Seven Different Glucose-6-phosphate Dehydrogenase Variants Including a New Variant Distributed in Lam Dong Province in Southern Vietnam.

We conducted a survey for glucose-6-phosphate dehydrogenase (G6PD) deficiency using blood samples from male outpatients of a local hospital in southern Vietnam. Most of the samples were from the Kinh (88.9%), the largest ethnic group in Vietnam, with a small number (11.1%) coming from the K'Ho, Chauma, Nung, and Tay minorities. We detected 25 G6PD-deficient cases among 1,104 samples (2.3%), and read the open reading frame of G6PD. A novel mutation (352T>C) predicting an aminoacid change of 118Tyr>His was found in a 1-year-old Kinh boy. His G6PD activity was estimated to be less than 10% residual activity, although he did not show chronic hemolytic anemia. Thus, we categorized this variant as Class II and named it G6PD Bao Loc. In the Kinh population, G6PD Viangchan (871G>A, 1311C>T, intron 11 nt93T>C), one of the most common variants in continental Southeast Asian populations, was the highest (6/19), followed by variants originating from the Chinese such as G6PD Canton (1376G>T) (5/19), G6PD Kaiping (1388G>A) (3/19), G6PD Gaohe (95A>G) (1/19), and G6PD Quing Yuan (392G>T) (1/19). In addition, G6PD Union (1360C>T) (2/19), which originated from the Oceania, was also detected. These findings suggest that the Kinh people are derived from various ancestries from continental Southeast Asia, China, and Oceania. In contrast, all of the 5 deficient cases in the K'Ho population were G6PD Viangchan, suggesting that they were very close to Southeast Asian populations such as the Khmer in Cambodia and the Lao in Laos. It is interesting that G6PD Mahidol (487G>A), another common variant in continental Southeast Asian populations in Myanmar, Thailand, and Malaysia, has not been detected from the Vietnamese

Development of airflow limitation, dyspnoea, and both in the general population: the Nagahama study

Subjects with subclinical respiratory dysfunction who do not meet the chronic obstructive pulmonary disease (COPD) criteria have attracted attention with regard to early COPD intervention. Our aim was to longitudinally investigate the risks for the development of airflow limitation (AFL) and dyspnoea, the main characteristics of COPD, in a large-scale community-based general population study. The Nagahama study included 9789 inhabitants, and a follow-up evaluation was conducted after 5 years. AFL was diagnosed using a fixed ratio (forced expiratory volume in one second (FEV₁)/forced vital capacity (FVC) < 0.7). We enrolled normal subjects aged 40-75 years with no AFL, dyspnoea or prior diagnosis of asthma or COPD at baseline. In total, 5865 subjects were analysed, 310 subjects had subclinical respiratory dysfunction (FEV₁/FVC < the lower limit of normal; n = 57, and FEV₁ < 80% of the predicted value (preserved ratio impaired spirometry); n = 256). A total of 5086 subjects attended the follow-up assessment, and 449 and 1021 subjects developed AFL and dyspnoea, respectively. Of these, 100 subjects developed AFL with dyspnoea. Baseline subclinical respiratory dysfunction was independently and significantly associated with AFL with dyspnoea development within 5 years. Subjects with subclinical respiratory dysfunction are at risk of developing COPD-like features and require careful monitoring

Gastroesophageal reflux disease is a risk factor for sputum production in the general population: the Nagahama study

Background: Chronic sputum production in the general population is historically associated with clinical indices including male sex and smoking history. However, its relationship with gastroesophageal reflux disease (GERD), which may prove an underlying factor in sputum production, is unclear. We aimed to clarify factors associated with sputum production in the general population in cross-sectional and longitudinal manners. Methods: In the Nagahama study, a community-based cohort study, 9804 subjects were recruited between 2008 and 2010 (baseline assessment), 8293 of whom were followed from 2013 to 2015 (follow-up assessment). This study contained a self-completed questionnaire which included medical history, assessment of sputum production, and a frequency scale for symptoms of GERD. A Frequency Scale for Symptoms of Gastroesophageal Reflux Disease score of ≥ 8 was defined as GERD. In addition to the frequency of sputum production at each assessment, frequency of persistent sputum production defined as sputum production at both assessments was examined. Results: Frequency of sputum production was 32.0% at baseline and 34.5% at follow-up. Multivariable analysis demonstrated that sputum production at baseline was significantly associated with GERD [odds ratio (OR), 1.92; 95% confidence interval (CI) 1.73-2.13] and post-nasal drip (PND) (OR, 2.40; 95% CI 2.15-2.68), independent of other known factors such as older age, male sex and smoking history. These associations between sputum production and GERD or PND were also observed at follow-up. In longitudinal analysis, 19.4% had persistent sputum production and 12.3% had transient sputum production, i.e., at baseline only. Multivariable analysis for risk of persistence of sputum production revealed that persistent sputum production was associated with GERD and PND, in addition to the known risk factors listed above. The proportion of subjects with GERD at both assessments was highest among subjects with persistent sputum production. Conclusions: Cross-sectional and longitudinal analysis demonstrated an association in the general population between sputum production and GERD, as well as PND, independent of known risk factors. The presence of GERD should be assessed in patients complaining of sputum production

