Current genome-wide association studies do not yet capture sufficient diversity in populations and scope of phenotypes. To expand an atlas of genetic associations in non-European populations, we ...conducted 220 deep-phenotype genome-wide association studies (diseases, biomarkers and medication usage) in BioBank Japan (n = 179,000), by incorporating past medical history and text-mining of electronic medical records. Meta-analyses with the UK Biobank and FinnGen (n
= 628,000) identified ~5,000 new loci, which improved the resolution of the genomic map of human traits. This atlas elucidated the landscape of pleiotropy as represented by the major histocompatibility complex locus, where we conducted HLA fine-mapping. Finally, we performed statistical decomposition of matrices of phenome-wide summary statistics, and identified latent genetic components, which pinpointed responsible variants and biological mechanisms underlying current disease classifications across populations. The decomposed components enabled genetically informed subtyping of similar diseases (for example, allergic diseases). Our study suggests a potential avenue for hypothesis-free re-investigation of human diseases through genetics.
The overwhelming majority of participants in current genetic studies are of European ancestry. To elucidate disease biology in the East Asian population, we conducted a genome-wide association study ...(GWAS) with 212,453 Japanese individuals across 42 diseases. We detected 320 independent signals in 276 loci for 27 diseases, with 25 novel loci (P < 9.58 × 10
). East Asian-specific missense variants were identified as candidate causal variants for three novel loci, and we successfully replicated two of them by analyzing independent Japanese cohorts; p.R220W of ATG16L2 (associated with coronary artery disease) and p.V326A of POT1 (associated with lung cancer). We further investigated enrichment of heritability within 2,868 annotations of genome-wide transcription factor occupancy, and identified 378 significant enrichments across nine diseases (false discovery rate < 0.05) (for example, NKX3-1 for prostate cancer). This large-scale GWAS in a Japanese population provides insights into the etiology of complex diseases and highlights the importance of performing GWAS in non-European populations.
Abstract Background context Although explored in humans and animal models, the pathomechanisms of discogenic low back pain (LBP) remain unknown. Purpose The aim of this study was to review the ...literature about the pathomechanisms of discogenic LBP. Methods Animal models of discogenic pain and specimens from degenerated human intervertebral discs (IVDs) have provided clues about the pathomechanisms of discogenic LBP. Painful discs are characterized by a confluence of innervation, inflammation, and mechanical hypermobility. These three possible mechanisms are discussed in this review. Results Animal models and specimens from humans have revealed sensory innervation of lumbar IVDs and sensory nerve ingrowth into the inner layer of IVDs. Cytokines such as tumor necrosis factor-α and interleukins induce this ingrowth. Nerve growth factor has also been recently identified as an inducer of ingrowth. Finally, disc degeneration induces several collagenases; their action results in hypermobility and pain. Conclusions To treat discogenic LBP, it is important to prevent sensitization of sensory nerve fibers innervating the IVD, to suppress pathogenic increases of cytokines, and to decrease disc hypermobility.
The efficacy of gefitinib for patients with non‐adenocarcinoma non‐small‐cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations is unclear, because only a small ...percentage of patients enrolled in the clinical trials to evaluate the efficacy of gefitinib for tumors harboring EGFR mutation were non‐adenocarcinoma NSCLC. A pooled analysis was conducted to clarify the efficacy of gefitinib for non‐adenocarcinoma NSCLC patients harboring EGFR mutations. A systematic search of the PUBMED databases was conducted to identify all clinical reports that contained advanced non‐adenocarcinoma NSCLC patients harboring EGFR mutations and treated with gefitinib. The selected patients were advanced non‐adenocarcinoma NSCLC patients harboring EGFR mutations who were treated with gefitinib and described in reports containing the data of the histology, status of EGFR mutations and response to gefitinib. This study selected 33 patients from 15 reports. Twenty‐seven and three of the 33 patients were squamous cell carcinoma and adenosquamous cell carcinoma, respectively. One patient each had large‐cell carcinoma, pleomorphic carcinoma and spindle cell carcinoma. Twenty‐one patients (64%) had sensitive EGFR mutations. The response rate (RR), disease control rate (DCR) and median progression‐free survival (mPFS) was 27%, 67–70% and 3.0 months, respectively. These factors were statistically significantly inferior in the non‐adenocarcinoma NSCLC patients harboring EGFR mutations to adenocarcinoma patients harboring EGFR mutations selected from the same published reports (RR: 27%vs 66%, P = 0.000028; DCR: 67–70%vs 92–93%, P = 0.000014; mPFS: 3.0 vs 9.4 months, P = 0.0001, respectively). Gefitinib is less effective in non‐adenocarcinoma NSCLC harboring EGFR mutations than adenocarcinoma harboring EGFR mutations. (Cancer Sci 2011; 102: 1032–1037)
Polygenic risk scores suffer reduced accuracy in non-European populations, exacerbating health disparities. We propose PolyPred, a method that improves cross-population polygenic risk scores by ...combining two predictors: a new predictor that leverages functionally informed fine-mapping to estimate causal effects (instead of tagging effects), addressing linkage disequilibrium differences, and BOLT-LMM, a published predictor. When a large training sample is available in the non-European target population, we propose PolyPred
, which further incorporates the non-European training data. We applied PolyPred to 49 diseases/traits in four UK Biobank populations using UK Biobank British training data, and observed relative improvements versus BOLT-LMM ranging from +7% in south Asians to +32% in Africans, consistent with simulations. We applied PolyPred
to 23 diseases/traits in UK Biobank east Asians using both UK Biobank British and Biobank Japan training data, and observed improvements of +24% versus BOLT-LMM and +12% versus PolyPred. Summary statistics-based analogs of PolyPred and PolyPred
attained similar improvements.
