Factors governing the clinical trajectory of Plasmodium falciparum infection remain an important area of investigation. Here we present transcriptomic, proteomic and metabolomic analyses comparing clinical subtypes of severe Plasmodium falciparum malaria to matched controls with uncomplicated disease in 79 children from Mali. MMP8, IL1R2, and ARG1 transcription is higher across cerebral malaria, severe malarial anemia, and concurrent cerebral malaria and severe malarial anemia, indicating a shared inflammatory signature. Tissue inhibitor of metalloproteinases 1 is the most upregulated protein in cerebral malaria, which along with elevated MMP8 and MMP9 transcription, underscores the importance of the metalloproteinase pathway in central nervous system pathophysiology. L-arginine metabolites are decreased in cerebral malaria, which coupled with increased ARG1 transcription suggests a putative mechanism impairing cerebral vasodilation. Using multi-omics approaches, we thus describe the inflammatory cascade in severe malaria syndromes, and identify potential therapeutic targets and biological markers.

Some genetic variants are associated with lung function decline and chronic obstructive pulmonary disease (COPD), but functional studies are necessary to confirm causality. We investigated the genetic susceptibility-associated lung function decline with or without COPD, using data from a community-based cohort (N = 8554). A genome-wide interaction study was conducted to identify the association between genetic variants and pulmonary function, and the way variants relate to lung impairment in accordance with smoking status and amount was examined. We further used a linear mixed model to examine the association and interaction to time effect. We found annual mean FEV1 declines of 41.7 mL for men and 33.4 mL for women, and the annual rate of decline in FEV1 was the fastest for current smokers. We also found a previously identified locus near FAM13A, the most significant SNPs from the results of two likelihood ratio tests for FEV1/FVC (P = 1.56 × 10-10). These selected SNPs were located in the upstream region of FAM13A on chromosome 4 and had similar minor allele frequencies (MAFs). Furthermore, we found that certain SNPs tended to have lower FEV1/FVC values, and lung function decreased much faster with time interactions. The SNP most associated with lung function decline was the rs75679995 SNP on chromosome 7, and those SNPs located within the TAD of the DNAH11 region and the eQTL of rs9991425 revealed a higher expression of MFAP3L and AADAT genes (P = 2.28 × 10-7 and 2.01 × 10-6, respectively). This is the first study to investigate gene-time interactions in lung function decline as a risk factor for COPD in the Korean population. In addition to replicating previously known signals for FAM13A, we identified two genomic regions (DNAH11, AADAT) that are potentially involved in gene-environment interactions, warranting further investigation to confirm their roles.

Genetic variants related to susceptibility to chronic respiratory conditions such as interstitial lung disease (ILD) could share critical pathways in the pathogenesis of COVID-19 and be implicated in COVID-19 outcomes and post-COVID-19. We aimed to identify the participation of genetic variants in lung function and ILD genes in severe COVID-19 outcomes and post-COVID-19 condition. We studied 936 hospitalized patients with COVID-19. The requirement of invasive mechanical ventilation (IMV) and the acute respiratory distress syndrome (ARDS) classification were considered. The mortality was assessed as the in-hospital death. The post-COVID-19 group included 102 patients evaluated for pulmonary function tests four times during the year after discharge. Five variants (FAM13A rs2609255, DSP rs2076295, TOLLIP rs111521887, TERT rs2736100, and THSD4 rs872471) were genotyped using TaqMan assays. A multifactor dimensionality reduction method (MDR) was performed for epistasis estimation. The TERT rs2736100 and THSD4 rs872471 variants were associated with differential risk for ARDS severity (moderate vs. severe, CC + CA, p = 0.044, OR = 0.66, 95% CI = 0.44-0.99; and GG p = 0.034, OR = 2.22, 95% CI = 1.04-4.72, respectively). These variants and FAM13A rs2609255 were also related to pulmonary function post-COVID-19. The MDR analysis showed differential epistasis and correlation of the genetic variants included in this study. The well-known variants in recognized genes related to pulmonary function worsening and interstitial disorders are related to the severity and mortality of COVID-19 and lung performance in the post-COVID-19 condition.

Previous genome-wide association studies (GWAS) have established association between genetic variants and pulmonary function across various ethnics, whereas such associations are scarcely reported in Chinese adults. Therefore, we conducted an GWAS to explore relationships between genetic variants and pulmonary function among middle-aged Chinese dizygotic twins and further validated the top variants using data from the UK Biobank (UKB).

In the discovery phase, 139 dizygotic twin pairs were drawn from the Qingdao Twin Registry. Pulmonary function was assessed using three parameters: forced expiratory volume the first second (FEV1), forced vital capacity (FVC), and FEV1/FVC ratio. GWAS was performed using GEMMA, Gene-based analysis was conducted by VEGAS2. And pathway enrichment analysis was performed using PASCAL. In the validation phase, Single-nucleotide polymorphisms (SNPs) with suggestive significance were examined through linear regression analysis of the additive effect model among 1573 Chinese ethnic participants from UKB.

