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Integrated genomic and prospective clinical studies show the importance of modular pleiotropy for disease susceptibility, diagnosis and treatment.

ABSTRACT: BACKGROUND: Translational research typically aims to identify and functionally validate individual, disease-specific genes. However, reaching this aim is complicated by the involvement of thousands of genes in common diseases, and that many of those genes are pleiotropic, that is, shared by several diseases. METHODS: We integrated genomic meta-analyses with prospective clinical studies to systematically investigate the pathogenic, diagnostic and therapeutic roles of pleiotropic genes. In a novel approach, we first used pathway analysis of all published genome-wide association studies (GWAS) to find a cell type common to many diseases. RESULTS: The analysis showed over-representation of the T helper cell differentiation pathway, which is expressed in T cells. This led us to focus on expression profiling of CD4(+) T cells from highly diverse inflammatory and malignant diseases. We found that pleiotropic genes were highly interconnected and formed a pleiotropic module, which was enriched for inflammatory, metabolic and proliferative pathways. The general relevance of this module was supported by highly significant enrichment of genetic variants identified by all GWAS and cancer studies, as well as known diagnostic and therapeutic targets. Prospective clinical studies of multiple sclerosis and allergy showed the importance of both pleiotropic and disease specific modules for clinical stratification. CONCLUSIONS: In summary, this translational genomics study identified a pleiotropic module, which has key pathogenic, diagnostic and therapeutic roles.

SUBMITTER: Gustafsson M

PROVIDER: S-EPMC4064311 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Integrated genomic and prospective clinical studies show the importance of modular pleiotropy for disease susceptibility, diagnosis and treatment.

Gustafsson Mika M Edström Måns M Gawel Danuta D Nestor Colm E CE Wang Hui H Zhang Huan H Barrenäs Fredrik F Tojo James J Kockum Ingrid I Olsson Tomas T Serra-Musach Jordi J Bonifaci Núria N Pujana Miguel Angel MA Ernerudh Jan J Benson Mikael M

Genome medicine 20140226 2

<h4>Background</h4>Translational research typically aims to identify and functionally validate individual, disease-specific genes. However, reaching this aim is complicated by the involvement of thousands of genes in common diseases, and that many of those genes are pleiotropic, that is, shared by several diseases.<h4>Methods</h4>We integrated genomic meta-analyses with prospective clinical studies to systematically investigate the pathogenic, diagnostic and therapeutic roles of pleiotropic gene ...[more]

PMID: 24571673

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Project description:Medical research focuses on disease-specific genes. By contrast, here we systematically examined the roles of shared genes for disease susceptibility and as therapeutic and diagnostic targets. Meta-analysis of all published disease-related genome-wide association studies (GWAS) showed that T helper (Th) cell differentiation was the most shared pathway. Expression profiling data from highly diverse CD4+ T cell-associated diseases revealed shared disease-associated genes, which were enriched for Th cell differentiation, but also metabolic and proliferative pathways. This pleiotropy suggested that altered functions of shared genes could generally increase disease susceptibility. Indeed, compared to specific genes, the shared genes were enriched for disease-associated SNPs identified by allÂ published disease-related GWAS. To examine if the shared genes induced disease-relevant pathways, we focused on transcription factors (TFs) that induced Th differentiation. Those TFs were enriched among the shared genes, as well as for disease-associated SNPs identified by GWAS, and disease-phenotypes in mice knock-out studies. Original GWAS and profiling data fromÂ patients with multiple sclerosis and allergyÂ confirmed enrichment of disease-associated SNPs in the TFs, and that the TFs were differentially expressed at early disease stages, and their targets increased in parallel with disease development. From a clinical perspective, the shared genes were significantly enriched for known diagnostic and therapeutic targets. Prospective clinical studies of multiple sclerosis and allergy showed that shared or specific genes could be used to stratify patients for individualized medicine. Our findings show that shared disease genes generally increase disease susceptibility and are important therapeutic and diagnostic targets. Patients with seasonal allergic rhinitis (SAR) show considerable variations in response to glucocorticoids (GCs) treatment. Peripheral blood mononuclear cells (PBMCs) were collected from 8 high responders (HR) and 8 low responders (LR) to GC treatment. PBMCs were challenged with diluent, grass pollen extract (ALK-AbellÃ³ A/S; 100 Î¼g/mL) as well as grass pollen extract plus glucocorticoids (100ug/mL) for one week. Total CD4+ T cells were enriched for the gene expression microarray analysis, which was performed using SurePrint G3 Human Gene Expression 8X60K microarrays.

