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Study of the genetics of rheumatoid arthritis (RA) began about four decades ago with the discovery of HLA-DRB1. Since the beginning of this century, a number of non-HLA risk loci have been identified through genome-wide association studies (GWAS). We now know that over 100 loci are associated with RA risk. Because genetic information implies a clear causal relationship to the disease, research into the pathogenesis of RA should be promoted. However, only 20% of GWAS loci contain coding variants, with the remaining variants occurring in non-coding regions, and therefore, the majority of causal genes and causal variants remain to be identified. The use of epigenetic studies, high-resolution mapping of open chromatin, chromosomal conformation technologies and other approaches could identify many of the missing links between genetic risk variants and causal genetic components, thus expanding our understanding of RA genetics.

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 total  = 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. Genome-wide analyses in BioBank Japan, UK Biobank and FinnGen identify ~5,000 new loci associated with 220 human traits. Statistical decomposition of matrices of phenome-wide summary statistics further highlights variants underpinning diseases across populations.

Platelet activation after muscle trauma promotes extracellular trap release by macrophages and acute kidney injury. Rhabdomyolysis is a serious syndrome caused by skeletal muscle injury and the subsequent release of breakdown products from damaged muscle cells into systemic circulation 1 . The muscle damage most often results from strenuous exercise, muscle hypoxia, medications, or drug abuse and can lead to life-threatening complications, such as acute kidney injury (AKI) 1 . Rhabdomyolysis and the AKI complication can also occur during crush syndrome, an emergency condition that commonly occurs in victims of natural disasters, such as earthquakes, and man-made disasters, such as wars and terrorism 2 . Myoglobin released from damaged muscle is believed to trigger renal dysfunction in this form of AKI. Recently, macrophages were implicated in the disease pathogenesis of rhabdomyolysis-induced AKI 3 , 4 , but the precise molecular mechanism remains unclear. In the present study, we show that macrophages released extracellular traps (ETs) comprising DNA fibers and granule proteins in a mouse model of rhabdomyolysis. Heme-activated platelets released from necrotic muscle cells during rhabdomyolysis enhanced the production of macrophage extracellular traps (METs) through increasing intracellular reactive oxygen species generation and histone citrullination. Here we report, for the first time to our knowledge, this unanticipated role for METs and platelets as a sensor of myoglobin-derived heme in rhabdomyolysis-induced AKI. This previously unknown mechanism might be targeted for treatment of the disease. Finally, we found a new therapeutic tool for prevention of AKI after rhabdomyolysis, which might rescue some sufferers of this pathology.

The extent to which the biology of oncogenesis and ageing are shaped by factors that distinguish human populations is unknown. Haematopoietic clones with acquired mutations become common with advancing age and can lead to blood cancers 1 – 10 . Here we describe shared and population-specific patterns of genomic mutations and clonal selection in haematopoietic cells on the basis of 33,250 autosomal mosaic chromosomal alterations that we detected in 179,417 Japanese participants in the BioBank Japan cohort and compared with analogous data from the UK Biobank. In this long-lived Japanese population, mosaic chromosomal alterations were detected in more than 35.0% (s.e.m., 1.4%) of individuals older than 90 years, which suggests that such clones trend towards inevitability with advancing age. Japanese and European individuals exhibited key differences in the genomic locations of mutations in their respective haematopoietic clones; these differences predicted the relative rates of chronic lymphocytic leukaemia (which is more common among European individuals) and T cell leukaemia (which is more common among Japanese individuals) in these populations. Three different mutational precursors of chronic lymphocytic leukaemia (including trisomy 12, loss of chromosomes 13q and 13q, and copy-neutral loss of heterozygosity) were between two and six times less common among Japanese individuals, which suggests that the Japanese and European populations differ in selective pressures on clones long before the development of clinically apparent chronic lymphocytic leukaemia. Japanese and British populations also exhibited very different rates of clones that arose from B and T cell lineages, which predicted the relative rates of B and T cell cancers in these populations. We identified six previously undescribed loci at which inherited variants predispose to mosaic chromosomal alterations that duplicate or remove the inherited risk alleles, including large-effect rare variants at NBN , MRE11 and CTU2 (odds ratio, 28–91). We suggest that selective pressures on clones are modulated by factors that are specific to human populations. Further genomic characterization of clonal selection and cancer in populations from around the world is therefore warranted. Population-specific patterns of genomic mutations and selection of haematopoietic clones in Japanese and European participants predict the divergent rates of chronic lymphocytic leukaemia and T cell leukaemia in these populations.