The median age of twin pairs in the study was 49 years. 3 SNPs (rs80345886, rs117883876, and 75139439) related to FEV1 achieved genome-wide significance. Moreover, 222, 150, and 73 SNPs surpassed suggestive evidence level (p < 1 × 10- 5) for FEV1, FVC, and FEV1/FVC, respectively. Among them, 16 SNPs located in TBC1D16 for FEV1, 25 SNPs located in GPR126 for FVC, and 2 SNPs located in CCDC110 for FEV1/FVC, the three genes were also revealed by gene-based analysis. Moreover, 12 novel SNPs related to pulmonary function were validated to reach the nominal significance level (p < 0.05) in the UKB, with some located in the TBC1D16, TAFA5, and MTHFD1L genes.

Our GWAS results on Chinese dizygotic twins provide new references for the genetic regulation on pulmonary function. Twelve novel susceptibility loci are considered as possible crucial to pulmonary function.

Since their discovery, corticosteroids have been widely used in the treatment of several diseases, including asthma, acute lymphoblastic leukemia, chronic obstructive pulmonary disease, and many other conditions. However, it has been noted that some patients develop undesired side effects or even fail to respond to treatment. The reasons behind this have not yet been fully elucidated. This poses a significant challenge to effective treatment that needs to be addressed urgently. Recent genomic, transcriptomic, and other omics-based approximations have begun to shed light into the genetic factors influencing interindividual variability in corticosteroid efficacy and its side effects. Here, we comprehensively revise the recent literature on corticosteroid response in various critical and chronic diseases, with a focus on omics approaches, and highlight existing knowledge gaps where further investigation is urgently needed.

Genetic factors play a role in asthma severity. However, low- and middle-income countries have minimal contribution to genomic asthma research. The current study investigates the influence of an important genetic asthma region (6p21) on severe asthma in a cohort of asthmatics in Pakistan.

In this case-control study, mild to severe asthmatic patients (n = 255) and controls (n = 260) were enrolled from Lahore, Pakistan. Blood samples were collected, and genomic DNA was extracted for the genotyping of 11 single nucleotide polymorphisms located in the 6p21 region. Severe asthma was defined based on the defined daily dose of inhaled corticosteroids equivalent to 200 mcg of beclomethasone dipropionate (as per the global initiative for asthma guidelines). An additive genetic model was followed to find the associations between these variants and the outcome. Univariate and multivariate logistic regression, adjusted for confounders, was performed. Odds ratio (OR), 95% confidence interval (95% CI), p-value, and q-values after FDR adjustment were estimated.

The genetic variants rs3025028, rs987870, and rs3025039 showed strong associations with the incidence of asthma with odds ratios of 1.58, 1.62, and 2.70 (95% CI = 1.16-2.16, 1.15-2.30, and 1.40-5.39, respectively). Further stratification analysis to study the risk of severe asthma also revealed markedly significant associations for rs3025020 and rs1799964 (OR = 2.28 and 2.99; 95% CI = 1.39-3.86 and 1.75-5.33, respectively). However, the SNPs rs2070600, rs987870, and rs3025039 also showed a significant relationship with the severity (OR = 2.34, 1.75, and 2.72; 95% CI = 1.02-5.97, 1.07-2.98, and 1.11-7.71, respectively), but FDR-adjusted q-values were insignificant (0.10, 0.07, and 0.07, respectively).

The 6p21 region variants rs3025028, rs987870, and rs3025039 are associated with the incidence, whereas rs3025020 and rs1799964 are associated with the risk of more severe asthma in the Pakistani population.

The receptor for advanced glycation end product (RAGE) is a transmembrane receptor accelerating a pro-inflammatory signal. RAGE signalling is promoted by decreased soluble isoform of RAGE (sRAGE), which is a decoy receptor for RAGE ligands, and RAGE SNP rs2070600 minor allele. In Caucasian and Japanese cohorts, low circulatory sRAGE levels and presence of the minor allele are associated with poor survival of idiopathic pulmonary fibrosis (IPF) and increased disease susceptibility to interstitial lung disease, respectively. However, whether sRAGE and RAGE SNP rs2070600 are associated with acute exacerbation of IPF (AE-IPF) is unclear.

This retrospective cohort study evaluated the association between the onset of AE-IPF and serum sRAGE levels in 69 German and 102 Japanese patients with IPF. The association of AE-IPF with RAGE SNP rs2070600 in 51 German and 84 Japanese patients, whose DNA samples were stored, was also investigated.

In each cohort, the incidence of AE-IPF was significantly and reproducibly higher in the patients with sRAGE < 467.1 pg/mL. In a pooled exploratory analysis, the incidence of AE-IPF was lowest in the patients with higher sRAGE levels and rs2070600 minor allele, although no significant difference in the incidence was observed between the patients with and without the rs2070600 minor allele.

Low sRAGE levels were associated with increased incidence of AE-IPF in two independent cohorts of different ethnicities. The combination of rs2070600 and sRAGE levels may stratify patients with IPF for the risk of AE.