Project description:Medical research focuses on disease-specific genes. By contrast, here we systematically examined the roles of shared genes for disease susceptibility and as therapeutic and diagnostic targets. Meta-analysis of all published disease-related genome-wide association studies (GWAS) showed that T helper (Th) cell differentiation was the most shared pathway. Expression profiling data from highly diverse CD4+ T cell-associated diseases revealed shared disease-associated genes, which were enriched for Th cell differentiation, but also metabolic and proliferative pathways. This pleiotropy suggested that altered functions of shared genes could generally increase disease susceptibility. Indeed, compared to specific genes, the shared genes were enriched for disease-associated SNPs identified by allÂ published disease-related GWAS. To examine if the shared genes induced disease-relevant pathways, we focused on transcription factors (TFs) that induced Th differentiation. Those TFs were enriched among the shared genes, as well as for disease-associated SNPs identified by GWAS, and disease-phenotypes in mice knock-out studies. Original GWAS and profiling data fromÂ patients with multiple sclerosis and allergyÂ confirmed enrichment of disease-associated SNPs in the TFs, and that the TFs were differentially expressed at early disease stages, and their targets increased in parallel with disease development. From a clinical perspective, the shared genes were significantly enriched for known diagnostic and therapeutic targets. Prospective clinical studies of multiple sclerosis and allergy showed that shared or specific genes could be used to stratify patients for individualized medicine. Our findings show that shared disease genes generally increase disease susceptibility and are important therapeutic and diagnostic targets. Patients with multiple sclerosis (MS) display variations in response to natalizumab treatment. PBMCs were collected from 8 high responders (HR) and 8 low responders (LR) to natalizumab treatment. CD4+ T cells were cultured for 48h. Cells were activated with anti-CD3 and anti-CD28 mAbs (0.5 Âµg/mL), either with natalizumab (25 Âµg/mL BiogenIdec) or without additional stimulus. Gene expression analysis was performed using SurePrint G3 Human Gene Expression 8X60K microarrays.

Project description:Universal access to drug susceptibility testing for newly diagnosed tuberculosis patients is recommended. Access to culture-based diagnostics remains limited, and targeted molecular assays are vulnerable to emerging resistance mutations. Improved protocols for direct-from-sputum Mycobacterium tuberculosis sequencing would accelerate access to comprehensive drug susceptibility testing and molecular typing. We assessed a thermo-protection buffer-based direct-from-sample M. tuberculosis whole-genome sequencing protocol. We prospectively analyzed 60 acid-fast bacilli smear-positive clinical sputum samples in India and Madagascar. A diversity of semiquantitative smear positivity-level samples were included. Sequencing was performed using Illumina and MinION (monoplex and multiplex) technologies. We measured the impact of bacterial inoculum and sequencing platforms on genomic read depth, drug susceptibility prediction performance, and typing accuracy. M. tuberculosis was identified by direct sputum sequencing in 45/51 samples using Illumina, 34/38 were identified using MinION-monoplex sequencing, and 20/24 were identified using MinION-multiplex sequencing. The fraction of M. tuberculosis reads from MinION sequencing was lower than from Illumina, but monoplexing grade 3+ samples on MinION produced higher read depth than Illumina (P < 0.05) and MinION multiplexing (P < 0.01). No significant differences in sensitivity and specificity of drug susceptibility predictions were seen across sequencing modalities or within each technology when stratified by smear grade. Illumina sequencing from sputum accurately identified 1/8 (rifampin) and 6/12 (isoniazid) resistant samples, compared to 2/3 (rifampin) and 3/6 (isoniazid) accurately identified with Nanopore monoplex. Lineage agreement levels between direct and culture-based sequencing were 85% (MinION-monoplex), 88% (Illumina), and 100% (MinION-multiplex). M. tuberculosis direct-from-sample whole-genome sequencing remains challenging. Improved and affordable sample treatment protocols are needed prior to clinical deployment.

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Integrated genomic and prospective clinical studies show the importance of modular pleiotropy for disease susceptibility, diagnosis and treatment.

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Integrated genomic and prospective clinical studies show the importance of modular pleiotropy for disease susceptibility, diagnosis and treatment.

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