The tumor microenvironment can be classified into immunologically active "inflamed" tumors and inactive "non-inflamed" tumors based on the infiltration of cytotoxic immune cells. Previous studies on liver cancer have reported a superior prognosis for inflamed tumors compared to non-inflamed tumors. However, liver cancer is highly heterogeneous immunologically and genetically, and a finer classification of the liver cancer microenvironment may improve our understanding of its immunological diversity and response to immune therapy. We characterized the immune gene signatures of 234 primary liver cancers, mainly virus-related, from a Japanese population using RNA-Seq of tumors and matched non-tumorous hepatitis livers. We then compared them with the somatic alterations detected using the whole-genome sequencing. Liver cancers expressed lower levels of immune marker genes than non-tumorous hepatitis livers, indicating immunosuppression in the tumor microenvironment. Several immunosuppression mechanisms functioned actively and mutually exclusively, resulting in four immune subclasses of liver cancer: tumor-associated macrophage (TAM), CTNNB1, cytolytic activity (CYT), and regulatory T cell (Treg). The CYT and Treg subclasses represented inflamed tumors, while the TAM and CTNNB1 subclasses represented non-inflamed tumors. The TAM subclass, which comprised 31% of liver cancers, showed a poor survival, expressed elevated levels of extracellular matrix genes, and was associated with somatic mutations of chromatin regulator ARID2. The results of cell line experiments suggested a functional link between ARID2 and chemokine production by liver cancer cells. Primary liver cancer was classified into four subclasses based on mutually exclusive mechanisms for immunosuppression. This classification indicate the importance of immunosuppression mechanisms, such as TAM and Treg, as therapeutic targets for liver cancer. The Japan Agency for Medical Research and Development (AMED).

Host genetics is a key determinant of COVID-19 outcomes. Previously, the COVID-19 Host Genetics Initiative genome-wide association study used common variants to identify multiple loci associated with COVID-19 outcomes. However, variants with the largest impact on COVID-19 outcomes are expected to be rare in the population. Hence, studying rare variants may provide additional insights into disease susceptibility and pathogenesis, thereby informing therapeutics development. Here, we combined whole-exome and whole-genome sequencing from 21 cohorts across 12 countries and performed rare variant exome-wide burden analyses for COVID-19 outcomes. In an analysis of 5,085 severe disease cases and 571,737 controls, we observed that carrying a rare deleterious variant in the SARS-CoV-2 sensor toll-like receptor TLR7 (on chromosome X) was associated with a 5.3-fold increase in severe disease (95% CI: 2.75–10.05, p = 5.41x10^-7). This association was consistent across sexes. These results further support TLR7 as a genetic determinant of severe disease and suggest that larger studies on rare variants influencing COVID-19 outcomes could provide additional insights.

Aberrant immune responses to viral pathogens contribute to pathogenesis, but our understanding of pathological immune responses caused by viruses within the human virome, especially at a population scale, remains limited. We analyzed whole-genome sequencing datasets of 6,321 Japanese individuals, including patients with autoimmune diseases (psoriasis vulgaris, rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), pulmonary alveolar proteinosis (PAP) or multiple sclerosis) and coronavirus disease 2019 (COVID-19), or healthy controls. We systematically quantified two constituents of the blood DNA virome, endogenous HHV-6 (eHHV-6) and anellovirus. Participants with eHHV-6B had higher risks of SLE and PAP; the former was validated in All of Us. eHHV-6B-positivity and high SLE disease activity index scores had strong correlations. Genome-wide association study and long-read sequencing mapped the integration of the HHV-6B genome to a locus on chromosome 22q. Epitope mapping and single-cell RNA sequencing revealed distinctive immune induction by eHHV-6B in patients with SLE. In addition, high anellovirus load correlated strongly with SLE, RA and COVID-19 status. Our analyses unveil relationships between the human virome and autoimmune and infectious diseases.

Gout is a common arthritis caused by monosodium urate crystals. The heritability of serum urate levels is estimated to be 30–70%; however, common genetic variants account for only 7.9% of the variance in serum urate levels. This discrepancy is an example of “missing heritability.” The “missing heritability” suggests that variants associated with uric acid levels are yet to be found. By using genomic sequences of the ToMMo cohort, we identified rare variants of the SLC22A12 gene that affect the urate transport activity of URAT1. URAT1 is a transporter protein encoded by the SLC22A12 gene. We grouped the participants with variants affecting urate uptake by URAT1 and analyzed the variance of serum urate levels. The results showed that the heritability explained by the SLC22A12 variants of men and women exceeds 10%, suggesting that rare variants underlie a substantial portion of the “missing heritability” of serum urate levels.

Summary: It is known that some mutant peptides, such as those resulting from missense mutations and frameshift insertions, can bind to the major histocompatibility complex and be presented to antitumor T cells on the surface of a tumor cell. These peptides are termed neoantigen, and it is important to understand this process for cancer immunotherapy. Here, we introduce an R package termed Neoantimon that can predict a list of potential neoantigens from a variety of mutations, which include not only somatic point mutations but insertions, deletions and structural variants. Beyond the existing applications, Neoantimon is capable of attaching and reflecting several additional information, e.g. wild-type binding capability, allele specific RNA expression levels, single nucleotide polymorphism information and combinations of mutations to filter out infeasible peptides as neoantigen. Availability and implementation: The R package is available at http://github/hase62/Neoantimon.

Amylase genes reside in a structurally complex locus, and their copy numbers vary greatly, and several studies have reported their association with obesity. The mechanism of this effect was partially explained by changes in the oral and gut microbiome compositions; however, a detailed mechanism has been unclarified. In this study, we showed their association with diabetes in addition to obesity, and further discovered a plausible mechanism of this association based on the function of commensal bacteria. First, we confirmed that the amylase copy number in the population tends to be larger than that reported in other studies and that there is a positive association between obesity and diabetes (p = 1.89E–2 and 8.63E–3). Second, we identified that relative abundance of some genus level microbiome, Capnocytophaga, Dialister, and previously reported bacteria, were significantly associated with amylase copy numbers. Finally, through functional gene-set analysis using shotgun sequencing, we observed that the abundance of genes in the Acarbose pathway in the gut microbiome was significantly decreased with an increase in the amylase copy number (p-value = 5.80E–4). Our findings can partly explain the mechanism underlying obesity and diabetes in populations with high amylase copy numbers.