Metagenome-wide association study of gut microbiome revealed novel aetiology of rheumatoid arthritis in the Japanese population
Metagenome-wide association study of gut microbiome revealed novel aetiology of rheumatoid arthritis in the Japanese population
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DOI：
10.1136/annrheumdis-2019-215743
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发表时间：
2020-01-01
影响因子：
27.4
通讯作者：
Okada, Yukinori
中科院分区：
文献类型：
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作者：
Kishikawa, Toshihiro;Maeda, Yuichi;Okada, Yukinori
目的在包括类风湿关节炎（RA）等自身免疫性疾病在内的许多疾病中，微生物组组成的因果关系和致病机制尚不清楚。本研究旨在通过一项全面的宏基因组关联研究（MWAS）来阐明肠道微生物组在RA病理中的作用。方法采用高深度（平均每样本13 Gb）的全基因组霰弹枪测序方法，对日本人群（n（病例）=82,n（对照组）=42）RA肠道微生物组进行MWAS分析。我们的MWAS包括三个主要的生物信息学分析管道（系统发育分析、功能基因分析和途径分析）。结果系统发育病例对照关联试验显示，类风湿关节炎病例元基因组中存在多种普雷沃氏菌属（如齿状普雷沃氏菌）。非线性机器学习方法有效地消除了病例-对照系统发育差异。基因功能评估显示，与对照组相比，RA宏基因组中一个氧化还原反应相关基因（R6FCZ7）的丰度显著降低。包括代谢相关的多种生物学途径（如脂肪酸生物合成和糖胺聚糖降解）在病例对照中得到了丰富。通过比较类风湿关节炎宏基因组和类风湿关节炎全基因组关联研究结果之间的生物途径富集，确定了类风湿关节炎宏基因组与宿主基因组之间的群体特异性联系。类风湿关节炎病例和对照组之间宏基因组的α和β多样性没有明显差异。结论基于霰弹枪测序的MWAS强调了肠道微生物组、宿主基因组和RA病理之间的新联系，这有助于我们理解微生物组在RA病因学中的作用。
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.