data from cigarette smoke-exposed mice, and identified the monocyte/macrophage compartment as a principal site of NDUFA12/Ndufa12 expression. Human THP-1 macrophages treated with cigarette smoke extract demonstrated selective inhibition of NDUFA12 by network-defined miRNAs. These distinct, NDUFA12-targeting, smoking-associated miRNA signatures, revealed through network analysis, describe new smoking-mitochondrial interactions that may serve as novel targets for therapeutic intervention.

Molecular Biology↗

bioRxiv2026

Lipid Composition Modulates Secondary Structure at the Biocondensate-Membrane Interface

Biomolecular condensates (BMCs) formed through liquid-liquid phase separation (LLPS) play key roles in cellular organization, yet their molecular-scale interactions with membranes remain poorly understood. Here, we use surface-enhanced infrared absorption spectroscopy (SEIRAS) to quantify the secondary structure of poly-GR (glycine-arginine) inside condensates in contact supported lipid bilayers. Amide I SEIRAS provides a surface-sensitive measure of the peptide backbone conformation at the membrane-condensate interface. Results show that neutral POPC bilayers preserve the {beta}-sheet rich organization of the bulk condensate, whereas negatively charged POPC/POPS bilayers reduce {beta}-sheet content, and enhanced {beta}-turn formation, accompanied by perturbations of the lipid headgroups. These results demonstrate that membrane charge modulates condensate secondary structure, hydration, and interfacial behavior, providing molecular-level insight into electrostatic regulation of condensate organization at the membrane-water interface. TOC Graphic O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=199 SRC="FIGDIR/small/726873v1_ufig1.gif" ALT="Figure 1"> View larger version (112K): org.highwire.dtl.DTLVardef@9d9e27org.highwire.dtl.DTLVardef@1fa3fe4org.highwire.dtl.DTLVardef@78bcceorg.highwire.dtl.DTLVardef@b3a2ae_HPS_FORMAT_FIGEXP M_FIG C_FIG

biophysics↗

bioRxiv2026

Expansion and Differentiation of Adult Human Pancreas-Derived Progenitor Cells into Functional Islet-Like Organoids

Background and AimsAdult pancreas-derived islet progenitor cells (IPCs) have recently been shown to expand in culture and differentiate into endocrine-like organoids. However, translation of this approach to a clinically compatible workflow requires cell enrichment strategies and validation using tissue obtained during real-world clinical procedures. Here, we adapted our previously described IPC platform to non-endocrine pancreatic tissue fractions generated during clinical islet isolation procedures and evaluated their capacity to generate functional islet organoids. MethodsNon-endocrine pancreatic tissue fractions obtained during clinical islet isolation were expanded ex vivo and enriched using fluorescence-activated cell sorting (FACS) for CD81 and CD9, surface markers previously identified in IPC populations. Sorted cells were expanded, induced to form IPC clusters, and differentiated with ISX9 to generate islet organoids. Differentiation was assessed by gene expression analysis, flow cytometry, immunofluorescence, calcium flux assays, glucose-stimulated insulin and glucagon secretion, and single-cell RNA sequencing. ResultsClinically derived non-endocrine cell fractions yielded expandable IPC populations expressing progenitor-associated markers. FACS-purified and expanded CD81+/CD9+ IPCs were enriched with BMPR1A and P2RY1. Sorted cells generated three-dimensional BMPR1A+ and RGS16+ IPC clusters. IPC clusters differentiated into islet organoids with upregulated expression of canonical beta-and alpha-cell transcription factors. Single-cell transcriptomic profiling revealed activation of coordinated endocrine gene programs and alignment with reference human islet endocrine signatures, while the undifferentiated IPC compartment was marked by enrichment of PTX3, FST, CEMIP, and GREM1. Terminally differentiated cells exhibited depolarization-induced calcium influx and glucose-regulated insulin and glucagon secretion. ConclusionsThese findings establish an adaptable workflow for expansion and production of functional islet organoids recovered from clinically derived pancreatic tissue. This strategy may provide an unlimited autologous source of adult progenitor-derived islets for future islet cell replacement therapies in diabetes.

cell biology↗

bioRxiv2026

AT2-intrinsic Z-AAT expression drives conserved inflammatory and proteotoxic stress responses and predisposes to emphysema

