Leveraging global multi-ancestry meta-analysis in the study of idiopathic pulmonary fibrosis genetics.
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ABSTRACT:
SUBMITTER: Partanen JJ
PROVIDER: S-EPMC9903787 | biostudies-literature | 2022 Oct
REPOSITORIES: biostudies-literature
Publications
Leveraging global multi-ancestry meta-analysis in the study of idiopathic pulmonary fibrosis genetics.
Partanen Juulia J JJ Häppölä Paavo P Zhou Wei W Lehisto Arto A AA Ainola Mari M Sutinen Eva E Allen Richard J RJ Stockwell Amy D AD Leavy Olivia C OC Oldham Justin M JM Guillen-Guio Beatriz B Cox Nancy J NJ Hirbo Jibril B JB Schwartz David A DA Fingerlin Tasha E TE Flores Carlos C Noth Imre I Yaspan Brian L BL Jenkins R Gisli RG Wain Louise V LV Ripatti Samuli S Pirinen Matti M Laitinen Tarja T Kaarteenaho Riitta R Myllärniemi Marjukka M Daly Mark J MJ Koskela Jukka T JT
Cell genomics 20221012 10
The research of rare and devastating orphan diseases, such as idiopathic pulmonary fibrosis (IPF) has been limited by the rarity of the disease itself. The prognosis is poor-the prevalence of IPF is only approximately four times the incidence, limiting the recruitment of patients to trials and studies of the underlying biology. Global biobanking efforts can dramatically alter the future of IPF research. We describe a large-scale meta-analysis of IPF, with 8,492 patients and 1,355,819 population ...[more]
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Project description:Idiopathic pulmonary fibrosis (IPF) is the most common form of interstitial lung disease. IPF is a complex disease, with environmental and genetic factors variably contributing to disease susceptibility and outcomes. A host of common gene variants with modest effect size impart disease risk in patients with sporadic IPF, while rare variants with large effect size influence disease risk in those with familial interstitial pneumonia. In this review, we highlight several common and rare variants underpinning IPF risk and call attention to recently published studies informing our understanding of this risk.
| S-EPMC10538522 | biostudies-literature
Project description:Idiopathic pulmonary fibrosis (IPF) is a severe progressive interstitial lung disease with a prevalence of 2 to 29 per 100,000 of the world's population. Aging is a significant risk factor for IPF, and the mechanisms of aging (telomere depletion, genomic instability, mitochondrial dysfunction, loss of proteostasis) are involved in the pathogenesis of IPF. The pathogenesis of IPF consists of TGF-β activation, epithelial-mesenchymal transition, and SIRT7 expression decrease. Genetic studies have shown a role of mutations and polymorphisms in mucin genes (MUC5B), in the genes responsible for the integrity of telomeres (TERC, TERC, TINF2, DKC1, RTEL1, PARN), in surfactant-related genes (SFTPC, SFTPCA, SFTPA2, ABCA3, SP-A2), immune system genes (IL1RN, TOLLIP), and haplotypes of HLA genes (DRB1*15:01, DQB1*06:02) in IPF pathogenesis. The investigation of the influence of reversible epigenetic factors on the development of the disease, which can be corrected by targeted therapy, shows promise. Among them, an association of a number of specific microRNAs and long noncoding RNAs was revealed with IPF. Therefore, dysregulation of transposons, which serve as key sources of noncoding RNA and affect mechanisms of aging, may serve as a driver for IPF development. This is due to the fact that pathological activation of transposons leads to violation of the regulation of genes, in the epigenetic control of which microRNA originating from these transposons are involved (due to the complementarity of nucleotide sequences). Analysis of the MDTE database (miRNAs derived from Transposable Elements) allowed the detection of 12 different miRNAs derived in evolution from transposons and associated with IPF (miR-31, miR-302, miR-326, miR-335, miR-340, miR-374, miR-487, miR-493, miR-495, miR-630, miR-708, miR-1343). We described the relationship of transposons with TGF-β, sirtuins and telomeres, dysfunction of which is involved in the pathogenesis of IPF. New data on IPF epigenetic mechanisms can become the basis for improving results of targeted therapy of the disease using noncoding RNAs.