Genetic factors play an important part in the disease heterogeneity observed in patients with rheumatoid arthritis (RA). Genome-wide association studies (GWAS) have linked common single-nucleotide polymorphisms with the risk of developing RA, but have also highlighted the genetic heterogeneity between Asian and European patients with this disease. In this Perspectives article, the authors discuss recent advances from GWAS in Asian patients with RA, and suggest that better knowledge of the interface between genetic and environmental factors could help our understanding of the disease. Genome-wide association studies (GWAS) have uncovered numerous susceptibility genes for rheumatoid arthritis (RA) in patients of European, Asian and other ethnic ancestries. Although previous transethnic GWAS meta-analyses enabled the identification of several novel loci, the genetic heterogeneity observed in the PADI4 and PTPN22 genes suggests that ethnic variation should be considered. In addition, the effects of genetic polymorphisms on gene expression profiles are important when assessing the association of genetic information with disease pathogenesis and will influence the development of personalized medicine. Gene expression is controlled by epigenetic modifications, which in turn can be affected by environmental stimuli. Altogether, genetic and epigenetic information of Asian populations will contribute considerably to future rheumatology research.

Cap analysis of gene expression (CAGE) was developed to detect the 5′ end of RNA. Trapping of the RNA 5′-cap structure enables the enrichment and selective sequencing of complete transcripts. Upscaled high-throughput versions of CAGE have enabled the genome-wide identification of transcription start sites, including transcriptionally active promoters and enhancers. CAGE sequencing can be exploited to draw comprehensive maps of active genomic regulatory elements in a cell type- and activation-specific manner. The cells of the immune system are among the best candidates to be analyzed in humans, since they are easily accessible. In this review, we discuss how CAGE data are instrumental for integrative analyses with quantitative trait loci and omics data, and their usefulness in the mechanistic interpretation of the effects of genetic variations over the entire human genome. Integrating CAGE data with the currently available omics information will contribute to better understanding of the genome-wide association study variants that lie outside of annotated genes, deepening our knowledge on human diseases, and enabling the targeted design of more specific therapeutic interventions.

Previous studies have reported that motor behavior is affected by short-term physical inactivity using cast immobilization; however, the effects of inactivity on postural sway are not well-understood. This study aimed to investigate the effects of short-term lower limb disuse on postural sway in the upright position after cast removal. Twenty-two healthy young adults were enrolled, and each participant’s lower limb on one side was fixed with a soft bandage and medical splint made from metal and soft urethane for 10 h. Fluctuations in the center of pressure (COP) were measured before and after immobilization; the total trajectory length, mean velocity, COP root mean square (RMS) area, mean medial-lateral (M-L) COP, and mean anterior-posterior (A-P) COP were selected as evaluation parameters. Compared with the postural sway before cast application, we noted an increase and shift (from the fixed to the nonfixed side) in the postural sway after cast removal. Our results therefore suggest that short-term disuse may cause acute changes in COP movements during quiet standing. Moreover, patients may maintain their standing posture by adopting a compensatory strategy involving lateral control, similar to individuals with stroke and patients who have undergone total knee arthroplasty.