Chronic obstructive pulmonary disease (COPD) is a highly prevalent disease, making it a leading cause of death worldwide. Several genome-wide association studies (GWAS) have been conducted to identify loci associated with COPD. However, different ancestral genetic compositions for the same disease across various populations present challenges in studies involving multi-population data. In this study, we aimed to identify protein-coding genes associated with COPD by prioritizing genes for each population's GWAS data, and then combining these results instead of performing a common meta-GWAS due to significant sample differences in different population cohorts. Lung function measurements are often used as indicators for COPD risk prediction; therefore, we used lung function GWAS data from two populations, Japanese and European, and re-evaluated them using a multi-population gene prioritization approach. This study identified significant single nucleotide variants (SNPs) in both Japanese and European populations. The Japanese GWAS revealed nine significant SNPs and four lead SNPs in three genomic risk loci. In comparison, the European population showed five lead SNPs and 17 independent significant SNPs in 21 genomic risk loci. A comparative analysis of the results found 28 similar genes in the prioritized gene lists of both populations. We also performed a standard meta-analysis for comparison and identified 18 common genes in both populations. Our approach demonstrated that trans-ethnic linkage disequilibrium (LD) could detect some significant novel associations and genes that have yet to be reported or were missed in previous analyses. The study suggests that a gene prioritization approach for multi-population analysis using GWAS data may be a feasible method to identify new associations in data with genetic diversity across different populations. It also highlights the possibility of identifying generalized and population-specific treatment and diagnostic options.

Early-life (EL) respiratory infections increase pulmonary disease risk, especially EL-Respiratory Syncytial Virus (EL-RSV) infections linked to asthma. Mechanisms underlying asthma predisposition remain unknown. In this study, we examined the long-term effects on the lung after four weeks post EL-RSV infection. We identified alterations in the lung epithelial cell, with a rise in the percentage of alveolar type 2 epithelial cells (AT2) and a decreased percentage of cells in the AT1 and AT2-AT1 subclusters, as well as upregulation of Bmp2 and Krt8 genes that are associated with AT2-AT1 trans-differentiation, suggesting potential defects in lung repair processes. We identified persistent upregulation of asthma-associated genes, including Il33. EL-RSV-infected mice allergen-challenged exhibited exacerbated allergic response, with significant upregulation of Il33 in the lung and AT2 cells. Similar long-term effects were observed in mice exposed to EL-IL-1β. Notably, treatment with IL-1ra during acute EL-RSV infection mitigated the long-term alveolar alterations and the allergen-exacerbated response. Finally, epigenetic modifications in the promoter of the Il33 gene were detected in AT2 cells harvested from EL-RSV and EL-IL1β groups, suggesting that long-term alteration in the epithelium after RSV infection is dependent on the IL-1β pathway. This study provides insight into the molecular mechanisms of asthma predisposition after RSV infection.

Chronic obstructive pulmonary disease (COPD) is caused by interactions between many factors across the life course, including genetics. A proportion of COPD may be due to reduced lung growth in childhood. We hypothesized that a polygenic risk score (PRS) for COPD is associated with lower lung function already in childhood and up to adulthood.

A weighted PRS was calculated based on the 82 association signals (p ≤ 5 × 10-8) revealed by the largest GWAS of airflow limitation (defined as COPD) to date. This PRS was tested in association with lung function measures (FEV1, FVC, and FEV1/FVC) in subjects aged 4-50 years from 16 independent cohorts participating in the Chronic Airway Diseases Early Stratification (CADSET) Clinical Research Collaboration. Age-stratified meta-analyses were conducted combining the results from each cohort (n = 45,406). These findings were validated in subjects >50 years old.

We found significant associations between the PRS for airflow limitation and: (1) lower pre-bronchodilator FEV1/FVC from school age (7-10 years; β: -0.13 z-scores per one PRS z-score increase [-0.15, -0.11], q-value = 7.04 × 10-53) to adulthood (41-50 years; β: -0.16 [-0.19, -0.13], q-value = 1.31 × 10-24); and (2) lower FEV1 (from school age: 7-10 years; β: -0.07 [-0.09, -0.05], q-value = 1.65 × 10-9, to adulthood: 41-50 years; β: -0.17 [-0.20, -0.13], q-value = 4.48 x 10-20). No effect modification by smoking, sex, or a diagnosis of asthma was observed.

We provide evidence that a higher genetic risk for COPD is linked to lower lung function from childhood onwards.

This study was supported by CADSET, a Clinical Research Collaboration of the European Respiratory Society.

Chronic respiratory diseases, such as chronic obstructive pulmonary disease (COPD), asthma and interstitial lung diseases are frequently occurring disorders with a polygenic basis that account for a large global burden of morbidity and mortality. Recent large-scale genetic epidemiology studies have identified associations between genetic variation and individual respiratory diseases and linked specific genetic variants to quantitative traits related to lung function. These associations have improved our understanding of the genetic basis and mechanisms underlying common lung diseases. Moreover, examining the overlap between genetic associations of different respiratory conditions, along with evidence for gene-environment interactions, has yielded additional biological insights into affected molecular pathways. This genetic information could inform the assessment of respiratory disease risk and contribute to stratified treatment approaches.

Damage-associated molecular patterns (DAMPs) are endogenous danger signals that alert and activate the immune system upon cellular damage or death. It has previously been shown that DAMP release is increased in patients with COPD, leading to higher levels in extracellular fluids such as serum. In the current study we investigated whether the serum levels of DAMPs were associated with survival rates in COPD patients.

A panel of seven DAMPs, consisting of HMGB1, fibrinogen, α-defensin, heat shock protein 70, S100A8, galectin-9 and double-stranded DNA (dsDNA), was measured in serum of 949 severe COPD patients. Maximally selected rank statistics was used to define cut-off values and a Cox proportional hazards model was used to evaluate the effect of high or low DAMP levels on 4-year survival. For DAMPs that were found to affect survival significantly, baseline characteristics were compared between the two DAMP groups.

