Hepatobiliary complications of immune checkpoint inhibitors in cancer.

Immune checkpoint inhibitors (ICIs) have dramatically changed the landscape of cancer therapy. Over the last decade, both their primary focus in trials and clinical application have exponentially risen, with repeated demonstrations of their efficacy in improving survival in various cancer types. The adverse effects of these drugs on various organ systems were recognised in early phase studies. Given their relatively new emergence on the market, there has been increasing interest into short- and long-term effects and management of ICIs in real-world settings. ICI-related hepatobiliary toxicities are often challenging to diagnose and difficult to distinguish from other causes of deranged liver biochemical tests. The aim of this review is to provide an up-to-date and detailed exploration of the hepatobiliary complications of ICIs, including pathogenesis and approaches to diagnosis and management.

Advancing quantitative PCR with color cycle multiplex amplification.

Quantitative PCR (qPCR) is the gold standard for detection and quantitation of known DNA targets, but the scarcity of spectrally distinct fluorophores and filter sets limits the number of detectable targets. Here, we introduce color cycle multiplex amplification (CCMA) to significantly increase the number of detectable DNA targets in a single qPCR reaction using standard instrumentation. In CCMA, presence of one DNA target species results in a pre-programmed pattern of fluorescence increases. This pattern is distinguished by cycle thresholds (Cts) through rationally designed delays in amplification. For example, we design an assay wherein Staphylococcus aureus sequentially induces FAM, then Cy5.5, then ROX fluorescence increases with more than 3 cycles between each signal. CCMA offers notably higher potential for multiplexing because it uses fluorescence permutation rather than combination. With 4 distinct fluorescence colors, CCMA theoretically allows the detection of up to 136 distinct DNA target sequences using fluorescence permutation. Experimentally, we demonstrated a single-tube qPCR assay screening 21 sepsis-related bacterial DNA targets in samples of blood, sputum, pleural effusion and bronchoalveolar lavage fluid, with 89% clinical sensitivity and 100% clinical specificity, showing its potential as a powerful tool for advanced quantitative screening in molecular diagnostics.

Bariatric-induced microbiome changes alter MASLD development in association with changes in the innate immune system.

Introduction: Metabolic dysfunction-associated steatotic liver disease (MASLD) affects nearly 25% of the population and is the leading cause for liver-related mortality. Bariatric surgery is a well-known treatment for MASLD and obesity. Understanding the fundamental mechanisms by which bariatric surgery can alter MASLD can lead to new avenues of therapy and research. Previous studies have identified the microbiome's role in bariatric surgery and in inflammatory immune cell populations. The host innate immune system modulates hepatic inflammation and fibrosis, and thus the progression of MASLD. The precise role of immune cell types in the pathogenesis of MASLD remains an active area of investigation. The aim of this study was to understand the interplay between microbiota composition post-bariatric surgery and the immune system in MASLD. Methods: Eighteen morbidly obese females undergoing sleeve gastrectomy were followed pre-and post-surgery. Stool from four patients, showing resolved MASLD post-surgery with sustained weight loss, was transplanted into antibiotic treated mice. Mice received pre-or post-surgery stool and were fed a standard or high-fat diet. Bodyweight, food intake, and physiological parameters were tracked weekly. Metabolic parameters were measured post-study termination. Results: The human study revealed that bariatric surgery led to significant weight loss (p > 0.05), decreased inflammatory markers, and improved glucose levels six months post-surgery. Patients with weight loss of 20% or more showed distinct changes in blood metabolites and gut microbiome composition, notably an increase in Bacteroides. The mouse model confirmed surgery-induced microbiome changes to be a major factor in the reduction of markers and attenuation of MASLD progression. Mice receiving post-surgery fecal transplants had significantly less weight gain and liver steatosis compared to pre-surgery recipients. There was also a significant decrease in inflammatory cytokines interferon gamma, interleukin 2, interleukin 15, and mig. This was accompanied by alterations in liver immunophenotype, including an increase in natural killer T cells and reduction of Kupfer cells in the post-surgery transplant group. Discussion: Our findings suggest surgery induced microbial changes significantly reduce inflammatory markers and fatty liver progression. The results indicate a potential causal link between the microbiome and the host immune system, possibly mediated through modulation of liver NKT and Kupffer cells.

Protein-truncating variant in APOL3 increases chronic kidney disease risk in epistasis with APOL1 risk alleles.

