[A case of autoimmune glial fibrillary acidic protein astrocytopathy with various symptoms such as optic disc edema and cerebellar ataxia].

A 59-year-old man had developed visual abnormality, nausea, headache, and weight loss since three months before. The ophthalmologist found severe optic disc edema in both eyes, and referred him to our hospital. The patient had mild cerebellar ataxia. Increased cerebrospinal fluid pressure, increased protein and cell counts, positive oligoclonal band, and contrast-enhanced head MRI showed multiple linear perivascular radial gadolinium enhancement around bilateral lateral ventricles. His subjective and objective findings significantly improved with steroid treatment. The cerebrospinal fluid was found to be positive for glial fibrillary acidic protein (GFAP) antibodies, and a diagnosis of GFAP astrocytopathy was obtained. When optic edema or radial contrast effects was observed on contrast-enhanced MRI, GFAP astrocytopathy should be considerd. Prompt immunotherapy is required to circumvent the development of permanent visual impairment.

Analysis of gut microbiome, host genetics, and plasma metabolites reveals gut microbiome-host interactions in the Japanese population.

Interaction between the gut microbiome and host plays a key role in human health. Here, we perform a metagenome shotgun-sequencing-based analysis of Japanese participants to reveal associations between the gut microbiome, host genetics, and plasma metabolome. A genome-wide association study (GWAS) for microbial species (n = 524) identifies associations between the PDE1C gene locus and Bacteroides intestinalis and between TGIF2 and TGIF2-RAB5IF gene loci and Bacteroides acidifiaciens. In a microbial gene ortholog GWAS, agaE and agaS, which are related to the metabolism of carbohydrates forming the blood group A antigen, are associated with blood group A in a manner depending on the secretor status determined by the East Asian-specific FUT2 variant. A microbiome-metabolome association analysis (n = 261) identifies associations between bile acids and microbial features such as bile acid metabolism gene orthologs including bai and 7ß-hydroxysteroid dehydrogenase. Our publicly available data will be a useful resource for understanding gut microbiome-host interactions in an underrepresented population.

Reconstruction of the personal information from human genome reads in gut metagenome sequencing data.

Human DNA present in faecal samples can result in a small number of human reads in gut shotgun metagenomic sequencing data. However, it is presently unclear how much personal information can be reconstructed from such reads, and this has not been quantitatively evaluated. Such a quantitative evaluation is necessary to clarify the ethical concerns related to data sharing and to enable efficient use of human genetic information in stool samples, such as for research and forensics. Here we used genomic approaches to reconstruct personal information from the faecal metagenomes of 343 Japanese individuals with associated human genotype data. Genetic sex could be accurately predicted based on the sequencing depth of sex chromosomes for 97.3% of the samples. Individuals could be re-identified from the matched genotype data based on human reads recovered from the faecal metagenomic data with 93.3% sensitivity using a likelihood score-based method. This method also enabled us to predict the ancestries of 98.3% of the samples. Finally, we performed ultra-deep shotgun metagenomic sequencing of five faecal samples as well as whole-genome sequencing of blood samples. Using genotype-calling approaches, we demonstrated that the genotypes of both common and rare variants could be reconstructed from faecal samples. This included clinically relevant variants. Our approach can be used to quantify personal information contained within gut metagenome data.

Whole gut virome analysis of 476 Japanese revealed a link between phage and autoimmune disease.

OBJECTIVE: The relationship between autoimmune diseases and the gut microbiome has been intensively studied, and several autoimmunity-associated bacterial taxa have been identified. However, much less is known about the roles of the gut virome in autoimmune diseases. METHODS: Here, we performed a whole gut virome analysis based on the shotgun sequencing of 476 Japanese which included patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis and healthy control subjects. RESULTS: Our case-control comparison of the viral abundance revealed that crAss-like phages, which are one of the main components of a healthy gut virome, significantly decreased in the gut of the patients with autoimmune disease, specifically the patients with RA and SLE. In addition, Podoviridae significantly decreased in the gut of the patients with SLE. To understand how these viruses affected the bacteriome, we performed a quantitative virus-bacterium association analysis and clustered regularly interspaced short palindromic repeat-based virus-bacterium interaction analysis. We identified a symbiosis between Podoviridae and Faecalibacterium. In addition, multiple bacterial targets of crAss-like phages were identified (eg, Ruminococcus spp). CONCLUSION: Our data suggest that the gut virome can affect our body either directly or via bacteria. Our analyses have elucidated a previously missing part of the autoimmunity-associated gut microbiome and presented new candidates that contribute to the development of autoimmune diseases.

Prokaryotic and viral genomes recovered from 787 Japanese gut metagenomes revealed microbial features linked to diets, populations, and diseases.

We reconstructed 19,084 prokaryotic and 31,395 viral genomes from 787 Japanese gut metagenomes as Japanese metagenome-assembled genomes (JMAG) and Japanese Virus Database (JVD), which are large microbial genome datasets for a single population. Population-specific enrichment of the Bacillus subtilis and ß-porphyranase among the JMAG could derive from the Japanese traditional food natto (fermented soybeans) and nori (laver), respectively. Dairy-related Enterococcus_B lactis and Streptococcus thermophilus were nominally associated with the East Asian-specific missense variant rs671:G>A in ALDH2, which was associated with dairy consumption. Of the species-level viral genome clusters in the JVD, 62.9% were novel. The ß crAss-like phage composition was low among the Japanese but relatively high among African and Oceanian peoples. Evaluations of the association between crAss-like phages and diseases showed significant disease-specific associations. Our large catalog of virus-host pairs identified the positive correlation between the abundance of the viruses and their hosts.