Out of the seven DAMPs, only dsDNA was significantly associated with 4-year survival. Patients with elevated serum level of dsDNA had higher 4-year mortality rates, lower FEV1 % predicted values and higher emphysema scores.

In conclusion, in a clinical cohort of 949 patients with moderate-to-severe COPD, elevated serum levels of dsDNA were associated with a higher risk of death. This study further illustrates the potential role of circulating DAMPs, such as dsDNA, in the progression of COPD. Together, the results of this study suggest that levels of circulating dsDNA might serve as an additional prognostic biomarker for survival in COPD patients.

Generation Scotland (GS) is a large family-based cohort study established as a longitudinal resource for research into the genetic, lifestyle and environmental determinants of physical and mental health. It comprises extensive genetic, sociodemographic and clinical data from volunteers in Scotland.

A total of 24 084 adult participants, including 5501 families, were recruited between 2006 and 2011. Within the cohort, 59% (approximately 14 209) are women, with an average age at recruitment of 49 years. Participants completed a health questionnaire and attended an in-person clinic visit, where detailed baseline data were collected on lifestyle information, cognitive function, personality traits and mental and physical health. Genotype array data are available for 20 026 (83%) participants, and blood-based DNA methylation (DNAm) data for 18 869 (78%) participants. Linkage to routine National Health Service datasets has been possible for 93% (n=22 402) of the cohort, creating a longitudinal resource that includes primary care, hospital attendance, prescription and mortality records. Multimodal brain imaging is available in 1069 individuals.

GS has been widely used by researchers across the world to study the genetic and environmental basis of common complex diseases. Over 350 peer-reviewed papers have been published using GS data, contributing to research areas such as ageing, cancer, cardiovascular disease and mental health. Recontact studies have built on the GS cohort to collect additional prospective data to study chronic pain, major depressive disorder and COVID-19.

To create a larger, richer, longitudinal resource, 'Next Generation Scotland' launched in May 2022 to expand the existing cohort by a target of 20 000 additional volunteers, now including anyone aged 12+ years. New participants complete online consent and questionnaires and provide postal saliva samples, from which genotype and salivary DNAm array data will be generated. The latest cohort information and how to access data can be found on the GS website (www.generationscotland.org).

Higher 25-hydroxyvitamin D (25(OH)D) concentrations in serum has a positive association with pulmonary function. Investigating genome-wide interactions with 25(OH)D may reveal new biological insights into pulmonary function.

We aimed to identify novel genetic variants associated with pulmonary function by accounting for 25(OH)D interactions.

We included 211,264 participants from the observational United Kingdom Biobank study with pulmonary function tests (PFTs), genome-wide genotypes, and 25(OH)D concentrations from 4 ancestral backgrounds-European, African, East Asian, and South Asian. Among PFTs, we focused on forced expiratory volume in the first second (FEV1) and forced vital capacity (FVC) because both were previously associated with 25(OH)D. We performed genome-wide association study (GWAS) analyses that accounted for variant×25(OH)D interaction using the joint 2 degree-of-freedom (2df) method, stratified by participants' smoking history and ancestry, and meta-analyzed results. We evaluated interaction effects to determine how variant-PFT associations were modified by 25(OH)D concentrations and conducted pathway enrichment analysis to examine the biological relevance of our findings.

Our GWAS meta-analyses, accounting for interaction with 25(OH)D, revealed 30 genetic variants significantly associated with FEV1 or FVC (P2df <5.00×10-8) that were not previously reported for PFT-related traits. These novel variant signals were enriched in lung function-relevant pathways, including the p38 MAPK pathway. Among variants with genome-wide-significant 2df results, smoking-stratified meta-analyses identified 5 variants with 25(OH)D interactions that influenced FEV1 in both smoking groups (never smokers P1df interaction<2.65×10-4; ever smokers P1df interaction<1.71×10-5); rs3130553, rs2894186, rs79277477, and rs3130929 associations were only evident in never smokers, and the rs4678408 association was only found in ever smokers.

Genetic variant associations with lung function can be modified by 25(OH)D, and smoking history can further modify variant×25(OH)D interactions. These results expand the known genetic architecture of pulmonary function and add evidence that gene-environment interactions, including with 25(OH)D and smoking, influence lung function.

COPD is a major cause of morbidity and mortality globally. While the significance of environmental exposures in disease pathogenesis is well established, the functional contribution of genetic factors has only in recent years drawn attention. Notably, many genes associated with COPD risk are also linked with lung function. Because reduced lung function precedes COPD onset, this association is consistent with the possibility that derangements leading to COPD could arise during lung development. In this review, we summarise the role of leading genes (HHIP, FAM13A, DSP, AGER and TGFB2) identified by genome-wide association studies in lung development and COPD. Because many COPD genome-wide association study genes are enriched in lung epithelial cells, we focus on the role of these genes in the lung epithelium in development, homeostasis and injury.