BACKGROUND: Two coding alleles within the APOL1 gene, G1 and G2, found almost exclusively in individuals genetically similar to West African populations, contribute substantially to the pathogenesis of chronic kidney disease (CKD). The APOL gene cluster on chromosome 22 contains a total of six APOL genes that have arisen as a result of gene duplication. METHODS: Using a genome-first approach in the Penn Medicine Biobank, we identified 62 protein-altering variants in the six APOL genes with a minor allele frequency > 0.1% in a population of participants genetically similar to African reference populations and performed population-specific phenome-wide association studies. RESULTS: We identified rs1108978, a stop-gain variant in APOL3 (p.Q58*), to be significantly associated with increased CKD risk, even after conditioning on APOL1 G1/G2 carrier status. These findings were replicated in the Veterans Affairs Million Veteran Program and the All of Us Research Program. APOL3 p.Q58* was also significantly associated with a number of quantitative traits linked to CKD including decreased kidney volume. This truncating variant contributed the most risk for CKD in patients monoallelic for APOL1 G1/G2, suggesting an epistatic interaction and a potential protective effect of wild-type APOL3 against APOL1-induced kidney disease. CONCLUSION: This study demonstrates the utility of targeting population-specific variants in a genome-first approach, even in the context of well-studied gene-disease relationships. FUNDING: National Heart, Lung, and Blood Institute (F30HL172382, R01HL169378, R01HL169458), Doris Duke Foundation (grant 2023-0224), National Institute of Biomedical Imaging and Bioengineering (P41EB029460), National Center for Advancing Translational Sciences (UL1-TR-001878).

Novel Two-Terminal Synapse/Neuron Based on an Antiferroelectric Hafnium Zirconium Oxide Device for Neuromorphic Computing.

Functionally diverse devices with artificial neuron and synapse properties are critical for neuromorphic systems. We present a two-terminal artificial leaky-integrate-fire (LIF) neuron based on 6 nm Hf0.1Zr0.9O2 (HZO) antiferroelectric (AFE) thin films and develop a synaptic device through work function (WF) engineering. LIF neuron characteristics, including integration, firing, and leakage, are achieved in W/HZO/W devices due to the accumulated polarization and spontaneous depolarization of AFE HZO films. By engineering the top electrode with asymmetric WFs, we found that Au/Ti/HZO/W devices exhibit synaptic weight plasticity, such as paired-pulse facilitation and long-term potentiation/depression, achieving >90% accuracy in digit recognition within constructed artificial neural network systems. These findings suggest that AFE HZO capacitor-based neurons and WF-engineered artificial synapses hold promise for constructing efficient spiking neuron networks and artificial neural networks, thereby advancing neuromorphic computing applications based on emerging AFE HZO devices.

Low breakdown voltage and CMOS compatible avalanche photodiode based on SOI substrate.

In this work, we present a novel, to the best of our knowledge, lateral avalanche photodiode (APD) with low breakdown voltage and high bandwidth which has the potential to serve as a core device in future large-scale advanced optoelectronic hybrid chips. By taking advantage of a silicon-on-insulator (SOI) substrate combined with a separation absorption multiplier (SAM) structure, the demonstrated APDs exhibit a high gain of 148. Furthermore, the minimum breakdown voltage of the measured device is 6.1 V, which represents the lowest breakdown voltage for Si-APD, making it compatible with the existing CMOS technology for low voltage operation. Benefiting from an ultra-thin top silicon and lateral SAM structure, the problem of edge breakdown has been completely solved. Additionally, a set of device arrays with absorption and avalanche regions of different sizes is also manufactured and compared. Our findings indicate that the proposed APD has fascinating application prospects in the CMOS process-based LIDAR chips.

Polypharmacy and Guideline-Directed Medical Therapy Initiation Among Adults Hospitalized With Heart Failure.

