Resequencing to Fine Map Known Idiopathic Pulmonary Fibrosis Risk Genes. Homing in on Causal Variants.
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ABSTRACT:
SUBMITTER: Allen R
PROVIDER: S-EPMC6635787 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description: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.
| S-EPMC6635791 | biostudies-literature
Project description:Sequence variation, methylation differences, and transcriptional changes in desmoplakin (DSP) have been observed in patients with idiopathic pulmonary fibrosis (IPF).To identify novel variants in DSP associated with IPF and to characterize the relationship of these IPF sequence variants with DSP gene expression in human lung.A chromosome 6 locus (7,370,061-7,606,946) was sequenced in 230 subjects with IPF and 228 control subjects. Validation genotyping of disease-associated variants was conducted in 936 subjects with IPF and 936 control subjects. DSP gene expression was measured in lung tissue from 334 subjects with IPF and 201 control subjects.We identified 23 sequence variants in the chromosome 6 locus associated with IPF. Genotyping of selected variants in our validation cohort revealed that noncoding intron 1 variant rs2744371 (odds ratio?=?0.77, 95% confidence interval [CI]?=?0.66-0.91, P?=?0.002) is protective for IPF, and a previously described IPF-associated intron 5 variant (rs2076295) is associated with increased risk of IPF (odds ratio?=?1.36, 95% CI?=?1.19-1.56, P?<?0.001) after controlling for sex and age. DSP expression is 2.3-fold increased (95% CI?=?1.91-2.71) in IPF lung tissue (P?<?0.0001). Only the minor allele at rs2076295 is associated with decreased DSP expression (P?=?0.001). Staining of fibrotic and normal human lung tissue localized DSP to airway epithelia.Sequence variants in DSP are associated with IPF, and rs2076295 genotype is associated with differential expression of DSP in the lung. DSP expression is increased in IPF lung and concentrated in the airway epithelia, suggesting a potential role for DSP in the pathogenesis of IPF.
| S-EPMC4872666 | biostudies-literature
Project description:Background Although the association between hypothyroidism and idiopathic pulmonary fibrosis (IPF) is found in observational studies, it remains uncertain whether hypothyroidism causally influences IPF. Methods Two-sample Mendelian randomisation (MR) was conducted with hypothyroidism genome-wide association study (GWAS) data in the UK Biobank from 289,307 individuals (18,740 cases and 270,567 controls) and the largest GWAS summary statistics of IPF from 11,259 individuals (2,668 cases and 8,591 controls). Findings were verified using an independent validation dataset, as well as through different MR methods with different model assumptions. A multivariable MR based on Bayesian model averaging was further performed to evaluate whether hypothyroidism, even given several other comorbidities of IPF, remained to be the true causal one of IPF. Findings A positive causal effect of hypothyroidism on IPF was revealed (MR inverse-variance weighted [MR-IVW], odds ratio [OR]=1.125, 95% confidence interval [CI] 1.028-1.231; P=0.011), which was further verified in an independent validation set (MR-IVW, OR=1.229, 95% CI 1.054-1.432; P=0.008). The results were consistent from a variety of MR methods. Bidirectional analyses also indicated no reverse causation. Multivariable MR analysis showed hypothyroidism had the strongest marginal evidence (marginal inclusion probability=0.397, false discovery rate=0.025) compared with other comorbidities of IPF. Interpretation Our results illustrate the significant causal effect of hypothyroidism on IPF, which holds even given several other comorbidities of IPF. These findings may have an important insight into pathogenesis and possible future therapies of IPF. Funding National Natural Science Foundation of China, the Natural Science Foundation of Shandong Province and the Young Scholars Program of Shandong University.
| S-EPMC8586742 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2022-07-01 | GSE175459 | GEO
Project description:Specific common and rare single nucleotide variants (SNVs) increase the likelihood of developing sporadic idiopathic pulmonary fibrosis (IPF). We performed target-enriched sequencing on three loci previously identified by a genome-wide association study to gain a deeper understanding of the full spectrum of IPF genetic risk and performed a two-stage case-control association study. A total of 1.7 Mb of DNA from 181 IPF patients was deep sequenced (>100×) across 11p15.5, 14q21.3 and 17q21.31 loci. Comparisons were performed against 501 unrelated controls and replication studies were assessed in 3968 subjects. 36 SNVs were associated with IPF susceptibility in the discovery stage (p<5.0×10-8). After meta-analysis, the strongest association corresponded to rs35705950 (p=9.27×10-57) located upstream from the mucin 5B gene (MUC5B). Additionally, a novel association was found for two co-inherited low-frequency SNVs (<5%) in MUC5AC, predicting a missense amino acid change in mucin 5AC (lowest p=2.27×10-22). Conditional and haplotype analyses in 11p15.5 supported the existence of an additional contribution of MUC5AC variants to IPF risk. This study reinforces the significant IPF associations of these loci and implicates MUC5AC as another key player in IPF susceptibility.
| S-EPMC6556557 | biostudies-literature
Project description: Not available
| S-EPMC7958523 | biostudies-literature
Project description:Idiopathic pulmonary fibrosis (IPF) is a disease related to AT2 cell. We used flow cytometry to analyze the epithelial component of donor and IPF lungs. From the live cells, we first excluded the CD31PosCD45Pos and then selected the EPCAMPos cells for further analysis using the human AT2 cell marker HTll-280 and the surface marker PD-L1. Our data indicate that, the bona fide differentiated AT2 cells (HTll-280High PD-L1Neg), were drastically reduced in the context of IPF. More interestingly, the number of HTll-280Low/Neg PD-L1High was drastically increased, suggesting that HTll-280Low PD-L1High epithelial cells could represent a pool of progenitors linked to the deficient AT2 lineage. The aim of this experiment is further characterization of AT2 and PDL1+ cells in donor and IPF.
2023-01-01 | GSE195770 | GEO
Project description:A subset of patients with hypersensitivity pneumonitis (HP) develop lung fibrosis that is clinically similar to idiopathic pulmonary fibrosis (IPF). To address the aetiological determinants of fibrotic HP, we investigated whether the common IPF genetic risk variants were also relevant in study subjects with fibrotic HP. Our findings indicate that common genetic variants in TERC, DSP, MUC5B and IVD were significantly associated with fibrotic HP. These findings provide support for a shared etiology and pathogenesis between fibrotic HP and IPF.
| S-EPMC9013199 | biostudies-literature
Project description:Idiopathic pulmonary fibrosis (IPF)
| PRJNA802122 | ENA
Project description:Idiopathic pulmonary fibrosis (IPF) is a devastating disease for patients and their loved ones. Since initial efforts to characterize this disease in the 1960s, understanding of IPF has evolved considerably. Such evolution has continually challenged prior diagnostic and treatment paradigms, ushering in an era of higher confidence diagnoses with less invasive procedures and more effective treatments. This review details how research and clinical experience over the past half century have led to a rethinking of IPF. Here, the evolution in understanding of IPF pathogenesis, diagnostic evaluation and treatment approach is discussed.
| S-EPMC9075032 | biostudies-literature