Advanced glycation end products (AGEs) are compounds formed via non-enzymatic reactions between reducing sugars and amino acids or proteins. AGEs can accumulate in various tissues and organs and have been implicated in the development and progression of various diseases, including lung diseases. The receptor of advanced glycation end products (RAGE) is a receptor that can bind to advanced AGEs and induce several cellular processes such as inflammation and oxidative stress. Several studies have shown that both AGEs and RAGE play a role in the pathogenesis of lung diseases, such as chronic obstructive pulmonary disease, asthma, idiopathic pulmonary fibrosis, cystic fibrosis, and acute lung injury. Moreover, the soluble form of the receptor for advanced glycation end products (sRAGE) has demonstrated its ability to function as a decoy receptor, possessing beneficial characteristics such as anti-inflammatory, antioxidant, and anti-fibrotic properties. These qualities make it an encouraging focus for therapeutic intervention in managing pulmonary disorders. This review highlights the current understanding of the roles of AGEs and (s)RAGE in pulmonary diseases and their potential as biomarkers and therapeutic targets for preventing and treating these pathologies.

In 1992, a transcendental report suggested that the receptor of advanced glycation end-products (RAGE) functions as a cell surface receptor for a wide and diverse group of compounds, commonly referred to as advanced glycation end-products (AGEs), resulting from the non-enzymatic glycation of lipids and proteins in response to hyperglycemia. The interaction of these compounds with RAGE represents an essential element in triggering the cellular response to proteins or lipids that become glycated. Although initially demonstrated for diabetes complications, a growing body of evidence clearly supports RAGE's role in human diseases. Moreover, the recognizing capacities of this receptor have been extended to a plethora of structurally diverse ligands. As a result, it has been acknowledged as a pattern recognition receptor (PRR) and functionally categorized as the RAGE axis. The ligation to RAGE leads the initiation of a complex signaling cascade and thus triggering crucial cellular events in the pathophysiology of many human diseases. In the present review, we intend to summarize basic features of the RAGE axis biology as well as its contribution to some relevant human diseases such as metabolic diseases, neurodegenerative, cardiovascular, autoimmune, and chronic airways diseases, and cancer as a result of exposure to AGEs, as well as many other ligands.

The extracellular matrix (ECM) determines functional properties of connective tissues through structural components, such as collagens, elastic fibers, or proteoglycans. The ECM also instructs cell behavior through regulatory proteins, including proteases, growth factors, and matricellular proteins, which can be soluble or tethered to ECM scaffolds. The secreted a disintegrin and metalloproteinase with thrombospondin type 1 repeats/motifs-like (ADAMTSL) proteins constitute a family of regulatory ECM proteins that are related to ADAMTS proteases but lack their protease domains. In mammals, the ADAMTSL protein family comprises seven members, ADAMTSL1-6 and papilin. ADAMTSL orthologs are also present in the worm, Caenorhabditis elegans, and the fruit fly, Drosophila melanogaster. Like other matricellular proteins, ADAMTSL expression is characterized by tight spatiotemporal regulation during embryonic development and early postnatal growth and by cell type- and tissue-specific functional pleiotropy. Although largely quiescent during adult tissue homeostasis, reexpression of ADAMTSL proteins is frequently observed in the context of physiological and pathological tissue remodeling and during regeneration and repair after injury. The diverse functions of ADAMTSL proteins are further evident from disorders caused by mutations in individual ADAMTSL proteins, which can affect multiple organ systems. In addition, genome-wide association studies (GWAS) have linked single nucleotide polymorphisms (SNPs) in ADAMTSL genes to complex traits, such as lung function, asthma, height, body mass, fibrosis, or schizophrenia. In this review, we summarize the current knowledge about individual members of the ADAMTSL protein family and highlight recent mechanistic studies that began to elucidate their diverse functions.

Chronic obstructive pulmonary disease (COPD) is a common respiratory disease and represents the third leading cause of death worldwide. This study aimed to investigate miRNA regulation of Receptor for Advanced Glycation End-products (RAGE), a causal receptor in the pathogenesis of cigarette smoke (CS)-related COPD, to guide development of therapeutic strategies.

RAGE expression was quantified in lung tissue of COPD patients and healthy controls, and in mice with CS-induced COPD. RNA-sequencing of peripheral blood from COPD patients with binding site prediction was used to screen differentially expressed miRNAs that may interact with RAGE. Investigation of miR-23a-5p as a potential regulator of COPD progression was conducted with miR-23a-5p agomir in COPD mice in vivo using histology and SCIREQ functional assays, while miR-23a-5p mimics or RAGE inhibitor were applied in 16-HBE human bronchial epithelial cells in vitro. RNA-sequencing, ELISA, and standard molecular techniques were used to characterize downstream signaling pathways in COPD mice and 16-HBE cells treated with cigarette smoke extract (CSE).

RAGE expression is significantly increased in lung tissue of COPD patients, COPD model mice, and CSE-treated 16-HBE cells, while inhibiting RAGE expression significantly reduces COPD severity in mice. RNA-seq analysis of peripheral blood from COPD patients identified miR-23a-5p as the most significant candidate miRNA interaction partner of RAGE, and miR-23a-5p is significantly downregulated in mice and cells treated with CS or CSE, respectively. Injection of miR-23a-5p agomir leads to significantly reduced airway inflammation and alleviation of symptoms in COPD mice, while overexpressing miR-23a-5p leads to improved lung function. RNA-seq with validation confirmed that reactive oxygen species (ROS) signaling is increased under CSE-induced aberrant upregulation of RAGE, and suppressed in CSE-stimulated cells treated with miR-23a-5p mimics or overexpression. ERK phosphorylation and subsequent cytokine production was also increased under RAGE activation, but inhibited by increasing miR-23a-5p levels, implying that the miR-23a-5p/RAGE/ROS axis mediates COPD pathogenesis via ERK activation.