Background: Underprescribing of guideline-directed medical therapy (GDMT) for heart failure (HF) persists. Objectives: The purpose of this study was to assess polypharmacy as a barrier to GDMT. Methods: We examined participants hospitalized for HF with reduced ejection fraction and HF with mildly reduced ejection fraction between 2003 and 2017 from the Reasons for Geographic and Racial Differences in Stroke study. Participants were stratified by admission medication count-0 to 4, 5 to 9, and ≥10 medications. We examined GDMT use at admission, GDMT contraindications, and initiation of eligible indicated GDMT by medication count. We conducted a multivariable Poisson regression with robust standard errors to examine the association between medication count and GDMT initiation. GDMT included agents for HF with reduced ejection fraction/HF with mildly reduced ejection fraction, antiplatelet agents and statins for coronary artery disease, and anticoagulants for atrial fibrillation. Results: Among 545 participants with HF, 34% were not taking a beta-blocker, 39% were not taking an angiotensin-converting enzyme inhibitor/angiotensin receptor blocker/angiotensin receptor-neprilysin inhibitor, or hydralazine-isosorbide dinitrate, and 90% were not taking a mineralocorticoid receptor antagonist at admission; among participants with coronary artery disease, 36% were not taking an antiplatelet agent, and 38% were not taking a statin; and among participants with atrial fibrillation, 49% were not taking an anticoagulant. Polypharmacy was inversely associated with initiation of at least one indicated medication (5-9 medications: relative risk [RR]: 0.67; 95% CI: 0.56-0.82; P < 0.001; ≥10 medications: RR: 0.50; 95% CI: 0.39-0.64; P < 0.001) and initiation of at least half of indicated medications (5-9 medications: RR: 0.64; 95% CI: 0.51-0.81; P < 0.001; ≥10 medications: RR: 0.50; 95% CI: 0.38-0.67; P < 0.001). Conclusions: Polypharmacy is an important barrier to GDMT.

Implementation of Digital Pathology and Artificial Intelligence in Routine Pathology Practice.

The advent of affordable technology has significantly influenced the practice of digital pathology, leading to its growing adoption within the pathology community. This review article aimed to outline the latest developments in digital pathology, the cutting-edge advancements in artificial intelligence (AI) applications within this field, and the pertinent United States regulatory frameworks. The content is based on a thorough analysis of original research articles and official United States Federal guidelines. Findings from our review indicate that several Food and Drug Administration-approved digital scanners and image management systems are establishing a solid foundation for the seamless integration of advanced technologies into everyday pathology workflows, which may reduce device and operational costs in the future. AI is particularly transforming the way morphologic diagnoses are automated, notably in cancers like prostate and colorectal, within screening initiatives, albeit challenges such as data privacy issues and algorithmic biases remain. The regulatory environment, shaped by standards from the Food and Drug Administration, Centers for Medicare & Medicaid Services/Clinical Laboratory Improvement Amendments, and College of American Pathologists, is evolving to accommodate these innovations while ensuring safety and reliability. Centers for Medicare & Medicaid Services/Clinical Laboratory Improvement Amendments have issued policies to allow pathologists to review and render diagnoses using digital pathology remotely. Moreover, the introduction of new digital pathology Current Procedural Terminology codes designed to complement existing pathology Current Procedural Terminology codes is facilitating reimbursement processes. Overall, these advancements are heralding a new era in pathology that promises enhanced diagnostic precision and efficiency through digital and AI technologies, potentially improving patient care as well as bolstering educational and research activities.

Postinfectious Pulmonary Complications: Establishing Research Priorities to Advance the Field: An Official American Thoracic Society Workshop Report.

Continued improvements in the treatment of pulmonary infections have paradoxically resulted in a growing challenge of individuals with postinfectious pulmonary complications (PIPCs). PIPCs have been long recognized after tuberculosis, but recent experiences such as the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic have underscored the importance of PIPCs following other lower respiratory tract infections. Independent of the causative pathogen, most available studies of pulmonary infections focus on short-term outcomes rather than long-term morbidity among survivors. In this document, we establish a conceptual scope for PIPCs with discussion of globally significant pulmonary pathogens and an examination of how these pathogens can damage different components of the lung, resulting in a spectrum of PIPCs. We also review potential mechanisms for the transition from acute infection to PIPC, including the interplay between pathogen-mediated injury and aberrant host responses, which together result in PIPCs. Finally, we identify cross-cutting research priorities for the field to facilitate future studies to establish the incidence of PIPCs, define common mechanisms, identify therapeutic strategies, and ultimately reduce the burden of morbidity in survivors of pulmonary infections.

Visualizing and Controlling of Photogenerated Electron-Hole Pair Separation in Monolayer WS2 Nanobubbles under Piezoelectric Field.