Individuals homozygous for the SERPINA1 "Z" mutation with alpha-1 antitrypsin deficiency (AATD) are highly susceptible to emphysema. This predisposition has classically been attributed to a relative deficiency of circulating alpha-1 antitrypsin (AAT) reaching the lungs and associated protease-antiprotease imbalance. Accumulating evidence suggests that the presence of misfolded Z-AAT protein either in the circulation, the lung interstitium, or within resident lung cells could contribute to emphysema pathogenesis. We have shown that type 2 alveolar epithelial cells (AT2s), progenitor cells of the lung alveolus, heterogeneously retain Z-AAT and exhibit a transcriptional disease signature in AATD patient samples. However, a lack of model systems that faithfully recapitulate AT2 biology and associated Z-AAT expression has limited our ability to study this phenomenon. Here, we apply syngeneic induced pluripotent stem cell-derived AT2s (iAT2s) and a novel mouse model featuring AT2-specific inducible human SERPINA1 expression to interrogate the cell-instrinsic consequences of Z-AAT expression, validating findings in an independent dataset of human COPD lung tissue comparing ZZ to MM SERPINA1 genotypes. We find further evidence of Z-AAT retention within AT2s and identify shared AT2 transcriptomic disease signatures conserved across model systems, characterized by innate immune and inflammatory signaling, NF-{kappa}B activation, and endoplasmic reticulum stress. Mice with AT2-specific Z-AAT expression additionally demonstrate increased susceptibility to elastase-induced emphysema, providing functional evidence for AT2-intrinsic contributions to AATD-associated lung disease. Within iAT2s, a subpopulation of Z-AAT expressing cells exhibits activation of the PERK-eIF2 signaling axis and markers of an alveolar basal intermediate (ABI) state, emerging cell-autonomously in the absence of mesenchymal co-culture.Together, these data provide evidence that Z-AAT expression in AT2s induces heterogenous cell-intrinsic stress responses including proteotoxic stress, inflammatory signaling, and aberrant cell fate adoption, and is sufficient to result in predisposition to injury, supporting a potential contribution of AT2-intrinsic Z-AAT toxicity to human AATD-associated emphysema pathogenesis.

cell biology↗

bioRxiv2026

Depression symptoms are associated with affective neural processing during sleep and rest

Sleep supports offline information processing and is essential for cognitive and emotional functioning. Abnormal sleep patterns are a hallmark of affective disorders. We hypothesized that affective symptoms occur with maladaptive neural processing during offline periods. To test this idea, we used multivariate EEG decoding with cross-state classification. A model trained on EEG data acquired while participants (N = 52) viewed emotional images was used to classify stimulus valence. Applying this model to data collected during a nap revealed the re-emergence of affective neural patterns. Critically, offline reinstatement of patterns reflecting negatively valenced processing predicted greater depressive symptoms across participants. These associations reflected both cognitive-affective and somatic-performance depression subscales, and they generalized across sleep stages and wakeful rest. The finding that offline neural information processing is linked with emotional well-being supports a model whereby maladaptive negative biases can be perpetuated during rest, potentially shaping the progression of affective disorders.

neuroscience↗

bioRxiv2025

Nanoscopy of Organelle Handoff Portals Reveals Direct Coupling between ER Remodeling and Microtubule-Based Transport

How biosynthetic organelles leave the endoplasmic reticulum (ER) and engage with microtubule tracks remains a central question. Combining interferometric scattering with fluorescence nanoscopy, we tracked nanometer-scale handoff events in living cells. ER-derived organelles undergo biased diffusion along ER tubules toward nearby microtubules. ER three-way junctions function as nanoscopic hubs where cargo pauses, contacts multiple microtubules, and then launches onto a track for long-range travel. Remarkably, the ER maintains a membrane tether to the departing cargo, extending its tubules and forming new junctions, thereby coupling inter-network transfer with membrane morphogenesis. These observations reveal an integrated mechanism that links organelle biogenesis, directional trafficking, and continual ER- and cellular remodeling, underscoring the ERs active role in steering transport and repurposing its own output within the crowded intracellular environment.

cell biology↗

bioRxiv2025

Navigational Frames of Reference as Critical Regulators of Hippocampal Interneuron Coding Properties