ObjectivesAutoimmune and allergic diseases are outcomes of the dysregulation of the immune system. Our study aimed to elucidate differences or shared components in genetic backgrounds between autoimmune and allergic diseases.MethodsWe estimated genetic correlation and performed multi-trait and cross-population genome-wide association study (GWAS) meta-analysis of six immune-related diseases: rheumatoid arthritis, Graves’ disease, type 1 diabetes for autoimmune diseases and asthma, atopic dermatitis and pollinosis for allergic diseases. By integrating large-scale biobank resources (Biobank Japan and UK biobank), our study included 105 721 cases and 433 663 controls. Newly identified variants were evaluated in 21 778 cases and 712 767 controls for two additional autoimmune diseases: psoriasis and systemic lupus erythematosus. We performed enrichment analyses of cell types and biological pathways to highlight shared and distinct perspectives.ResultsAutoimmune and allergic diseases were not only mutually classified based on genetic backgrounds but also they had multiple positive genetic correlations beyond the classifications. Multi-trait GWAS meta-analysis newly identified six allergic disease-associated loci. We identified four loci shared between the six autoimmune and allergic diseases (rs10803431 at PRDM2, OR=1.07, p=2.3×10−8, rs2053062 at G3BP1, OR=0.90, p=2.9×10−8, rs2210366 at HBS1L, OR=1.07, p=2.5×10−8 in Japanese and rs4529910 at POU2AF1, OR=0.96, p=1.9×10−10 across ancestries). Associations of rs10803431 and rs4529910 were confirmed at the two additional autoimmune diseases. Enrichment analysis demonstrated link to T cells, natural killer cells and various cytokine signals, including innate immune pathways.ConclusionOur multi-trait and cross-population study should elucidate complex pathogenesis shared components across autoimmune and allergic diseases.

Splicing quantitative trait loci (sQTLs) are one of the major causal mechanisms in genome-wide association study (GWAS) loci, but their role in disease pathogenesis is poorly understood. One reason is the complexity of alternative splicing events producing many unknown isoforms. Here, we propose two approaches, namely integration and selection, for this complexity by focusing on protein-structure of isoforms. First, we integrate isoforms with the same coding sequence (CDS) and identify 369-601 integrated-isoform ratio QTLs (i 2 -rQTLs), which altered protein-structure, in six immune subsets. Second, we select CDS incomplete isoforms annotated in GENCODE and identify 175-337 isoform-ratio QTL (i-rQTL). By comprehensive long-read capture RNA-sequencing among these incomplete isoforms, we reveal 29 full-length isoforms with unannotated CDSs associated with GWAS traits. Furthermore, we show that disease-causal sQTL genes can be identified by evaluating their trans-eQTL effects. Our approaches highlight the understudied role of protein-altering sQTLs and are broadly applicable to other tissues and diseases. Splicing QTL (sQTL), genetic variants regulating alternative splicing, can be biologically important, but complex to detect and interpret. Here, the authors identify sQTL by focusing on protein coding sequences, as an alternative to junction-based approaches.

Purpose While the need for preventive strategies to reduce the incidence of aspiration pneumonia has been indicated, it is also important to investigate effective training methods to improve cough function, which is associated with the development of aspiration pneumonia. This study aimed to investigate whether a 4-week home-based unsupervised cough training (CT) or inspiratory muscle training (IMT) program was effective in improving cough strength in older adults. Methods Fifty-three ambulatory older adults without airflow limitations were randomly assigned to one of three groups: a CT group ( n  = 18), an IMT group ( n  = 18), or a control group ( n  = 17). The CT and IMT groups performed home-based unsupervised training with a device for 4 weeks. Cough strength (cough peak flow), forced vital capacity, and respiratory muscle strength were assessed at the 4-week and 16-week follow-up. Intention-to-treat analyses were performed to investigate differences between the three groups using linear mixed models. Results At the 4-week follow-up, the CT group showed significant increases in cough peak flow and forced vital capacity compared with the control group, while the IMT group showed significant increases in inspiratory muscle strength compared with the cough training and control groups. At the 16-week follow-up, the CT group showed a significant increase in cough peak flow compared with the IMT group. Conclusion These preliminary results suggest that a 4-week home-based CT program may have short-term effectiveness in improving cough peak flow in ambulatory older adults. Trial registration : This trial was registered on UMIN-CTR on 01/05/2018 (UMIN000031656).