The piezoelectric properties of two-dimensional semiconductor nanobubbles present remarkable potential for application in flexible optoelectronic devices, and the piezoelectric field has emerged as an efficacious pathway for both the separation and migration of photogenerated electron-hole pairs, along with inhibition of recombination. However, the comprehension and control of photogenerated carrier dynamics within nanobubbles still remain inadequate. Hence, this study is dedicated to underscore the importance of in situ detection and detailed characterization of photogenerated electron-hole pairs in nanobubbles to enrich understanding and strategic manipulation in two-dimensional semiconductor materials. Utilizing frequency modulation kelvin probe force microscopy (FM-KPFM) and strain gradient distribution techniques, the existence of a piezoelectric field in monolayer WS2 nanobubbles was confirmed. Combining w/o and with illumination FM-KPFM, second-order capacitance gradient technique and in situ nanoscale tip-enhanced photoluminescence characterization techniques, the interrelationships among the piezoelectric effect, interlayer carrier transfer, and the funneling effect for photocarrier dynamics process across various nanobubble sizes were revealed. Notably, for a WS2/graphene bubble height of 15.45 nm, a 0 mV surface potential difference was recorded in the bubble region w/o and with illumination, indicating a mutual offset of piezoelectric effect, interlayer carrier transfer, and the funneling effect. This phenomenon is prevalent in transition metal dichalcogenides materials exhibiting inversion symmetry breaking. The implication of our study is profound for advancing the understanding of the dynamics of photogenerated electron-hole pair in nonuniform strain piezoelectric systems, and offers a reliable framework for the separation and modulation of photogenerated electron-hole pair in flexible optoelectronic devices and photocatalytic applications.

Clinical Impact of Telomere Length Testing for Interstitial Lung Disease.

BACKGROUND: Shortened telomere length (TL) is a genomic risk factor for fibrotic interstitial lung disease (ILD), but its role in clinical management is unknown. RESEARCH QUESTION: What is the clinical impact of TL testing on the management of ILD? STUDY DESIGN AND METHODS: Patients were evaluated in the Columbia University ILD clinic and underwent Clinical Laboratory Improvement Amendments-certified TL testing by flow cytometry and fluorescence in situ hybridization (FlowFISH) as part of clinical treatment. Short TL was defined as below the 10th age-adjusted percentile for either granulocytes or lymphocytes by FlowFISH. Patients were offered genetic counseling and testing if they had short TL or a family history of ILD. FlowFISH TL was compared with research quantitative polymerase chain reaction (qPCR) TL measurement. RESULTS: A total of 108 patients underwent TL testing, including those with clinical features of short telomere syndrome such as familial pulmonary fibrosis (50%) or extrapulmonary manifestations in the patient (25%) or a relative (41%). The overall prevalence of short TL was 46% and was similar across clinical ILD diagnoses. The number of short telomere clinical features was independently associated with detecting short TL (OR, 2.00; 95% CI, 1.27-3.32). TL testing led to clinical treatment changes for 35 patients (32%), most commonly resulting in reduction or avoidance of immunosuppression. Of the patients who underwent genetic testing (n = 34), a positive or candidate diagnostic finding in telomere-related genes was identified in 10 patients (29%). Inclusion of TL testing below the 1st percentile helped reclassify eight of nine variants of uncertain significance into actionable findings. The qPCR test correlated with FlowFISH, but age-adjusted percentile cutoffs may not be equivalent between the two assays. INTERPRETATION: Incorporating TL testing in ILD impacted clinical management and led to the discovery of new actionable genetic variants.

Metal-insulator-semiconductor photoelectrodes for enhanced photoelectrochemical water splitting.

Photoelectrochemical (PEC) water splitting provides a scalable and integrated platform to harness renewable solar energy for green hydrogen production. The practical implementation of PEC systems hinges on addressing three critical challenges: enhancing energy conversion efficiency, ensuring long-term stability, and achieving economic viability. Metal-insulator-semiconductor (MIS) heterojunction photoelectrodes have gained significant attention over the last decade for their ability to efficiently segregate photogenerated carriers and mitigate corrosion-induced semiconductor degradation. This review discusses the structural composition and interfacial intricacies of MIS photoelectrodes tailored for PEC water splitting. The application of MIS heterostructures across various semiconductor light-absorbing layers, including traditional photovoltaic-grade semiconductors, metal oxides, and emerging materials, is presented first. Subsequently, this review elucidates the reaction mechanisms and respective merits of vacuum and non-vacuum deposition techniques in the fabrication of the insulator layers. In the context of the metal layers, this review extends beyond the conventional scope, not only by introducing metal-based cocatalysts, but also by exploring the latest advancements in molecular and single-atom catalysts integrated within MIS photoelectrodes. Furthermore, a systematic summary of carrier transfer mechanisms and interface design principles of MIS photoelectrodes is presented, which are pivotal for optimizing energy band alignment and enhancing solar-to-chemical conversion efficiency within the PEC system. Finally, this review explores innovative derivative configurations of MIS photoelectrodes, including back-illuminated MIS photoelectrodes, inverted MIS photoelectrodes, tandem MIS photoelectrodes, and monolithically integrated wireless MIS photoelectrodes. These novel architectures address the limitations of traditional MIS structures by effectively coupling different functional modules, minimizing optical and ohmic losses, and mitigating recombination losses.