Efficient spatial navigation relies on the hippocampus integrating local (proximal) and global (distal) cues, collectively called frames of reference, to guide behavior and support memory. Although these cues control the anchoring of principal cell fields, how these frames tune interneuron functions remains unknown. Traditionally, interneurons such as O-LM and VIP cells have been viewed primarily as speed encoders, although some also encode spatial information or respond to discrete stimuli. Using calcium imaging in freely behaving mice performing a new spatial learning task that differentiates between reference frames, we demonstrate that O-LM cells displayed a striking bimodal activity pattern, altering both their speed and spatial encoding properties. In contrast, VIP interneurons were largely unaffected by changes in the frame of reference, instead correlating with familiarization. Notably, linear decoding using speed scores revealed that only O-LM interneurons provide an accurate readout of the dominant reference frame, enabling prediction of the animals navigation strategy. These findings highlight that hippocampal interneurons can flexibly adapt their functions depending on cognitive factors such as the reference frames used to guide behavior.

neuroscience↗

bioRxiv2024

Transcriptional Regulation of human NMNAT2: Insights from 3D Genome Sequencing and Bioinformatics

AbstractNicotinamide mononucleotide adenylyl transferases 2 (NMNAT2) is a crucial nicotinamide adenine dinucleotide (NAD)-synthesizing enzyme essential for neuronal health. In the Religious Orders Study/Memory and Aging Project (ROSMAP), human brain levels of NMNAT2 mRNA positively correlated with cognitive capabilities in older adults. NMNAT2 mRNA abundance is significantly reduced following various insults or proteinopathies. To elucidate the transcriptional regulation of NMNAT2, we employed circular chromosome conformation capture followed by high-throughput sequencing (4C-seq) to identify potential NMNAT2 enhancer and silencer regions by determining genomic regions interacting with the NMNAT2 promoter in human SH-SY5Y cells. We discovered distinct NMNAT2 promoter interactomes in undifferentiated versus neuron-like SH-SY5Y cells. Utilizing bioinformatics analyses, we identified putative transcriptional factors and NMNAT2-associated genes. Notably, the mRNA levels of many of these genes showed a significant correlation with NMNAT2 mRNA levels in [~]400 single-nuclei RNA-seq datasets from ROSMAP. Additionally, using CRISPR-Cas9 strategies, we confirmed the requirement of two specific genomic regions within the interactomes and four transcription factors in regulating NMNAT2 transcription. In summary, our study identifies genomic loci containing NMNAT2 regulatory elements and predicts associated genes and transcription factors through computational analyses.

neuroscience↗

bioRxiv2024

Senescent cell clearance ameliorates temporal lobe epilepsy and associated spatial memory deficits in mice

Current therapies for the epilepsies only treat the symptoms, but do not prevent epileptogenesis (the process in which epilepsy develops). Many cellular responses during epileptogenesis are also common hallmarks of cellular senescence, which halts proliferation of damaged cells. Clearing senescent cells (SCs) restores function in several age-associated and neurodegenerative disease models. It is unknown whether SC accumulation contributes to epileptogenesis and associated cognitive impairments. To address this question, we used a mouse model of temporal lobe epilepsy (TLE) and characterized the senescence phenotype throughout epileptogenesis. SCs accumulated 2 weeks after SE and were predominantly microglia. We ablated SCs and reduced (and in some cases prevented) the emergence of spontaneous seizures and normalized cognitive function in mice. Suggesting that this is a translationally-relevant target we also found SC accumulation in resected hippocampi from patients with TLE. These findings indicate that SC ablation after an epileptogenic insult is a potential anti-epileptogenic therapy.

neuroscience↗

bioRxiv2024

Determination of the absolute concentration of Rayleigh particles via scattering microscopy

Nanoparticles are crucial in diverse fields such as healthcare, electronics, and energy. Their small size allows them to cross biological barriers, enhancing drug delivery but also posing health risks. Accurate characterization of nanoparticles is essential for assessing their safety and efficacy, particularly in medical applications. Traditional methods such as dynamic light scattering and mass spectrometry have limitations in sensitivity and range of application. To address these challenges, we introduce the interferometric Concentration Analyzer and Ultrasmall Nanoparticle Tracker (iCAUNT), a technique for detecting and quantifying nanoparticles smaller than one-tenth of the imaging light wavelength. As a non-invasive method, iCAUNT provides precise size and concentration measurements of biological and synthetic nanoparticles, offering significant potential for diagnostics, therapeutics, and broader nanoscience applications.