This study identifies a miR-23a-5p/RAGE/ROS signaling axis required for pathogenesis of COPD. MiR-23a-5p functions as a negative regulator of RAGE and downstream activation of ROS signaling, and can inhibit COPD progression in vitro and in vivo, suggesting therapeutic targets to improve COPD treatment.

Chronic obstructive pulmonary disease (COPD) and asthma associate with high morbidity and mortality. High levels of advanced glycation end products (AGEs) were found in tissue and plasma of COPD patients but their role in COPD and asthma is unclear.

In the Rotterdam Study (n = 2577), AGEs (by skin autofluorescence (SAF)), FEV1 and lung diffusing capacity (DLCOc and DLCOc /alveolar volume [VA]) were measured. Associations of SAF with asthma, COPD, GOLD stage, and lung function were analyzed using logistic and linear regression adjusted for covariates, followed by interaction and stratification analyses. sRAGE and EN-RAGE associations with COPD prevalence were analyzed by logistic regression.

SAF associated with COPD prevalence (OR = 1.299 [1.060, 1.591]) but not when adjusted for smoking (OR = 1.106 [0.89, 1.363]). SAF associated with FEV1% predicted (β=-3.384 [-4.877, -1.892]), DLCOc (β=-0.212 [-0.327, -0.097]) and GOLD stage (OR = 4.073, p = 0.001, stage 3&4 versus 1). Stratified, the association between SAF and FEV1%predicted was stronger in COPD (β=-6.362 [-9.055, -3.670]) than non-COPD (β=-1.712 [-3.306, -0.118]). Association of SAF with DLCOc and DLCOc/VA were confined to COPD (β=-0.550 [-0.909, -0.191]; β=-0.065 [-0.117, -0.014] respectively). SAF interacted with former smoking and COPD prevalence for associations with lung function. Lower sRAGE and higher EN-RAGE associated with COPD prevalence (OR = 0.575[0.354, 0.931]; OR = 1.778[1.142, 2.768], respectively).

Associations between SAF, lung function and COPD prevalence were strongly influenced by smoking. SAF associated with COPD severity and its association with lung function was more prominent within COPD. These results fuel further research into interrelations and causality between SAF, smoking and COPD.

Skin AGEs associated with prevalence and severity of COPD and lung function in the general population with a stronger effect in COPD, calling for further research into interrelations and causality between SAF, smoking and COPD.

Airway remodeling is one of the reasons for severe steroidresistant asthma related to HMGB1/RAGE signaling or Th17 immunity.

Our study aims to investigate the relationship between the HMGB1/RAGE signaling and the Th17/IL-17 signaling in epithelial-mesenchymal transformation (EMT) of airway remodeling.

CD4+ T lymphocytes were collected from C57 mice. CD4+ T cell and Th17 cell ratio was analyzed by flow cytometry. IL-17 level was detected by ELISA. The Ecadherin and α-SMA were analyzed by RT-qPCR and immunohistochemistry. The Ecadherin, α-SMA, and p-Smad3 expression were analyzed by western blot.

The HMGB1/RAGE signaling promoted the differentiation and maturation of Th17 cells in a dose-dependent manner in vitro. The HMGB1/RAGE signaling also promoted the occurrence of bronchial EMT. The EMT of bronchial epithelial cells was promoted by Th17/IL-17 and the HMGB1 treatment in a synergic manner. Silencing of RAGE reduced the signaling transduction of HMGB1 and progression of bronchial EMT.

HMGB1/RAGE signaling synergistically enhanced TGF-β1-induced bronchial EMT by promoting the differentiation of Th17 cells and the secretion of IL-17.

To quantify the association of polycyclic aromatic hydrocarbons (PAHs) and the polygenic risk score (PRS) with lung function decline, we developed a repeated-measures study with 4681 observations from baseline and 6-year follow-up of the Wuhan-Zhuhai cohort. Lung function and urinary monohydroxylated PAH metabolites (OH-PAHs) were measured for each observation. The PRS was derived from 246 lung function-associated genetic variants weighted by the effect size of the decreasing ratio of forced expiratory volume in 1 s by forced vital capacity (FEV1/FVC). Linear mixed models were used to estimate the longitudinal exposure-response relationships between OH-PAHs and lung function, and to evaluate the interactions between OH-PAHs and PRS on the longitudinal change of lung function. We found that each 1-unit increase in log-transformed values of 9-hydroxyfluorene, 2-hydroxyfluorene, 4-hydroxyphenanthrene, 9-hydroxyphenanthrene, 2-hydroxyphenanthrene, 1-hydroxyphenanthrene, 1-hydroxypyrene, low molecular weight OH-PAHs (ΣLMW-OH-PAHs), and total OH-PAHs (ΣOH-PAHs) was associated with an annual change in FEV1/FVC of -0.140, -0.112, -0.260, -0.300, -0.159, -0.220, -0.145, -0.156, and -0.177 %/year, respectively. Interactions on the annual decline of FEV1/FVC were detected between ΣLMW-OH-PAHs and PRS (-0.010 %/year, 95% confidence interval -0.018 to -0.001, Pint = 0.0228), and between ΣOH-PAHs and PRS (-0.010 %/year, -0.018 to -0.001, Pint = 0.0203). These results indicated that specific and total urinary OH-PAHs were associated with the longitudinal FEV1/FVC decline, and ΣLMW-OH-PAHs as well as ΣOH-PAHs interacted with PRS on the annual decline of FEV1/FVC.