A Novel High-Speed Split-Gate Trench Carrier-Stored Trench-Gate Bipolar Transistor with Enhanced Short-Circuit Roughness.

A novel high-speed and process-compatible carrier-stored trench-gate bipolar transistor (CSTBT) combined with split-gate technology is proposed in this paper. The device features a split polysilicon electrode in the trench, where the left portion is equipotential with the cathode. This design mitigates the impact of the anode on the trench gate, resulting in a reduction in the gate-collector capacitance (CGC) to improve the dynamic characteristics. On the left side of the device cell, the P-layer, the carrier-stored (CS) layer and the P-body are formed from the bottom up by ion implantation and annealing. The P-layer beneath the trench bottom can decrease the electric field at the bottom of the trench, thereby improving breakdown voltage (BV) performance. Simultaneously, the highly doped CS layer strengthens the hole-accumulation effect at the cathode. Moreover, the PNP doping layers on the left form a self-biased pMOS. In a short-circuit state, the self-biased pMOS turns on at a certain collector voltage, causing the potential of the CS-layer to be clamped by the hole channel. Consequently, the short-circuit current no longer increases with the collector voltage. The simulation results reveal significant improvements in comparison with the conventional CSTBT under the same on-state voltage (1.48 V for 100 A/cm2). Specifically, the turn-off time (toff) and turn-off loss (Eoff) are reduced by 38.4% and 41.8%, respectively. The short-circuit current is decreased by 50%, while the short-circuit time of the device is increased by 2.46 times.

The annotation of GBA1 has been concealed by its protein-coding pseudogene GBAP1.

Mutations in GBA1 cause Gaucher disease and are the most important genetic risk factor for Parkinson's disease. However, analysis of transcription at this locus is complicated by its highly homologous pseudogene, GBAP1. We show that >50% of short RNA-sequencing reads mapping to GBA1 also map to GBAP1. Thus, we used long-read RNA sequencing in the human brain, which allowed us to accurately quantify expression from both GBA1 and GBAP1. We discovered significant differences in expression compared to short-read data and identify currently unannotated transcripts of both GBA1 and GBAP1. These included protein-coding transcripts from both genes that were translated in human brain, but without the known lysosomal function-yet accounting for almost a third of transcription. Analyzing brain-specific cell types using long-read and single-nucleus RNA sequencing revealed region-specific variations in transcript expression. Overall, these findings suggest nonlysosomal roles for GBA1 and GBAP1 with implications for our understanding of the role of GBA1 in health and disease.

Post-stroke cognitive impairment and brain hemorrhage are augmented in hypertensive mice.

Hypertension is a major risk factor for both stroke and cognitive impairment, but it is unclear whether it may specifically affect post-stroke cognitive impairment. We assessed the effect of hypertension and/or stroke on brain injury, cognitive outcome, and the brain transcriptomic profile. C57BL/6J mice (n = 117; 3-5 mo.) received s.c. infusion of either saline or angiotensin II followed by sham surgery or photothrombotic stroke targeting the prefrontal cortex seven days later. Cognitive function was assessed with the Barnes maze and RNA sequencing was used to quantify transcriptomic changes in the brain. Angiotensin II treatment produced spontaneous hemorrhaging after stroke. In the Barnes maze, hypertensive mice that received stroke surgery had an increased escape latency compared to other groups (day 3: hypertensive + stroke = 166.6 ± 6.0 s vs. hypertensive + sham = 122.8 ± 13.8 s vs. normotensive + stroke = 139.9 ± 10.1 s vs. normotensive + sham = 101.9 ± 16.7 s), consistent with impaired cognition. RNA sequencing revealed >1500 differentially expressed genes related to neuroinflammation in hypertensive + stroke vs. normotensive + stroke, which included genes associated with apoptosis, microRNAs, autophagy, anti-cognitive biomarkers and Wnt signaling. Overall, we show that the combination of hypertension and stroke resulted in greater learning impairment and brain injury.

A Comprehensive Study of NF3-Based Selective Etching Processes: Application to the Fabrication of Vertically Stacked Horizontal Gate-All-around Si Nanosheet Transistors.