biophysics↗

bioRxiv2024

Recruitment of CTCF to the SIRT1 promoter after Oxidative Stress mediates Cardioprotective Transcription

Because most DNA-binding transcription factors (dbTFs), including the architectural regulator CTCF, bind RNA and exhibit di-/multimerization, a central conundrum is whether these distinct properties are regulated post-transcriptionally to modulate transcriptional programs. Here, investigating stress-dependent activation of SIRT1, encoding an evolutionarily-conserved protein deacetylase, we show that induced phosphorylation of CTCF acts as a rheostat to permit CTCF occupancy of low-affinity promoter DNA sites to precisely the levels necessary. This CTCF recruitment to the SIRT1 promoter is eliciting a cardioprotective cardiomyocyte transcriptional activation program and provides resilience against the stress of the beating heart in vivo. Mice harboring a mutation in the conserved low-affinity CTCF promoter binding site exhibit an altered, cardiomyocyte-specific transcriptional program and a systolic heart failure phenotype. This transcriptional role for CTCF reveals that a covalent dbTF modification regulating signal-dependent transcription serves as a previously unsuspected component of the oxidative stress response.

cell biology↗

bioRxiv2024

Gene Therapy Mediates Therapeutic Improvement in Cardiac Hypertrophy and Survival in a Murine Model of MYBPC3-Associated Cardiomyopathy

BackgroundHypertrophic cardiomyopathy (HCM) affects an estimated 600,000 people in the U.S. and is the leading cause of sudden cardiac arrest in those under 18. Loss-of-function mutations in Myosin Binding Protein C3, MYBPC3, are the most common genetic cause of HCM. The majority of MYBPC3 mutations causative for HCM result in truncations. The sarcomeric pathophysiology of the majority of HCM patients with MYBPC3 mutations appears to be due to haploinsufficiency, as the total amount of MYBPC3 protein incorporated into sarcomeres falls significantly below normal. MethodsA clear path for the treatment of haploinsufficiency is the restoration of the insufficient gene product; in this case wild-type MYBPC3. To achieve this, we engineered an AAV vector (TN-201) with superior properties for mediating cardiomyocyte-selective expression of MYBPC3 after systemic delivery. ResultsWe have demonstrated for the first time with AAV gene therapy the ability of both a mouse surrogate and TN-201, which encodes human MYBPC3 to reverse cardiac hypertrophy and systolic dysfunction and to improve diastolic dysfunction and survival in a symptomatic MYBPC3-deficient murine model of disease. Dose-ranging efficacy studies exhibited restoration of wild-type MYBPC3 protein levels and saturation of cardiac improvement at the clinically relevant dose of 3E13 vg/kg, outperforming a previously published construct. Further, we have established stable cardiac benefit for greater than one year post-injection, as well as reversal of cardiac dysfunction even in late-stage models of disease. ConclusionsOur data suggest that by restoring MYBPC3 to the sarcomere, TN-201 has the potential to slow and even reverse the course of the disease in patients with MYBPC3-associated HCM.

genetics↗

bioRxiv2023

BetaBuddy: An end-to-end computer vision pipeline for the automated analysis of insulin secreting β-cells

Insulin secretion from pancreatic {beta}-cells is integral in maintaining the delicate equilibrium of blood glucose levels. Calcium is known to be a key regulator and triggers the release of insulin. This sub-cellular process can be monitored and tracked through live-cell imaging and subsequent cell segmentation, registration, tracking, and analysis of the calcium level in each cell. Current methods of analysis typically require the manual outlining of {beta}-cells, involve multiple software packages, and necessitate multiple researchers - all of which tend to introduce biases. Utilizing deep learning algorithms, we have therefore created a pipeline to automatically segment and track thousands of cells, which greatly reduces the time required to gather and analyze a large number of sub-cellular images and improve accuracy. Tracking cells over a time-series image stack also allows researchers to isolate specific calcium spiking patterns and spatially identify those of interest, creating an efficient and user-friendly analysis tool. Using our automated pipeline, a previous dataset used to evaluate changes in calcium spiking activity in {beta}-cells post-electric field stimulation was reanalyzed. Changes in spiking activity were found to be underestimated previously with manual segmentation. Moreover, the machine learning pipeline provides a powerful and rapid computational approach to examine, for example, how calcium signaling is regulated by intracellular interactions in a cluster of {beta}-cells.