Existing SNP-heritability estimators that leverage summary statistics from genome-wide association studies (GWAS) are much less efficient (i.e., have larger standard errors) than the restricted maximum likelihood (REML) estimators which require access to individual-level data. We introduce a new method for local heritability estimation-Heritability Estimation with high Efficiency using LD and association Summary Statistics (HEELS)-that significantly improves the statistical efficiency of summary-statistics-based heritability estimator and attains comparable statistical efficiency as REML (with a relative statistical efficiency >92%). Moreover, we propose representing the empirical LD matrix as the sum of a low-rank matrix and a banded matrix. We show that this way of modeling the LD can not only reduce the storage and memory cost, but also improve the computational efficiency of heritability estimation. We demonstrate the statistical efficiency of HEELS and the advantages of our proposed LD approximation strategies both in simulations and through empirical analyses of the UK Biobank data.

Numerous genes have been associated with allergic diseases (asthma, allergic rhinitis, and eczema), but they explain only part of their heritability. This is partly because most previous studies ignored complex mechanisms such as gene-environment (G-E) interactions and complex phenotypes such as co-morbidity. However, it was recently evidenced that the co-morbidity of asthma-plus-eczema appears as a sub-entity depending on specific genetic factors. Besides, evidence also suggest that gene-by-early life environmental tobacco smoke (ETS) exposure interactions play a role in asthma, but were never investigated for asthma-plus-eczema. To identify genetic variants interacting with ETS exposure that influence asthma-plus-eczema susceptibility.

To conduct a genome-wide interaction study (GWIS) of asthma-plus-eczema according to ETS exposure, we applied a 2-stage strategy with a first selection of single nucleotide polymorphisms (SNPs) from genome-wide association meta-analysis to be tested at a second stage by interaction meta-analysis. All meta-analyses were conducted across 4 studies including a total of 5,516 European-ancestry individuals, of whom 1,164 had both asthma and eczema.

Two SNPs showed significant interactions with ETS exposure. They were located in 2 genes, NRXN1 (2p16) and TNS1 (2q35), never reported associated and/or interacting with ETS exposure for asthma, eczema or more generally for allergic diseases. TNS1 is a promising candidate gene because of its link to lung and skin diseases with possible interactive effect with tobacco smoke exposure.

This first GWIS of asthma-plus-eczema with ETS exposure underlines the importance of studying sub-phenotypes such as co-morbidities as well as G-E interactions to detect new susceptibility genes.

Globally, chronic obstructive pulmonary disease (COPD) is the cause of high morbidity and mortality, and constitutes a huge public health burden. Previous studies have reported that inflammation is closely related to COPD, but its potential mechanism is still unclear. Since the polarization of macrophages is involved in regulating inflammation, we assume that COPD changes the polarization of macrophages. To verify this, we investigated the relationship between the expression of S1PR1, HADC1, and inflammatory macrophages in COPD patients via flow cytometry, qRT-PCR, and western blot analysis. We found that macrophages of COPD individuals differentiated into M1 phenotype, and the expression of S1PR1 increased and HDAC1 decreased. S1PR1 also inhibits the expression of HDAC1, so S1PR1/HDAC1 signal regulates the polarization of macrophages. The results of the study put forward new ideas of the pathogenesis of COPD, and also proposed the possible treatment options.

The Hedgehog signalling pathway has crucial roles in embryonic tissue patterning, postembryonic tissue regeneration, and cancer, yet aspects of Hedgehog signal transmission and reception have until recently remained unclear. Biochemical and structural studies surprisingly reveal a central role for lipids in Hedgehog signalling. The signal - Hedgehog protein - is modified by cholesterol and palmitate during its biogenesis, thereby necessitating specialized proteins such as the transporter Dispatched and several lipid-binding carriers for cellular export and receptor engagement. Additional lipid transactions mediate response to the Hedgehog signal, including sterol activation of the transducer Smoothened. Access of sterols to Smoothened is regulated by the apparent sterol transporter and Hedgehog receptor Patched, whose activity is blocked by Hedgehog binding. Alongside these lipid-centric mechanisms and their relevance to pharmacological pathway modulation, we discuss emerging roles of Hedgehog pathway activity in stem cells or their cellular niches, with translational implications for regeneration and restoration of injured or diseased tissues.

Chronic obstructive pulmonary disease (COPD), the third leading cause of death worldwide, is influenced by genetic factors. The genetic signal rs10516526 in the glutathione S-transferase C-terminal domain containing (GSTCD) gene is a highly significant and reproducible signal associated with lung function and COPD on chromosome 4q24. In this study, comprehensive bioinformatics analyses and experimental verifications were detailly implemented to explore the regulation mechanism of rs10516526 and GSTCD in COPD. The results suggested that low expression of GSTCD was associated with COPD (p = 0.010). And C-Jun and CREB1 transcription factors were found to be essential for the regulation of GSTCD by rs80245547 and rs72673891. Moreover, rs80245547T and rs72673891G had a stronger binding ability to these transcription factors, which may promote the allele-specific long-range enhancer-promoter interactions on GSTCD, thus making COPD less susceptible. Our study provides a new insight into the relationship between rs10516526, GSTCD, and COPD.

