Rationale: Several common and rare genetic variants have been associated with idiopathic pulmonary fibrosis, a progressive fibrotic condition that is localized to the lung. Objectives: To develop an integrated understanding of the rare and common variants located in multiple loci that have been reported to contribute to the risk of disease. Methods: We performed deep targeted resequencing (3.69 Mb of DNA) in cases (n = 3,624) and control subjects (n = 4,442) across genes and regions previously associated with disease. We tested for associations between disease and 1) individual common variants via logistic regression and 2) groups of rare variants via sequence kernel association tests. Measurements and Main Results: Statistically significant common variant association signals occurred in all 10 of the regions chosen based on genome-wide association studies. The strongest risk variant is the MUC5B promoter variant rs35705950, with an odds ratio of 5.45 (95% confidence interval, 4.91-6.06) for one copy of the risk allele and 18.68 (95% confidence interval, 13.34-26.17) for two copies of the risk allele (P = 9.60 × 10-295). In addition to identifying for the first time that rare variation in FAM13A is associated with disease, we confirmed the role of rare variation in the TERT and RTEL1 gene regions in the risk of IPF, and found that the FAM13A and TERT regions have independent common and rare variant signals. Conclusions: A limited number of common and rare variants contribute to the risk of idiopathic pulmonary fibrosis in each of the resequencing regions, and these genetic variants focus on biological mechanisms of host defense and cell senescence.
- MeSH
- ABC transportéry genetika MeSH
- celogenomová asociační studie MeSH
- DNA-helikasy genetika MeSH
- exoribonukleasy genetika MeSH
- genetická predispozice k nemoci MeSH
- genetická variace MeSH
- idiopatická plicní fibróza genetika MeSH
- interakce hostitele a patogenu genetika MeSH
- lidé MeSH
- logistické modely MeSH
- mucin 5B genetika MeSH
- promotorové oblasti (genetika) genetika MeSH
- protein A asociovaný s plicním surfaktantem genetika MeSH
- protein C asociovaný s plicním surfaktantem genetika MeSH
- proteiny aktivující GTPasu genetika MeSH
- proteiny vázající telomery genetika MeSH
- RNA genetika MeSH
- sekvenční analýza DNA MeSH
- stárnutí buněk genetika MeSH
- studie případů a kontrol MeSH
- telomerasa genetika MeSH
- vysoce účinné nukleotidové sekvenování MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
OBJECTIVE: Inclusion body myositis (IBM) is characterized by a combination of inflammatory and degenerative changes affecting muscle. While the primary cause of IBM is unknown, genetic factors may influence disease susceptibility. To determine genetic factors contributing to the etiology of IBM, we conducted the largest genetic association study of the disease to date, investigating immune-related genes using the Immunochip. METHODS: A total of 252 Caucasian patients with IBM were recruited from 11 countries through the Myositis Genetics Consortium and compared with 1,008 ethnically matched controls. Classic HLA alleles and amino acids were imputed using SNP2HLA. RESULTS: The HLA region was confirmed as the most strongly associated region in IBM (P = 3.58 × 10(-33) ). HLA imputation identified 3 independent associations (with HLA-DRB1*03:01, DRB1*01:01, and DRB1*13:01), although the strongest association was with amino acid positions 26 and 11 of the HLA-DRB1 molecule. No association with anti-cytosolic 5'-nucleotidase 1A-positive status was found independent of HLA-DRB1*03:01. There was no association of HLA genotypes with age at onset of IBM. Three non-HLA regions reached suggestive significance, including the chromosome 3 p21.31 region, an established risk locus for autoimmune disease, where a frameshift mutation in CCR5 is thought to be the causal variant. CONCLUSION: This is the largest, most comprehensive genetic association study to date in IBM. The data confirm that HLA is the most strongly associated region and identifies novel amino acid associations that may explain the risk in this locus. These amino acid associations differentiate IBM from polymyositis and dermatomyositis and may determine properties of the peptide-binding groove, allowing it to preferentially bind autoantigenic peptides. A novel suggestive association within the chromosome 3 p21.31 region suggests a role for CCR5.
- MeSH
- autoprotilátky imunologie MeSH
- běloši genetika MeSH
- genetická predispozice k nemoci MeSH
- genetické asociační studie MeSH
- HLA-DRB1 řetězec genetika MeSH
- lidé MeSH
- lidské chromozomy, pár 3 genetika MeSH
- myozitida s inkluzními tělísky genetika imunologie MeSH
- receptory CCR5 genetika MeSH
- věk při počátku nemoci MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Plant species richness and the presence of certain influential species (sampling effect) drive the stability and functionality of ecosystems as well as primary production and biomass of consumers. However, little is known about these floristic effects on richness and community composition of soil biota in forest habitats owing to methodological constraints. We developed a DNA metabarcoding approach to identify the major eukaryote groups directly from soil with roughly species-level resolution. Using this method, we examined the effects of tree diversity and individual tree species on soil microbial biomass and taxonomic richness of soil biota in two experimental study systems in Finland and Estonia and accounted for edaphic variables and spatial autocorrelation. Our analyses revealed that the effects of tree diversity and individual species on soil biota are largely context dependent. Multiple regression and structural equation modelling suggested that biomass, soil pH, nutrients and tree species directly affect richness of different taxonomic groups. The community composition of most soil organisms was strongly correlated due to similar response to environmental predictors rather than causal relationships. On a local scale, soil resources and tree species have stronger effect on diversity of soil biota than tree species richness per se.
- MeSH
- biodiverzita * MeSH
- biomasa MeSH
- Eukaryota klasifikace genetika izolace a purifikace MeSH
- houby klasifikace genetika izolace a purifikace MeSH
- půda chemie parazitologie MeSH
- půdní mikrobiologie * MeSH
- společenstvo MeSH
- stromy mikrobiologie MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Finsko MeSH