bioinformatics↗

bioRxiv2023

Multifunctional Materials Strategies for Enhanced Safety of Wireless, Skin-Interfaced Bioelectronic Devices

Many recently developed classes of wireless, skin-interfaced bioelectronic devices rely on conventional thermoset silicone elastomer materials, such as poly(dimethylsiloxane) (PDMS), as soft encapsulating structures around collections of electronic components, radio frequency antennas and, commonly, rechargeable batteries. In optimized layouts and device designs, these materials provide attractive features, most prominently in their gentle, noninvasive interfaces to the skin even at regions of high curvature and large natural deformations. Past work, however, overlooks opportunities for developing variants of these materials for multimodal means to enhance the safety of the devices against failure modes that range from mechanical damage to thermal runaway. This paper presents a self-healing PDMS dynamic covalent matrix embedded with chemistries that provide thermochromism, mechanochromism, strain-adaptive stiffening, and thermal insulation, as a collection of attributes relevant to safety. Demonstrations of this materials system and associated encapsulation strategy involve a wireless, skin-interfaced device that captures mechanoacoustic signatures of health status. The concepts introduced here can apply immediately to many other related bioelectronic devices.

bioengineering↗

bioRxiv2022

Mosaic chromosomal alterations in blood across ancestries via whole-genome sequencing

Mosaic mutations in blood are common with increasing age and are prognostic markers for cancer, cardiovascular dysfunction and other diseases. This group of acquired mutations include megabase-scale mosaic chromosomal alterations (mCAs). These large mutations have mainly been surveyed using SNP array data from individuals of European (EA) or Japanese genetic ancestry. To gain a better understanding of mCA rates and associated risk factors in genetically diverse populations, we surveyed whole genome sequencing data from 67,390 individuals, including 20,132 individuals of African ancestry (AA), and 7,608 of Hispanic ancestry (HA) with deep (30X) whole genome sequencing data from the NHLBI Trans Omics for Precision Medicine (TOPMed) program. We adapted an existing mCA calling algorithm for application to WGS data, and observed higher sensitivity with WGS data, compared with array-based data, in uncovering mCAs at low mutant cell fractions. As in previous reports, we observed a strong association with age and a non-uniform distribution of mCAs across the genome. The presence of autosomal (but not chromosome X) mCAs was associated with an increased risk of both lymphoid and myeloid malignancies. After adjusting for age, we found that individuals of European ancestry have the highest rates of autosomal mCAs, mirroring the higher rate of leukemia in this group. Our analysis also uncovered higher rates of chromosome X mCAs in AA and HA compared to EA, again after adjusting for age. Germline variants in ATM and MPL showed strong associations with mCAs in cis, including ancestry specific variants. And rare variant gene-burden analysis confirmed the association of putatively protein altering variants in ATM and MPL with mCAs in cis. Individual rare variants in DCPS, ADM17, PPP1R16B, and TET2 were all associated with autosomal mCAs and rare variants in OR4C16 were associated with chromosome X mCAs in females. There was significant enrichment of co-occurrence of CHIP mutations and mCAs both altering cancer associated genes TET2, DNMT3A, JAK2, CUX1, and TP53. Overall, our study demonstrates that rates of mCAs differ across populations and that rare inherited germline variants are strongly associated with mCAs across genetically diverse populations. These results strongly motivate further studies of mCAs in under-represented populations to better understand the causes and consequences of this class of somatic variation.