Tensins are focal adhesion proteins that regulate various biological processes, such as mechanical sensing, cell adhesion, migration, invasion, and proliferation, through their multiple binding activities that transduce critical signals across the plasma membrane. When these molecular interactions and/or mediated signaling are disrupted, cellular activities and tissue functions are compromised, leading to disease development. Here, we focus on the significance of the tensin family in renal function and diseases. The expression pattern of each tensin in the kidney, their roles in chronic kidney diseases, renal cell carcinoma, and their potentials as prognostic markers and/or therapeutic targets are discussed in this review.

Chronic obstructive pulmonary disease (COPD) is a disease of the airways and lungs due to an enhanced inflammatory response, commonly caused by cigarette smoking. Patients with COPD are often multimorbid, as they commonly suffer from multiple chronic (inflammatory) conditions. This intensifies the burden of individual diseases, negatively affects quality of life, and complicates disease management. COPD and comorbidities share genetic and lifestyle-related risk factors and pathobiological mechanisms, including chronic inflammation and oxidative stress. The receptor for advanced glycation end products (RAGE) is an important driver of chronic inflammation. Advanced glycation end products (AGEs) are RAGE ligands that accumulate due to aging, inflammation, oxidative stress, and carbohydrate metabolism. AGEs cause further inflammation and oxidative stress through RAGE, but also through RAGE-independent mechanisms. This review describes the complexity of RAGE signaling and the causes of AGE accumulation, followed by a comprehensive overview of alterations reported on AGEs and RAGE in COPD and in important co-morbidities. Furthermore, it describes the mechanisms by which AGEs and RAGE contribute to the pathophysiology of individual disease conditions and how they execute crosstalk between organ systems. A section on therapeutic strategies that target AGEs and RAGE and could alleviate patients from multimorbid conditions using single therapeutics concludes this review.

The clinical and socioeconomic burden of asthma exacerbations (AEs) constitutes a major public health problem. In the last 4 years, there has been an increase in ethnic diversity in candidate-gene and genome-wide association studies of AEs, which in the latter case led to the identification of novel genes and underlying pathobiological processes. Pharmacogenomics, admixture mapping analyses, and the combination of multiple "omics" layers have helped to prioritize genomic regions of interest and/or facilitated our understanding of the functional consequences of genetic variation. Nevertheless, the field still lags behind the genomics of asthma, where a vast compendium of genetic approaches has been used (eg, gene-environment nteractions, next-generation sequencing, and polygenic risk scores). Furthermore, the roles of the DNA methylome and histone modifications in AEs have received little attention, and microRNA findings remain to be validated in independent studies. Likewise, the most recent transcriptomic studies highlight the importance of the host-airway microbiome interaction in the modulation of risk of AEs. Leveraging -omics and deep-phenotyping data from subtypes or homogenous subgroups of patients will be crucial if we are to overcome the inherent heterogeneity of AEs, boost the identification of potential therapeutic targets, and implement precision medicine approaches to AEs in clinical practice.

Existing SNP-heritability estimation methods that leverage GWAS summary statistics produce estimators that are less efficient than the restricted maximum likelihood (REML) estimator using individual-level data under linear mixed models (LMMs). Increasing the precision of a heritability estimator is particularly important for regional analyses, as local genetic variances tend to be small. We introduce a new estimator for local heritability, "HEELS", which attains comparable statistical efficiency as REML (\emph{i.e.} relative efficiency greater than 92%) but only requires summary-level statistics -- Z-scores from the marginal association tests plus the empirical LD matrix. HEELS significantly improves the statistical efficiency of the existing summary-statistics-based heritability estimators-- for instance, HEELS produces heritability estimates that are more than 3-fold and 7-times less variable than GRE and LDSC, respectively. Moreover, we introduce a unified framework to evaluate and compare the performance of different LD approximation strategies. We propose representing the empirical LD as the sum of a low-rank matrix and a banded matrix. This approximation not only reduces the storage and memory cost of using the LD matrix, but also improves the computational efficiency of the HEELS estimation. We demonstrate the statistical efficiency of HEELS and the advantages of our proposed LD approximation strategies both in simulations and through empirical analyses of the UK Biobank data.

Lung-function impairment underlies chronic obstructive pulmonary disease (COPD) and predicts mortality. In the largest multi-ancestry genome-wide association meta-analysis of lung function to date, comprising 580,869 participants, we identified 1,020 independent association signals implicating 559 genes supported by ≥2 criteria from a systematic variant-to-gene mapping framework. These genes were enriched in 29 pathways. Individual variants showed heterogeneity across ancestries, age and smoking groups, and collectively as a genetic risk score showed strong association with COPD across ancestry groups. We undertook phenome-wide association studies for selected associated variants as well as trait and pathway-specific genetic risk scores to infer possible consequences of intervening in pathways underlying lung function. We highlight new putative causal variants, genes, proteins and pathways, including those targeted by existing drugs. These findings bring us closer to understanding the mechanisms underlying lung function and COPD, and should inform functional genomics experiments and potentially future COPD therapies.