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Lung adenocarcinoma is the most common type of lung cancer. Known risk variants explain only a small fraction of lung adenocarcinoma heritability. Here, we conducted a two-stage genome-wide association study of lung adenocarcinoma of East Asian ancestry (21,658 cases and 150,676 controls; 54.5% never-smokers) and identified 12 novel susceptibility variants, bringing the total number to 28 at 25 independent loci. Transcriptome-wide association analyses together with colocalization studies using a Taiwanese lung expression quantitative trait loci dataset (n = 115) identified novel candidate genes, including FADS1 at 11q12 and ELF5 at 11p13. In a multi-ancestry meta-analysis of East Asian and European studies, four loci were identified at 2p11, 4q32, 16q23, and 18q12. At the same time, most of our findings in East Asian populations showed no evidence of association in European populations. In our studies drawn from East Asian populations, a polygenic risk score based on the 25 loci had a stronger association in never-smokers vs. individuals with a history of smoking (Pinteraction = 0.0058). These findings provide new insights into the etiology of lung adenocarcinoma in individuals from East Asian populations, which could be important in developing translational applications.

Objective: To summarize the general situation and focal points of research on the physical activity and mental health of older people over the past 15 years and provide references for future research. Methods: Literature published between January 1, 2009, and December 31, 2023, was retrieved from the Web of Science core database. A bibliometric visualization analysis of countries/regions, institutions, authors, keywords, and references was conducted using CiteSpace6.1.R6. Results: A total of 4,329 articles were included, and the annual number of articles published over the past 15 years showed an upward trend. The articles were primarily from 65 countries/regions and 626 institutions. The most represented country and institution were the USA and the University of Pittsburgh, respectively. Among the authors identified, Schuch and Callow were the most influential. The research focuses on four areas: the psychological effects of physical activity in older people; physical activity intervention approaches to the mental health of older people; physical activity and mental health assessment questionnaires; and the impact of physical activity on multidimensional aging. Research frontiers involve emerging topics such as the assessment and intervention of mental health in older people and the relationship between their physical activity and cognitive function. Conclusion: This study conducted a comprehensive, objective, and visual analysis of publications and revealed the status of relevant studies, trending topics, and trends concerning the physical activity and mental health of older people from 2009 to 2023. We hope that this work will help researchers identify new perspectives on potential collaborators, important topics, and research frontiers. [ABSTRACT FROM AUTHOR]

Plasmacytoid dendritic cells (pDCs) are a professional type I IFN producer that play critical roles in the pathogenesis of autoimmune diseases. However, both genetic regulation of the function of pDCs and their relationships with autoimmunity are largely undetermined. Here, we investigated the causality of the neutrophil cytosolic factor 1 (NCF1) missense variant, which is one of the most significant associated risk variants for lupus, and found that the substitution of arginine (R) for histidine (H) at position 90 in the NCF1 protein (NCF1 p.R90H) led to excessive activation of pDCs. A mechanism study demonstrated that p.R90H reduced the affinity of NCF1 for phospholipids, thereby impairing endosomal localization of NCF1. As NCF1 is a subunit of the NADPH oxidase 2 (NOX2) complex, this impairment led to an acidified endosomal pH and facilitated downstream TLR signaling. Consistently, the homozygous knockin mice manifested aggravated lupus progression in a pDC-dependent lupus model. More important, pharmaceutical intervention revealed that hydroxychloroquine (HCQ) could antagonize the detrimental function of NCF1 p.R90H in the lupus model and systemic lupus erythematosus samples, supporting the idea that NCF1 p.R90H could be identified as a genetic biomarker for HCQ application. Therefore, our study provides insights into the genetic control of pDC function and a paradigm for applying genetic variants to improve targeted therapy for autoimmune diseases., Introduction Genetic evidence and clinical studies have revealed that the type I interferon (IFN-I) pathway is a primary pathogenic factor in a variety of autoimmune diseases (1-3). As the major [...]

Objective: The diminished expression of microRNA‐146a (miR‐146a) in systemic lupus erythematosus (SLE) contributes to the aberrant activation of the interferon pathway. Despite its significance, the underlying mechanism driving this reduced expression remains elusive. Considering the integral role of enhancers in steering gene expression, our study seeks to pinpoint the SLE‐affected enhancers responsible for modulating miR‐146a expression. Additionally, we aim to elucidate the mechanisms by which these enhancers influence the contribution of miR‐146a to the activation of the interferon pathway. Methods: Circular chromosome conformation capture sequencing and epigenomic profiles were applied to identify candidate enhancers of miR‐146a. CRISPR activation was performed to screen functional enhancers. Differential analysis of chromatin accessibility was used to identify SLE‐dysregulated enhancers, and the mechanism underlying enhancer dysfunction was investigated by analyzing transcription factor binding. The therapeutic value of a lupus‐related enhancer was further evaluated by targeting it in the peripheral blood mononuclear cells (PBMCs) of patients with SLE through a CRISPR activation approach. Results: We identified shared and cell‐specific enhancers of miR‐146a in distinct immune cells. An enhancer 32.5 kb downstream of miR‐146a possesses less accessibility in SLE, and its chromatin openness was negatively correlated with SLE disease activity. Moreover, CCAAT/enhancer binding protein α, a down‐regulated transcription factor in patients with SLE, binds to the 32.5‐kb enhancer and induces the epigenomic change of this locus. Furthermore, CRISPR‐based activation of this enhancer in SLE PBMCs could inhibit the activity of interferon pathway. Conclusion: Our work defines a promising target for SLE intervention. We adopted integrative approaches to define cell‐specific and functional enhancers of the SLE critical gene and investigated the mechanism underlying its dysregulation mediated by a lupus‐related enhancer. [ABSTRACT FROM AUTHOR]

Background: Multiple negative health outcomes were linked to residential proximity to major roadways. Nevertheless, there is limited knowledge regarding the association between residential proximity to major roadways and chronic multimorbidity. Methods: We used data from the 2018 wave of the Chinese Longitudinal Healthy Longevity Survey, which included 12,214 individuals aged ≥ 60. We derived the residential proximity to major roadways from self-reported data, defining chronic multimorbidity as the presence of two or more concurrent chronic diseases. A binary logistic regression model was utilized to investigate the association between residential proximity to major roadways and chronic multimorbidity. The model accounted for some demographic features, socioeconomic conditions, social participation, and health conditions. Subsequently, we conducted subgroup analyses to examine potential interaction effects. Results: Residential proximity to major roadways was associated with chronic multimorbidity, even after adjusting for confounding factors. Compared with those living > 300 m from major roadways, the OR for those living 201-300 m, 101-200 m, 50-100 m, and < 50 m were increased. When subgroup analyses were conducted using a cutoff point of 200 m, the risk of chronic multimorbidity associated with residential proximity to major roadways was stronger in participants with education levels > 6 years (P = 0.017). Conclusion: Our findings provide important implications for improving residential area siting, transportation policies, and environmental regulations to reduce the risk of chronic multimorbidity caused by traffic-related exposure. [ABSTRACT FROM AUTHOR]