Metagenome-wide Association Studies Potentiate Precision Medicine for Rheumatoid Arthritis.
TL;DR: The findings suggest that the gut and oral microbiome composition of RA patients could be potentially used to stratify RA patients and facilitate disease diagnosis and prognosis.
About: This article is published in Genomics, Proteomics & Bioinformatics.The article was published on 2015-08-01 and is currently open access. It has received 2 citations till now. The article focuses on the topics: Oral Microbiome & Human microbiome.
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TL;DR: A list of the novel available tools applicable to design a human-oriented RA research, while fostering the need for a more holistic and preventive approach to the disease.
Abstract: Rheumatoid arthritis (RA) is a chronic systemic autoimmune inflammatory disease characterized by progressive bone and cartilage destruction, functional impairment, and long-term disability. Although RA has been described in the medical literature for over two hundred years, its etiology and pathophysiology are insufficiently understood. The current treatment of RA is mainly empirical or based on drugs that interfere with generic steps of the immune response, with limited efficacy and/or significant side effects. Much of RA research has been traditionally based on animals and simplistic in vitro models, which have been shown to poorly recapitulate human RA etiopathogenesis and drug responses. A revolution in science and technology has produced a new generation of more relevant and predictive tools. These tools, which include patient-derived cells, innovative 3D cell culture systems, computational analyses and models, together with omics and large-scale epidemiological studies represent novel and exciting approaches to enhance and forward RA research in a human biology-based perspective. After considering some pitfalls and flaws of traditional models, in this review we discuss novel tools applicable to design human-oriented RA research, while fostering the need for a more holistic and preventative approach to the disease. Our goal is to stimulate discussion, both at scientific and public level, on the need to explore new avenues in RA research and to support a paradigm-shift from animal-based towards human biology-based systems to better understand human pathophysiology and to develop more effective targeted therapies for personalized treatment and prevention.
21 citations
Cites methods from "Metagenome-wide Association Studies..."
...Although the relationships among diet, microbiota, and human health are complex, the new tools, such as the metagenome sequencing, provide new connections and insights (Tong, 2015; Zhang et al., 2015a)....
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TL;DR: An overview on the most recent progress of biomarker studies on some of the important autoimmune-related diseases, such as systemic lupus erythematosus (SLE), psoriasis, systemic sclerosis (SSc), and primary Sjogren’s syndrome is given.
Cites background from "Metagenome-wide Association Studies..."
...[12] Tong Y. Metagenome-wide association studies potentiate preci- sion medicine for rheumatoid arthritis....
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...Yigang Tong [12] also highlighted a recently-published study on the altered microbiomes in RA patients, which could potentially serve as a biomarker for disease diagnosis and treatment response [13]....
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...Other than the review articles on various AIDs, Dr. Yigang Tong [12] also highlighted a recently-published study on the altered microbiomes in RA patients, which could potentially serve as a biomarker for disease diagnosis and treatment response [13]....
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References
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TL;DR: This study has demonstrated that careful use of a shared control group represents a safe and effective approach to GWA analyses of multiple disease phenotypes; generated a genome-wide genotype database for future studies of common diseases in the British population; and shown that, provided individuals with non-European ancestry are excluded, the extent of population stratification in theBritish population is generally modest.
Abstract: There is increasing evidence that genome-wide association ( GWA) studies represent a powerful approach to the identification of genes involved in common human diseases. We describe a joint GWA study ( using the Affymetrix GeneChip 500K Mapping Array Set) undertaken in the British population, which has examined similar to 2,000 individuals for each of 7 major diseases and a shared set of similar to 3,000 controls. Case-control comparisons identified 24 independent association signals at P < 5 X 10(-7): 1 in bipolar disorder, 1 in coronary artery disease, 9 in Crohn's disease, 3 in rheumatoid arthritis, 7 in type 1 diabetes and 3 in type 2 diabetes. On the basis of prior findings and replication studies thus-far completed, almost all of these signals reflect genuine susceptibility effects. We observed association at many previously identified loci, and found compelling evidence that some loci confer risk for more than one of the diseases studied. Across all diseases, we identified a large number of further signals ( including 58 loci with single-point P values between 10(-5) and 5 X 10(-7)) likely to yield additional susceptibility loci. The importance of appropriately large samples was confirmed by the modest effect sizes observed at most loci identified. This study thus represents a thorough validation of the GWA approach. It has also demonstrated that careful use of a shared control group represents a safe and effective approach to GWA analyses of multiple disease phenotypes; has generated a genome-wide genotype database for future studies of common diseases in the British population; and shown that, provided individuals with non-European ancestry are excluded, the extent of population stratification in the British population is generally modest. Our findings offer new avenues for exploring the pathophysiology of these important disorders. We anticipate that our data, results and software, which will be widely available to other investigators, will provide a powerful resource for human genetics research.