Cutaneous T-cell-attracting chemokine as a novel biomarker for predicting prognosis of idiopathic pulmonary fibrosis: a prospective observational study

[Background] Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrotic lung disease that leads to respiratory failure and death. Although there is a greater understanding of the etiology of this disease, accurately predicting the disease course in individual patients is still not possible. This study aimed to evaluate serum cytokines/chemokines as potential biomarkers that can predict outcomes in IPF patients. [Methods] A multi-institutional prospective two-stage discovery and validation design using two independent cohorts was adopted. For the discovery analysis, serum samples from 100 IPF patients and 32 healthy controls were examined using an unbiased, multiplex immunoassay of 48 cytokines/chemokines. The serum cytokine/chemokine values were compared between IPF patients and controls; the association between multiplex measurements and survival time was evaluated in IPF patients. In the validation analysis, the cytokines/chemokines identified in the discovery analysis were examined in serum samples from another 81 IPF patients to verify the ability of these cytokines/chemokines to predict survival. Immunohistochemical assessment of IPF-derived lung samples was also performed to determine where this novel biomarker is expressed. [Results] In the discovery cohort, 18 cytokines/chemokines were significantly elevated in sera from IPF patients compared with those from controls. Interleukin-1 receptor alpha (IL-1Rα), interleukin-8 (IL-8), macrophage inflammatory protein 1 alpha (MIP-1α), and cutaneous T-cell-attracting chemokine (CTACK) were associated with survival: IL-1Rα, hazard ratio (HR) = 1.04 per 10 units, 95% confidence interval (95% CI) 1.01–1.07; IL-8, HR = 1.04, 95% CI 1.01–1.08; MIP-1α, HR = 1.19, 95% CI 1.00–1.36; and CTACK, HR = 1.12 per 100 units, 95% CI 1.02–1.21. A replication analysis was performed only for CTACK because others were previously reported to be potential biomarkers of interstitial lung diseases. In the validation cohort, CTACK was associated with survival: HR = 1.14 per 100 units, 95% CI 1.01–1.28. Immunohistochemistry revealed the expression of CTACK and CC chemokine receptor 10 (a ligand of CTACK) in airway and type II alveolar epithelial cells of IPF patients but not in those of controls. [Conclusions] CTACK is a novel prognostic biomarker of IPF

DOCK2 is involved in the host genetics and biology of severe COVID-19

「コロナ制圧タスクフォース」COVID-19疾患感受性遺伝子DOCK2の重症化機序を解明 --アジア最大のバイオレポジトリーでCOVID-19の治療標的を発見--. 京都大学プレスリリース. 2022-08-10.Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge. Here we conducted a genome-wide association study (GWAS) involving 2, 393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3, 289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target

Loss of SMAD4 From Colorectal Cancer Cells Promotes CCL15 Expression to Recruit CCR1(+) Myeloid Cells and Facilitate Liver Metastasis.

[Background & Aims]Loss of the tumor suppressor SMAD4 correlates with progression of colorectal cancer (CRC). In mice, colon tumors that express CCL9 recruit CCR1+ myeloid cells, which facilitate tumor invasion and metastasis by secreting matrix metalloproteinase 9. [Methods]We used human CRC cell lines to investigate the ability of SMAD4 to regulate expression of CCL15, a human ortholog of mouse CCL9. We used immunohistochemistry to compare levels of CCL15 and other proteins in 141 samples of human liver metastases. [Results]In human CRC cell lines, knockdown of SMAD4 increased CCL15 expression, and overexpression of SMAD4 decreased it. SMAD4 bound directly to the promoter region of the CCL15 gene to negatively regulate its expression; transforming growth factor-β increased binding of SMAD4 to the CCL15 promoter and transcriptional repression. In livers of nude mice, SMAD4-deficient human CRC cells up-regulated CCL15 to recruit CCR1+ cells and promote metastasis. In human tumor samples, there was a strong inverse correlation between levels of CCL15 and SMAD4; metastases that expressed CCL15 contained 3-fold more CCR1+cells than those without CCL15. Patients with CCL15-expressing metastases had significantly shorter times of disease-free survival than those with CCL15-negative metastases. CCR1+ cells in the metastases expressed the myeloid cell markers CD11b and myeloperoxidase, and also matrix metalloproteinase 9. [Conclusions]In human CRC cells, loss of SMAD4 leads to up-regulation of CCL15 expression. Human liver metastases that express CCL15 contain higher numbers CCR1+ cells; patients with these metastases have shorter times of disease-free survival. Reagents designed to block CCL15 recruitment of CCR1+ cells could prevent metastasis of CRC to liver