Assessing causal relationships between gut microbiota and asthma: evidence from two sample Mendelian randomization analysis DOI Creative Commons
Rong Li,

Qi Guo,

Jian Zhao

et al.

Frontiers in Immunology, Journal Year: 2023, Volume and Issue: 14

Published: July 19, 2023

Background Accumulating evidence has suggested that gut microbiota dysbiosis is commonly observed in asthmatics. However, it remains unclear whether a cause or consequence of asthma. We aimed to examine the genetic causal relationships with asthma and its three phenotypes, including adult-onset asthma, childhood-onset moderate-severe Methods To elucidate causality we applied two sample Mendelian randomization (MR) based on largest publicly available genome-wide association study (GWAS) summary statistics. Inverse variance weighting meta-analysis (IVW) was used obtain main estimates; Weighted median, MR-Egger, Robust Adjusted Profile Score (MR-RAPS), Maximum likelihood method (ML), MR pleiotropy residual sum outlier (MR-PRESSO) methods were sensitivity analyses. Finally, reverse analysis performed evaluate possibility causation. Results In absence heterogeneity horizontal pleiotropy, IVW revealed genetically predicted Barnesiella RuminococcaceaeUCG014 positively correlated risk while between CandidatusSoleaferrea negative. And for phenotypes Akkermansia reduced Collinsella increased FamilyXIIIAD3011group , Eisenbergiella Ruminiclostridium6 (all P <0.05). The didn’t find supporting from genus. Conclusion This microbial genera causally associated as well phenotypes. findings deepened our understanding role pathology which emphasizes potential opening up new vista prevention diagnosis

Language: Английский

Asthma DOI
Celeste Porsbjerg, Erik Melén, Lauri Lehtimäki

et al.

The Lancet, Journal Year: 2023, Volume and Issue: 401(10379), P. 858 - 873

Published: Jan. 20, 2023

Language: Английский

Citations

262
Maternal-Fetal Inflammation in the Placenta and the Developmental Origins of Health and Disease DOI Creative Commons
Jeffrey A. Goldstein, Kelly Gallagher,

Celeste Beck

et al.

Frontiers in Immunology, Journal Year: 2020, Volume and Issue: 11

Published: Nov. 13, 2020

Events in fetal life impact long-term health outcomes. The placenta is the first organ to form and site of juxtaposition between maternal circulations. Most diseases pregnancy are caused by, impact, or reflected placenta. purpose this review describe main inflammatory processes placenta, discuss their immunology, relate short- disease associations. Acute placental inflammation (API), including responses corresponds clinical diagnosis chorioamnionitis associated with respiratory neurodevelopmental diseases. chronic pathologies (CPI), include villitis unknown etiology, deciduitis, chorionitis, eosinophilic T-cell vasculitis, histiocytic intervillositis. These less-well studied, but have complex immunology show mechanistic impacts on immune system. Overall, much work remains be done describing offspring health.

Language: Английский

Citations

196
Genome-wide analysis highlights contribution of immune system pathways to the genetic architecture of asthma DOI Creative Commons
Yi Han, Qiong Jia, Pedram Shafiei-Jahani

et al.

Nature Communications, Journal Year: 2020, Volume and Issue: 11(1)

Published: April 15, 2020

Asthma is a chronic and genetically complex respiratory disease that affects over 300 million people worldwide. Here, we report genome-wide analysis for asthma using data from the UK Biobank Trans-National Genetic Consortium. We identify 66 previously unknown loci demonstrate susceptibility alleles in these regions are, either individually or as function of cumulative genetic burden, associated with risk to greater extent men than women. Bioinformatics analyses prioritize candidate causal genes at 52 loci, including CD52, asthma-associated variants are enriched open chromatin immune cells. Lastly, show murine anti-CD52 antibody mimics cell-depleting effects clinically used human reduces allergen-induced airway hyperreactivity mice. These results further elucidate architecture provide important insight into immunological sex-specific relevance variants.

Language: Английский

Citations

170
The Genetics of Epilepsy DOI Open Access
Piero Perucca, Melanie Bahlo, Samuel F. Berkovic

et al.

Annual Review of Genomics and Human Genetics, Journal Year: 2020, Volume and Issue: 21(1), P. 205 - 230

Published: April 27, 2020

Epilepsy encompasses a group of heterogeneous brain diseases that affect more than 50 million people worldwide. may have discernible structural, infectious, metabolic, and immune etiologies; however, in most with epilepsy, no obvious cause is identifiable. Based initially on family studies later advances gene sequencing technologies computational approaches, as well the establishment large collaborative initiatives, we now know genetics plays much greater role epilepsy was previously appreciated. Here, review progress field highlight molecular discoveries important groups, including those been long considered to nongenetic cause. We discuss where moving it enters new era which genetic architecture common epilepsies starting be unraveled.

Language: Английский

Citations

169
Functions and regulation of T cell-derived interleukin-10 DOI
Christian Neumann, Alexander Scheffold, Sascha Rutz

et al.

Seminars in Immunology, Journal Year: 2019, Volume and Issue: 44, P. 101344 - 101344

Published: Aug. 1, 2019

Language: Английский

Citations

163
Genetics and Epigenetics in Asthma DOI Open Access

Polyxeni Ntontsi,

Andreas Photiades, Εleftherios Ζervas

et al.