ALK, ROS1, and RET kinase fusions are important predictive biomarkers of tyrosine kinase inhibitors (TKIs) in non‐small‐cell lung cancer (NSCLC). Analysis of cell‐free DNA (cfDNA) provides a ...noninvasive method to identify gene changes in tumor cells. The present study sought to use cfRNA and cfDNA for identifying fusion genes. A reliable protocol was established to detect fusion genes using cfRNA and assessed the analytical validity and clinical usefulness in 30 samples from 20 cases of fusion‐positive NSCLC. The results of cfRNA‐based assays were compared with tissue biopsy and cfDNA‐based liquid biopsy (Guardant360 plasma next‐generation sequencing NGS assay). The overall sensitivity of the cfRNA‐based assay was 26.7% (8/30) and that of cfDNA‐based assay was 16.7% (3/18). When analysis was limited to the samples collected at chemo‐naïve or progressive disease status and available for both assays, the sensitivity of the cfRNA‐based assay was 77.8% (7/9) and that of cfDNA‐based assay was 33.3% (3/9). Fusion gene identification in cfRNA was correlated with treatment response. These results suggest that the proposed cfRNA assay is a useful diagnostic test for patients with insufficient tissues to facilitate effective administration of first‐line treatment and is a useful tool to monitor the progression of NSCLC for consideration of second‐line treatments.
cfRNA‐ and cfDNA‐based assays are evaluated in 20 cases of fusion‐positive NSCLC. cfRNA assay was superior to cfDNA assay for the detection of gene fusions. The results of the cfRNA assay were consistent with the therapeutic effect.
The discovery of oncogenic driver gene mutations, including epidermal growth factor receptor (EGFR) mutation, anaplastic lymphoma kinase (ALK) fusion, ROS proto-oncogene 1 (ROS1) fusion, and ret ...proto-oncogene (RET) fusion, has led to the development of molecularly targeted therapy for non-small-cell lung cancer (NSCLC). This therapy has changed the standard of care for NSCLC. Despite the dramatic response to molecularly targeted therapy, almost all patients ultimately develop resistance to the drugs. To understand the mechanisms of resistance to molecularly targeted agents, it is essential to understand the molecular pathways of NSCLC. Here, we review the mechanisms of resistance to molecularly targeted therapy and discuss strategies to overcome drug resistance.
The prevalence of and mortality from non-tuberculous mycobacteria (NTM) infections have been steadily increasing worldwide. Most NTM infections are caused by Mycobacterium avium-intracellulare ...complex (MAC). MAC can escape from killing by neutrophils, which are professional phagocytes. However, the involvement of neutrophils in the pathogenesis of MAC infection is poorly understood. The present study assessed the roles of neutrophil extracellular trap (NET) formation in neutrophil defense mechanisms against infection with MAC strains, including M. avium isolated from patients with severe or mild lung tissue destruction. Although all MAC induced NET formation, non-pathogenic mycobacteria (M. gordonae and M. smegmatis) slightly but not significantly induced NET formation. Peptidylarginine deiminase 4 (PAD4) inhibitor reduced MAC-induced NET formation but did not affect MAC escape from neutrophils. PAD4 inhibition attenuated the MAC-induced matrix metalloproteinase (MMP)-8 and 9 release to the levels of MMPs from non-pathogenic mycobacteria. MAC also induced interleukin (IL)-8 release by neutrophils, a process independent of MAC-induced NET formation. Taken together, these findings suggest that MAC induce NET formation, IL-8 release and NETs-dependent release of MMP-8 and -9 from neutrophils, leading to neutrophil accumulation and further inflammation, thereby enhancing the progression of infection in the lungs.
Asthma is considered a syndrome composed of heterogeneous disorders involving complex chronic airway inflammation. Patients with severe asthma, prolonged symptoms, and frequent asthma exacerbations, ...despite high doses of inhaled corticosteroids, may benefit from treatment with biologics. Four types of biologics are available for severe asthma, including an anti-immunoglobulin E (IgE) antibody (omalizumab), anti-interleukin (IL)-5 antibody (mepolizumab and reslizumab), anti-IL-5 receptor α antibody (benralizumab), and anti-IL-4 receptor α antibody (dupilumab). Biologics for patients with severe asthma demonstrate high therapeutic efficacy and provide significant clinical benefits, including the prevention of asthma exacerbations, alleviation of symptoms, improvement in the quality of life and respiratory function, and reduction in frequencies of hospitalization and emergency outpatient visits. This review provides an overview of the modulation of immunological features by each of the four established biologics in patients with severe allergic asthma. Given the extensive immunomodulatory effects of biologics, further analyses of their precise effects on the human immune system are warranted.
Among all types of cancer, incidence of lung cancer remains the highest with regard to cancer-related mortality. Problems contributing to recurrence of the disease include metastasis and drug ...resistance. Mounting evidence has demonstrated involvement of epithelial mesenchymal transition (EMT) in cancer progression. EMT is a critical mechanism ensuring tissue remodeling during morphogenesis of multicellular organisms. Therefore, understanding of the biology of this process for identification of potential EMT-targeted therapeutic strategies for the benefit cancer patients is necessary. This review describes recent evidence of EMT involvement in drug resistance and metastasis of cancers, with an emphasis on lung cancer.
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