9,244 citations
TL;DR: The faecal microbial communities of adult female monozygotic and dizygotic twin pairs concordant for leanness or obesity, and their mothers are characterized to address how host genotype, environmental exposure and host adiposity influence the gut microbiome.
Abstract: The human distal gut harbours a vast ensemble of microbes (the microbiota) that provide important metabolic capabilities, including the ability to extract energy from otherwise indigestible dietary polysaccharides. Studies of a few unrelated, healthy adults have revealed substantial diversity in their gut communities, as measured by sequencing 16S rRNA genes, yet how this diversity relates to function and to the rest of the genes in the collective genomes of the microbiota (the gut microbiome) remains obscure. Studies of lean and obese mice suggest that the gut microbiota affects energy balance by influencing the efficiency of calorie harvest from the diet, and how this harvested energy is used and stored. Here we characterize the faecal microbial communities of adult female monozygotic and dizygotic twin pairs concordant for leanness or obesity, and their mothers, to address how host genotype, environmental exposure and host adiposity influence the gut microbiome. Analysis of 154 individuals yielded 9,920 near full-length and 1,937,461 partial bacterial 16S rRNA sequences, plus 2.14 gigabases from their microbiomes. The results reveal that the human gut microbiome is shared among family members, but that each person's gut microbial community varies in the specific bacterial lineages present, with a comparable degree of co-variation between adult monozygotic and dizygotic twin pairs. However, there was a wide array of shared microbial genes among sampled individuals, comprising an extensive, identifiable 'core microbiome' at the gene, rather than at the organismal lineage, level. Obesity is associated with phylum-level changes in the microbiota, reduced bacterial diversity and altered representation of bacterial genes and metabolic pathways. These results demonstrate that a diversity of organismal assemblages can nonetheless yield a core microbiome at a functional level, and that deviations from this core are associated with different physiological states (obese compared with lean).
6,970 citations
"Metagenome-wide Association Studies..." refers background in this paper
...Many diseases, especially the chronic diseases including obesity [6], diabetes [7], and autism [8], have been reported to be associated with the microbiome—the so-called ‘‘second genome of human” [9]....
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TL;DR: MGWAS analysis showed that patients with type 2 diabetes were characterized by a moderate degree of gut microbial dysbiosis, a decrease in the abundance of some universal butyrate-producing bacteria and an increase in various opportunistic pathogens, as well as an enrichment of other microbial functions conferring sulphate reduction and oxidative stress resistance.
Abstract: Assessment and characterization of gut microbiota has become a major research area in human disease, including type 2 diabetes, the most prevalent endocrine disease worldwide. To carry out analysis on gut microbial content in patients with type 2 diabetes, we developed a protocol for a metagenome-wide association study (MGWAS) and undertook a two-stage MGWAS based on deep shotgun sequencing of the gut microbial DNA from 345 Chinese individuals. We identified and validated approximately 60,000 type-2-diabetes-associated markers and established the concept of a metagenomic linkage group, enabling taxonomic species-level analyses. MGWAS analysis showed that patients with type 2 diabetes were characterized by a moderate degree of gut microbial dysbiosis, a decrease in the abundance of some universal butyrate-producing bacteria and an increase in various opportunistic pathogens, as well as an enrichment of other microbial functions conferring sulphate reduction and oxidative stress resistance. An analysis of 23 additional individuals demonstrated that these gut microbial markers might be useful for classifying type 2 diabetes.
4,981 citations
TL;DR: The increased understanding of the immune mechanisms of rheumatoid arthritis has led to the development of a considerable number of new therapeutic agents that alter the natural history of the disease and reduce mortality.
Abstract: The increased understanding of the immune mechanisms of rheumatoid arthritis has led to the development of a considerable number of new therapeutic agents that alter the natural history of the disease and reduce mortality.
3,975 citations
TL;DR: Advances in understanding of the interactions between resident microbes and the immune system are reviewed and the implications for human health are reviewed.
Abstract: The large numbers of microorganisms that inhabit mammalian body surfaces have a highly coevolved relationship with the immune system. Although many of these microbes carry out functions that are critical for host physiology, they nevertheless pose the threat of breach with ensuing pathologies. The mammalian immune system plays an essential role in maintaining homeostasis with resident microbial communities, thus ensuring that the mutualistic nature of the host-microbial relationship is maintained. At the same time, resident bacteria profoundly shape mammalian immunity. Here, we review advances in our understanding of the interactions between resident microbes and the immune system and the implications of these findings for human health.
3,330 citations
"Metagenome-wide Association Studies..." refers background in this paper
...The microbial communities on human body surface (skin or mucosa) interact with the host immune system, help its maturation and enhance its defenses against harmful microorganisms [10]....
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...Microbiome is also considered to be closely related to the human immune system [10,11]....
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