A Genome-Wide Association Study Identified AFF1 as a Susceptibility Locus for Systemic Lupus Eyrthematosus in Japanese

Systemic lupus erythematosus (SLE) is an autoimmune disease that causes multiple organ damage. Although recent genome-wide association studies (GWAS) have contributed to discovery of SLE susceptibility genes, few studies has been performed in Asian populations. Here, we report a GWAS for SLE examining 891 SLE cases and 3,384 controls and multi-stage replication studies examining 1,387 SLE cases and 28,564 controls in Japanese subjects. Considering that expression quantitative trait loci (eQTLs) have been implicated in genetic risks for autoimmune diseases, we integrated an eQTL study into the results of the GWAS. We observed enrichments of cis-eQTL positive loci among the known SLE susceptibility loci (30.8%) compared to the genome-wide SNPs (6.9%). In addition, we identified a novel association of a variant in the AF4/FMR2 family, member 1 (AFF1) gene at 4q21 with SLE susceptibility (rs340630; P = 8.3×10−9, odds ratio = 1.21). The risk A allele of rs340630 demonstrated a cis-eQTL effect on the AFF1 transcript with enhanced expression levels (P<0.05). As AFF1 transcripts were prominently expressed in CD4+ and CD19+ peripheral blood lymphocytes, up-regulation of AFF1 may cause the abnormality in these lymphocytes, leading to disease onset

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

A survey on ethics education at certified graduate schools of clinical psychology in Japan

The aim of this study was to clarify practical problems in teaching professional ethics as course works. In 2005, the Japanese Association of Clinical Psychology (JACP) surveyed all the certified graduate schools of clinical psychology for current ethics educations and problems encountered in delivering and developing the curriculum. A questionnaire on ethics educations was sent to 842 faculty members of all the certified graduate schools, for which 279 respondents (33.1%) returned completed questionnaires. 159 (58.2%) were professors and 80 (29.3%) were associate professors. The main results of the survey were as follows: 1. Although many of them were strongly interested in teaching their students ethics through their lectures and clinical practices, they were unsatisfied with their current curriculums and teaching methods. 2. Even though many of them recognized psychotherapy supervision for beginner students as ethically indispensable, they faced severe difficulties in securing adequate supervisory chances for their students. Finally, several methods to solve these problems for the faculty members in teaching professional ethics were proposed and discussed

Complex interactions between ionizing radiation and carcinogenic chemicals on rat mammary carcinogenesis

Background: Mechanisms underlying combined effects of more than one carcinogens have not been well illustrated in experimental carcinogenesis models. Materials and Methods: Female Sprague-Dawley rats at 7 weeks of age were treated with ionizing radiation (IR; 0.2-2 Gy) and/or with 1-methyl-1-nitrosourea (MNU, 20 or 40 mg/kg) or 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP, 40 mg/kg/day for 10 days) and observed until 50 weeks of age. Results: Carcinoma incidence increased linearly as a function of IR dose in the absence of chemicals. Mathematical analysis suggested an additive increase when IR and chemicals were combined. Hras mutations were characteristic of carcinomas induced by chemicals and were overrepresented in carcinomas induced by the combination of IR and MNU, suggesting their interaction at the initiation level. Comprehensive screening using microarrays failed to identify differences in gene expression among carcinomas induced by different treatments. Conclusion: A complex interaction may underlie the combined effect of IR and carcinogenic chemicals in the experimental model.第72回日本癌学会学術総