A Metagenome-Wide Association Study of Gut Microbiome in Patients With Multiple Sclerosis Revealed Novel Disease Pathology.

While microbiome plays key roles in the etiology of multiple sclerosis (MS), its mechanism remains elusive. Here, we conducted a comprehensive metagenome-wide association study (MWAS) of the relapsing-remitting MS gut microbiome (ncase = 26, ncontrol = 77) in the Japanese population, by using whole-genome shotgun sequencing. Our MWAS consisted of three major bioinformatic analytic pipelines (phylogenetic analysis, functional gene analysis, and pathway analysis). Phylogenetic case-control association tests showed discrepancies of eight clades, most of which were related to the immune system (false discovery rate [FDR] < 0.10; e.g., Erysipelatoclostridium_sp. and Gemella morbillorum). Gene association tests found an increased abundance of one putative dehydrogenase gene (Clo1100_2356) and one ABC transporter related gene (Mahau_1952) in the MS metagenome compared with controls (FDR < 0.1). Molecular pathway analysis of the microbiome gene case-control comparisons identified enrichment of multiple Gene Ontology terms, with the most significant enrichment on cell outer membrane (P = 1.5 × 10-7). Interaction between the metagenome and host genome was identified by comparing biological pathway enrichment between the MS MWAS and the MS genome-wide association study (GWAS) results (i.e., MWAS-GWAS interaction). No apparent discrepancies in alpha or beta diversities of metagenome were found between MS cases and controls. Our shotgun sequencing-based MWAS highlights novel characteristics of the MS gut microbiome and its interaction with host genome, which contributes to our understanding of the microbiome's role in MS pathophysiology.

Next-generation sequencing identifies contribution of both class I and II HLA genes on susceptibility of multiple sclerosis in Japanese.

BACKGROUND: The spectrum of classical and non-classical HLA genes related to the risk of multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) in the Japanese population has not been studied in detail. We conducted a case-control analysis of classical and non-classical HLA genes. METHODS: We used next-generation sequencing (NGS)-based HLA genotyping methods for mapping risk for 45 MS patients, 31 NMOSD patients, and 429 healthy controls. We evaluated the association of the HLA variants with the risk of MS and NMOSD using logistic regression analysis and Fisher's exact test. RESULTS: We confirmed that HLA-DRB1*15:01 showed the strongest association with MS (P = 2.1 × 10-5; odds ratio [OR] = 3.44, 95% confidence interval [95% CI] = 1.95-6.07). Stepwise conditional analysis identified HLA-DRB1*04:05, HLA-B*39:01, and HLA-B*15:01 as being associated with independent MS susceptibility (PConditional < 8.3 × 10-4). With respect to amino acid polymorphisms in HLA genes, we found that phenylalanine at HLA-DQß1 position 9 had the strongest effect on MS susceptibility (P = 3.7 × 10-8, OR = 3.48, 95% CI = 2.23-5.43). MS risk at HLA-DQß1 Phe9 was independent of HLA-DRB1*15:01 (PConditional = 1.5 × 10-5, OR = 2.91, 95% CI = 1.79-4.72), while HLA-DRB1*15:01 was just significant when conditioned on HLA-DQß1 Phe9 (PConditional = 0.037). Regarding a case-control analysis for NMOSD, HLA-DQA1*05:03 had a significant association with NMOSD (P = 1.5 × 10-4, OR = 6.96, 95% CI = 2.55-19.0). CONCLUSIONS: We identified HLA variants associated with the risk of MS and NMOSD. Our study contributes to the understanding of the genetic architecture of MS and NMOSD in the Japanese population.

Prenatal exposure to HMG-CoA reductase inhibitors: effects on fetal and neonatal outcomes.

BACKGROUND: Use of HMG-CoA reductase inhibitors (statins) is becoming increasingly common. However, a recent study based on a series of cases reported to FDA suggests possible teratogenic effects of statins on embryogenesis, such as limb defects and severe central nervous system anomalies. METHODS: In a prospective, observational cohort study with a comparison group to examine a fetal toxicity risk of statins, we followed 64 pregnant women taking statins, and 64 comparison group women without exposure to known teratogens. The statin group women were exposed to atorvastatin (n=46), simvastatin (n=9), pravastatin (n=6), or rosuvastatin (n=3) during the first trimester. RESULTS: There was no difference in the rate of major malformations between the statin group (1/46 live birth: 2.2%) and the comparison group (1/52 live birth: 1.9%, p=0.93). Similarly, there were no statistical differences between the statin and comparison groups in live births (71.9% vs 81.2%), spontaneous abortions (14: 21.9% vs 11: 17.2%), therapeutic abortions (3: 4.7% vs 0: 0%) and stillbirths (1: 1.5% vs 1: 1.6%). Gestational age at birth (38.4+/-2.8 weeks vs 39.3+/-1.3 weeks: M+/-S.D., p=0.04) and birth weight (3.14+/-0.68kg vs 3.45+/-0.42kg, p=0.01) were lower in the statin group. CONCLUSIONS: The absolute risk of teratogenicity of statins, if any, appears relatively small. A large-scale study is needed to further characterize the teratogenic potential.

Use of lipid-lowering agents (statins) during pregnancy.

QUESTION: A 34-year-old patient of mine is taking a 'statin' for hyperlipidemia. She is planning pregnancy and is worried about the safety of the drug. How should I advise her? ANSWER: Limited evidence from animal and human studies indicates that statins should not be taken during pregnancy. If a patient is inadvertently exposed during pregnancy, however, termination does not appear to be medically indicated.