International Journal of Molecular Sciences, Journal Year: 2021, Volume and Issue: 22(5), P. 2412 - 2412

Published: Feb. 27, 2021

Asthma is one of the most common respiratory disease that affects both children and adults worldwide, with diverse phenotypes underlying pathogenetic mechanisms poorly understood. As technology in genome sequencing progressed, scientific efforts were made to explain predict asthma’s complexity heterogeneity, genome-wide association studies (GWAS) quickly became preferred study method. Several gene markers loci associated asthma susceptibility, atopic childhood-onset identified during last few decades. Markers near ORMDL3/GSDMB genes asthma, interleukin (IL)33 IL1RL1 SNPs Thymic Stromal Lymphopoietin (TSLP) was as protective against risk TH2-asthma. The latest advances identifying decoding susceptibility are focused on epigenetics, heritable characteristics affect expression without altering DNA sequence, methylation being described mechanism. Other less studied epigenetic include histone modifications alterations miR expression. Recent findings suggest pattern tissue cell-specific. attempt describe different types cells tissues asthmatic patients regulate airway remodeling, phagocytosis, other lung functions asthma. In this review, we briefly present advancements field genetics mainly epigenetics concerning susceptibility.

Language: Английский

Citations

148
Prioritization of candidate causal genes for asthma in susceptibility loci derived from UK Biobank DOI Creative Commons

Kim Valette,

Zhonglin Li, Valentin Bon-Baret

et al.

Communications Biology, Journal Year: 2021, Volume and Issue: 4(1)

Published: June 8, 2021

Abstract To identify candidate causal genes of asthma, we performed a genome-wide association study (GWAS) in UK Biobank on broad asthma definition (n = 56,167 cases and 352,255 controls). We then carried out functional mapping through transcriptome-wide studies (TWAS) Mendelian randomization lung 1,038) blood 31,684) tissues. The GWAS reveals 72 asthma-associated loci from 116 independent significant variants (P < 5.0E-8). most TWAS gene 17q12-q21 is GSDMB 1.42E-54). Other include TSLP 5q22, RERE 1p36, CLEC16A 16p13, IL4R 16p12, which all replicated GTEx 515). demonstrate that the largest fold enrichment regulatory annotations among blood. map 485 eQTL-regulated associated with 50 them are by randomization. Prioritization druggable known ( , IL6 TNFSF4 ) potentially new therapeutic targets for asthma.

Language: Английский

Citations

127
Human germline heterozygous gain-of-functionSTAT6variants cause severe allergic disease DOI Creative Commons
Mehul Sharma, Daniel Leung, Mana Momenilandi

et al.

The Journal of Experimental Medicine, Journal Year: 2023, Volume and Issue: 220(5)

Published: March 8, 2023

STAT6 (signal transducer and activator of transcription 6) is a factor that plays central role in the pathophysiology allergic inflammation. We have identified 16 patients from 10 families spanning three continents with profound phenotype early-life onset immune dysregulation, widespread treatment-resistant atopic dermatitis, hypereosinophilia esosinophilic gastrointestinal disease, asthma, elevated serum IgE, IgE-mediated food allergies, anaphylaxis. The cases were either sporadic (seven kindreds) or followed an autosomal dominant inheritance pattern (three kindreds). All carried monoallelic rare variants functional studies established their gain-of-function (GOF) sustained phosphorylation, increased target gene expression, TH2 skewing. Precision treatment anti–IL-4Rα antibody, dupilumab, was highly effective improving both clinical manifestations immunological biomarkers. This study identifies heterozygous GOF as novel disorder. anticipate our discovery multiple kindreds germline will facilitate recognition more affected individuals full definition this new primary

Language: Английский

Citations

63
Genetic adaptation to pathogens and increased risk of inflammatory disorders in post-Neolithic Europe DOI Creative Commons
Gaspard Kerner, Anna‐Lena Neehus, Quentin Philippot

et al.

Cell Genomics, Journal Year: 2023, Volume and Issue: 3(2), P. 100248 - 100248

Published: Jan. 13, 2023

Ancient genomics can directly detect human genetic adaptation to environmental cues. However, it remains unclear how pathogens have exerted selective pressures on genome diversity across different epochs and affected present-day inflammatory disease risk. Here, we use an ancestry-aware approximate Bayesian computation framework estimate the nature, strength, time of onset selection acting 2,879 ancient modern European genomes from last 10,000 years. We found that bulk occurred after start Bronze Age, <4,500 years ago, was enriched in genes relating host-pathogen interactions. Furthermore, detected directional specific leukocytic lineages experimentally demonstrated strongest negatively selected candidate variant immunity genes, lipopolysaccharide-binding protein (

Language: Английский

Citations

62
Decoding the genetic and epigenetic basis of asthma DOI Creative Commons
Bernard Stikker, Rudi W. Hendriks, Ralph Stadhouders

et al.

Allergy, Journal Year: 2023, Volume and Issue: 78(4), P. 940 - 956

Published: Feb. 2, 2023

Abstract Asthma is a complex and heterogeneous chronic inflammatory disease of the airways. Alongside environmental factors, asthma susceptibility strongly influenced by genetics. Given its high prevalence our incomplete understanding mechanisms underlying susceptibility, frequently studied in genome‐wide association studies (GWAS), which have identified thousands genetic variants associated with development. Virtually all these reside non‐coding genomic regions, has obscured functional impact asthma‐associated their translation into disease‐relevant mechanisms. Recent advances genomics technology epigenetics now offer methods to link gene regulatory elements embedded within started unravel molecular (epi)genetics asthma. Here, we provide an integrated overview (epi)genetic asthma, focusing on efforts associations biological insight pathophysiology using state‐of‐the‐art methodology. Finally, perspective as how decoding epigenetic basis potential transform clinical management predict risk

Language: Английский

Citations

47