In this paper, we demonstrate a comprehensive study of NF3-based selective etching processes for inner spacer formation and for channel release, enabling stacked horizontal gate-all-around Si nanosheet transistor architectures. A cyclic etching process consisting of an oxidation treatment step and an etching step is proposed and used for SiGe selective etching. The cyclic etching process exhibits a slower etching rate and higher etching selectivity compared to the direct etching process. The cycle etching process consisting of Recipe 1, which has a SiGe etching rate of 0.98 nm/cycle, is used for the cavity etch. The process achieved good interlayer uniformity of cavity depth (cavity depth ≤ 5 ± 0.3 nm), while also obtaining a near-ideal rectangular SiGe etch front shape (inner spacer shape = 0.84) and little Si loss (0.44 nm@ each side). The cycle etching process consisting of Recipe 4 with extremely high etching selectivity is used for channel release. The process realizes the channel release of nanosheets with a multi-width from 30 nm to 80 nm with little Si loss. In addition, a selective isotropic etching process using NF3/O2/Ar gas mixture is used to etch back the SiN film. The impact of the O2/NF3 ratio on the etching selectivity of SiN to Si and the surface roughness of SiN after etching is investigated. With the introduction of O2 into NF3/Ar discharge, the selectivity increases sharply, but when the ratio of O2/NF3 is up to 1.0, the selectivity tends to a constant value and the surface roughness of SiN increases rapidly. The optimal parameter is O2/NF3 = 0.5, resulting in a selectivity of 5.4 and a roughness of 0.19 nm.

Subcutaneous biodegradable scaffolds for restimulating the antitumour activity of pre-administered CAR-T cells.

The efficacy of adoptive T-cell therapies based on chimaeric antigen receptors (CARs) is limited by the poor proliferation and persistence of the engineered T cells. Here we show that a subcutaneously injected biodegradable scaffold that facilitates the infiltration and egress of specific T-cell subpopulations, which forms a microenvironment mimicking features of physiological T-cell activation, enhances the antitumour activity of pre-administered CAR-T cells. CAR-T-cell expansion, differentiation and cytotoxicity were driven by the scaffold's incorporation of co-stimulatory bound ligands and soluble molecules, and depended on the types of co-stimulatory molecules and the context in which they were presented. In mice with aggressive lymphoma, a single, local injection of the scaffold following non-curative CAR-T-cell dosing led to more persistent memory-like T cells and extended animal survival. Injectable biomaterials with optimized ligand presentation may boost the therapeutic performance of CAR-T-cell therapies.

The common p.Ile291Val variant of ERLIN1 enhances TM6SF2 function and is associated with protection against MASLD.

BACKGROUND: The ERLIN1 p.Ile291Val single-nucleotide polymorphism (rs2862954) is associated with protection from steatotic liver disease (SLD), but effects of this variant on metabolic phenotypes remain uncertain. METHODS: Metabolic phenotypes and outcomes associated with ERLIN1 p.Ile291Val were analyzed by using a genome-first approach in the UK Biobank (UKB), Penn Medicine BioBank (PMBB), and All of Us cohort. FINDINGS: ERLIN1 p.Ile291Val carriers exhibited significantly lower serum levels of alanine aminotransferase and aspartate aminotransferase as well as higher levels of triglycerides, low-density lipoprotein cholesterol, Apolipoprotein B, high-density lipoprotein cholesterol, and Apolipoprotein A1 in UKB, and these values were affected by ERLIN1 p.Ile291Val in an allele-dose-dependent manner. Homozygous ERLIN1 p.Ile291Val carriers had a significantly reduced risk of developing metabolic dysfunction-associated SLD (MASLD, adjusted odds ratio [aOR] = 0.92, 95% confidence interval [CI], 0.88-0.96). The protective effect of this variant was enhanced in patients with alcoholic liver disease. Our results were replicated in PMBB and the All of Us cohort. Strikingly, the protective effects of ERLIN1 p.Ile291Val were not apparent in individuals carrying the TM6SF2 p.Glu167Lys variant associated with increased risk of SLD. We analyzed the effects of predicted loss-of-function ERLIN1 variants and found that they had opposite effects, namely reduced plasma lipids, suggesting that ERLIN1 p.Ile291Val may be a gain-of-function variant. CONCLUSION: Our study contributes to a better understanding of ERLIN1 by investigating a coding variant that has emerged as a potential gain-of-function mutation with protective effects against MASLD development.