genomics↗

bioRxiv2022

Fast computation of principal components of genomic similarity matrices

The computation of a similarity measure for genomic data, for instance using the (genomic) covariance matrix, the Jaccard matrix, or the genomic relationship matrix (GRM), is a standard tool in computational genetics. The principal components of such matrices are routinely used to correct for biases in, for instance, linear regressions. However, the calculation of both a similarity matrix and its singular value decomposition (SVD) are computationally intensive. The contribution of this article is threefold. First, we demonstrate that the calculation of three matrices (the genomic covariance matrix, the weighted Jaccard matrix, and the genomic relationship matrix) can be reformulated in a unified way which allows for an exact, faster SVD computation. An exception is the Jaccard matrix, which does not have a structure applicable for the fast SVD computation. An exact algorithm is proposed to compute the principal components of the genomic covariance, weighted Jaccard, and genomic relationship matrices. The algorithm is adapted from an existing randomized SVD algorithm and ensures that all computations are carried out in sparse matrix algebra. Second, an approximate Jaccard matrix is introduced to which the fast SVD computation is applicable. Third, we establish guaranteed theoretical bounds on the distance (in L2 norm and angle) between the principal components of the Jaccard matrix and the ones of our proposed approximation, thus putting the proposed Jaccard approximation on a solid mathematical foundation. We illustrate all computations on both simulated data and data of the 1000 Genome Project, showing that the approximation error is very low in practice.

bioinformatics↗

bioRxiv2022

Genetic Regulators of Sputum Mucin Concentration and Their Associations with COPD Phenotypes

Hyper-secretion and/or hyper-concentration of mucus is a defining feature of multiple obstructive lung diseases, including chronic obstructive pulmonary disease (COPD). Mucus itself is composed of a mixture of water, ions, salt and proteins, of which the gel-forming mucins, MUC5AC and MUC5B, are the most abundant. Recent studies have linked the concentrations of these proteins in sputum to COPD phenotypes, including chronic bronchitis (CB) and acute exacerbations (AE). We sought to determine whether common genetic variants influence sputum mucin concentrations and whether these variants are also associated with COPD phenotypes, specifically CB and AE. We performed a GWAS to identify quantitative trait loci for sputum mucin protein concentration (pQTL) in the Sub-Populations and InteRmediate Outcome Measures in COPD Study (SPIROMICS, n=708 for total mucin, n=215 for MUC5AC, MUC5B). Subsequently, we tested for associations of mucin pQTL with CB and AE using regression modeling (n=822-1300). Replication analysis was conducted using data from COPDGene (n =5740) and by examining results from the UK Biobank. We identified one genome-wide significant pQTL for MUC5AC (rs75401036) and two for MUC5B (rs140324259, rs10001928). The strongest association for MUC5B, with rs140324259 on chromosome 11, explained 14% of variation in sputum MUC5B. Despite being associated with lower MUC5B, the C allele of rs140324259 conferred increased risk of CB (odds ratio (OR) = 1.42; 95% confidence interval (CI): 1.10-1.80) as well as AE ascertained over three years of follow up (OR=1.41; 95% CI: 1.02-1.94). Associations between rs140324259 and CB or AE did not replicate in COPDGene. However, in the UK Biobank, rs140324259 was associated with phenotypes that define CB, namely chronic mucus production and cough, again with the C allele conferring increased risk. We conclude that sputum MUC5AC and MUC5B concentrations are associated with common genetic variants, and the top locus for MUC5B may influence COPD phenotypes, in particular CB. Author SummaryChronic obstructive pulmonary disease (COPD) is characterized by presence of emphysema and/or chronic bronchitis. Excessive mucus production is a defining phenotype of chronic bronchitis, and is associated with several important features of COPD, including exacerbations and loss of lung function. Recent studies have demonstrated that the amount of mucus produced in COPD patients is an important marker of disease state. We investigated whether common genetic variants are associated with the concentration of two key proteins in mucus, MUC5AC and MUC5B, and whether the variants we identified are also associated with COPD outcomes. We identified multiple genetic variants that were associated with MUC5AC or MUC5B concentration. The strongest association we detected, for MUC5B on chromosome 11, was also associated with features of COPD, including chronic bronchitis and acute exacerbations, in one COPD study population but not another. Results from a much larger study, the UK Biobank, indicate that this variant is associated with chronic mucus production and chronic cough, which are key features of chronic bronchitis. Thus, we conclude that the concentration of key proteins in mucus are influenced by genetic variation, and that a variant on chromosome 11 that affects MUC5B may in turn alter COPD outcomes.

genetics↗