Metagenome-wide association study of gut microbiome revealed novel aetiology of rheumatoid arthritis in the Japanese population

Study information

Reviewed Marked as Reviewed by Claregrieve1 on 2023-4-22

study design

cross-sectional observational, not case-control

Citation

PMID PubMed identifier for scientific articles.

31699813

DOI Digital object identifier for electronic documents.

10.1136/annrheumdis-2019-215743

URI

Authors

Kishikawa T, Maeda Y, Nii T, Motooka D, Matsumoto Y, Matsushita M, Matsuoka H, Yoshimura M, Kawada S, Teshigawara S, Oguro E, Okita Y, Kawamoto K, Higa S, Hirano T, Narazaki M, Ogata A, Saeki Y, Nakamura S, Inohara H, Kumanogoh A, Takeda K, Okada Y

Journal

Annals of the rheumatic diseases

Year

2020

Keywords:

autoimmune diseases, gene polymorphism, rheumatoid arthritis

OBJECTIVE: The causality and pathogenic mechanism of microbiome composition remain elusive in many diseases, including autoimmune diseases such as rheumatoid arthritis (RA). This study aimed to elucidate gut microbiome's role in RA pathology by a comprehensive metagenome-wide association study (MWAS). METHODS: We conducted MWAS of the RA gut microbiome in the Japanese population (n case=82, n control=42) by using whole-genome shotgun sequencing of high depth (average 13 Gb per sample). Our MWAS consisted of three major bioinformatic analytic pipelines (phylogenetic analysis, functional gene analysis and pathway analysis). RESULTS: Phylogenetic case-control association tests showed high abundance of multiple species belonging to the genus Prevotella (e.g., Prevotella denticola) in the RA case metagenome. The non-linear machine learning method efficiently deconvoluted the case-control phylogenetic discrepancy. Gene functional assessments showed that the abundance of one redox reaction-related gene (R6FCZ7) was significantly decreased in the RA metagenome compared with controls. A variety of biological pathways including those related to metabolism (e.g., fatty acid biosynthesis and glycosaminoglycan degradation) were enriched in the case-control comparison. A population-specific link between the metagenome and host genome was identified by comparing biological pathway enrichment between the RA metagenome and the RA genome-wide association study results. No apparent discrepancy in alpha or beta diversities of metagenome was found between RA cases and controls. CONCLUSION: Our shotgun sequencing-based MWAS highlights a novel link among the gut microbiome, host genome and pathology of RA, which contributes to our understanding of the microbiome's role in RA aetiology.

Experiment 1

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Reviewed Marked as Reviewed by Claregrieve1 on 2023-4-22

Curated date: 2023/03/14

Curator: Nice25

Revision editor(s): Nice25, Claregrieve1

Subjects

Location of subjects: Japan

Host species Species from which microbiome was sampled. Contact us to have more species added.: Homo sapiens

Body site Anatomical site where microbial samples were extracted from according to the Uber Anatomy Ontology: Feces Cow dung,Cow pat,Droppings,Dung,Excrement,Excreta,Faeces,Fecal material,Fecal matter,Fewmet,Frass,Guano,Matières fécales@fr,Merde@fr,Ordure,Partie de la merde@fr,Piece of shit,Porción de mierda@es,Portion of dung,Portion of excrement,Portion of faeces,Portion of fecal material,Portion of fecal matter,Portion of feces,Portion of guano,Portion of scat,Portionem cacas,Scat,Spoor,Spraint,Stool,Teil der fäkalien@de,Feces,feces

Condition The experimental condition / phenotype studied according to the Experimental Factor Ontology: Rheumatoid arthritis Arthritis or polyarthritis, rheumatic,arthritis or polyarthritis, rheumatic,Arthritis, Rheumatoid,arthritis, rheumatoid,atrophic Arthritis,atrophic arthritis,autoimmune arthritis,Chronic rheumatic arthritis,Proliferative arthritis,RA,RA - Rheumatoid arthritis,RhA - Rheumatoid arthritis,Rheumatic gout,rheumatoid arthritis,Rheumatoid arthritis (disorder),Rheumatoid arthritis NOS,Rheumatoid arthritis NOS (disorder),rheumatoid arthritis, susceptibility to,Rheumatoid disease,Rheumatoid arthritis

Group 0 name Corresponds to the control (unexposed) group for case-control studies: healthy controls

Group 1 name Corresponds to the case (exposed) group for case-control studies: rheumatoid arthritis

Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group: Patients with RA

Group 0 sample size Number of subjects in the control (unexposed) group: 42

Group 1 sample size Number of subjects in the case (exposed) group: 82

Antibiotics exclusion Number of days without antibiotics usage (if applicable) and other antibiotics-related criteria used to exclude participants (if any): 12 weeks

Lab analysis

Sequencing type: WMS

16S variable region One or more hypervariable region(s) of the bacterial 16S gene: Not specified

Sequencing platform Manufacturer and experimental platform used for quantifying microbial abundance: Illumina

Statistical Analysis

Data transformation Data transformation applied to microbial abundance measurements prior to differential abundance testing (if any).: relative abundances

Statistical test: PERMANOVA

Significance threshold p-value or FDR threshold used for differential abundance testing (if any): 0.05

MHT correction Have statistical tests be corrected for multiple hypothesis testing (MHT)?: Yes

Matched on Factors on which subjects have been matched on in a case-control study: age, sex

Alpha Diversity

Shannon Estimator of species richness and species evenness: more weight on species richness: unchanged

Signature 1

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Reviewed Marked as Reviewed by Claregrieve1 on 2023-4-22

Curated date: 2023/03/15

Curator: Nice25

Revision editor(s): Nice25

Source: Table 1

Description: Taxonomic differences of fecal microbiota in RA and healthy groups.

Abundance in Group 1: increased abundance in rheumatoid arthritis

NCBI	Quality Control	Links
Gardnerella
Gardnerella vaginalis
Porphyromonas somerae
Prevotella amnii
Prevotella corporis
Prevotella denticola
Prevotella disiens
Hoylesella marshii DSM 16973 = JCM 13450
Phocaeicola sartorii

Revision editor(s): Nice25