| S-EPMC9170936 | biostudies-literature
Project description:Genetic studies hold promise in helping to identify patients with early idiopathic pulmonary fibrosis (IPF). Recent studies using chest computed tomograms (CTs) in smokers and in the general population have demonstrated that imaging abnormalities suggestive of an early stage of pulmonary fibrosis are not uncommon and are associated with respiratory symptoms, physical examination abnormalities, and physiologic decrements expected, but less severe than those noted in patients with IPF. Similarly, recent genetic studies have demonstrated strong and replicable associations between a common promoter polymorphism in the mucin 5B gene (MUC5B) and both IPF and the presence of abnormal imaging findings in the general population. Despite these findings, it is important to note that the definition of early-stage IPF remains unclear, limited data exist to definitively connect abnormal imaging findings to IPF, and genetic studies assessing early-stage pulmonary fibrosis remain in their infancy. In this perspective we provide updated information on interstitial lung abnormalities and their connection to IPF. We summarize information on the genetics of pulmonary fibrosis by focusing on the recent genetic findings of MUC5B. Finally, we discuss the implications of these findings and suggest a roadmap for the use of genetics in the detection of early IPF.
| S-EPMC4225831 | biostudies-literature
Project description:BackgroundUnraveling the genetic background in a significant proportion of patients with both sporadic and familial IPF provided new insights into the pathogenic pathways of pulmonary fibrosis.AimThe aim of the present study is to overview the clinical significance of genetics in IPF.PerspectiveIt is fascinating to realize the so-far underestimated but dynamically increasing impact that genetics has on aspects related to the pathophysiology, accurate and early diagnosis, and treatment and prevention of this devastating disease. Genetics in IPF have contributed as no other in unchaining the disease from the dogma of a "a sporadic entity of the elderly, limited to the lungs" and allowed all scientists, but mostly clinicians, all over the world to consider its many aspects and "faces" in all age groups, including its co-existence with several extra pulmonary conditions from cutaneous albinism to bone-marrow and liver failure.ConclusionBy providing additional evidence for unsuspected characteristics such as immunodeficiency, impaired mucus, and surfactant and telomere maintenance that very often co-exist through the interaction of common and rare genetic variants in the same patient, genetics have created a generous and pluralistic yet unifying platform that could lead to the understanding of the injurious and pro-fibrotic effects of many seemingly unrelated extrinsic and intrinsic offending factors. The same platform constantly instructs us about our limitations as well as about the heritability, the knowledge and the wisdom that is still missing.
| S-EPMC9777433 | biostudies-literature
Project description:Idiopathic Pulmonary Fibrosis (IPF) is a chronic progressive lung disease that affects more than 5 million people worldwide with a steady increase in both incidence and mortality. There is currently no effective therapy and the median survival without transplant is 2-5 years. The etiological factor is unknown, but several observational and pathogenesis studies suggest that environmental agents may cause IPF. DNA methylation is a type of chemical modification of DNA such environmental and occupational factors, that can induced a changes in the regulation of biological processes and link to diseases such as a cancer. We hypothesize that the global changes in methylation patterns of IPF lungs caused by environmental factors. In this study we will identify the global methylation signatures of the IPF lung and to compare to methylation signature of lung cancer. The DNA methylation profiles of IPF lung tissue differs from control lung but it shares great similarity with that of lung cancer. Immunoprecipitated methylated DNA from 12 IPF lungs, 10 lung adenocarcinomas and 10 normal histology lungs obtained from the same group of adenocarcinoma patients was hybridized to Agilent human CpG Islands Microarrays. Only probes with a hybridization Tm value between 79 C and 93C were included in the analysis because these show higher quality signal. All probes were divided according to their Tm into 14 groups/bins differing by 1C. Probe signals in each bin were standardized to have an average of 0 and a standard deviation of 1. To work in a CpG island oriented manner, we scored each island for its likelihood to be methylated. For that purpose, each probe was mapped to the genome and the signals of the probes that were mapped to a single CpG island were averaged to obtain the islandM-bM-^@M-^Ys methylation score. Data analysis was performed using BRB-Array Tools and DAVID Bioinformatics Resources software packages.
2012-04-18 | E-GEOD-29895 | biostudies-arrayexpress
Project description:BACKGROUND:Idiopathic Pulmonary Fibrosis (IPF) is characterized by profound changes in the lung phenotype including excessive extracellular matrix deposition, myofibroblast foci, alveolar epithelial cell hyperplasia and extensive remodeling. The role of epigenetic changes in determining the lung phenotype in IPF is unknown. In this study we determine whether IPF lungs exhibit an altered global methylation profile. METHODOLOGY/PRINCIPAL FINDINGS:Immunoprecipitated methylated DNA from 12 IPF lungs, 10 lung adenocarcinomas and 10 normal histology lungs was hybridized to Agilent human CpG Islands Microarrays and data analysis was performed using BRB-Array Tools and DAVID Bioinformatics Resources software packages. Array results were validated using the EpiTYPER MassARRAY platform for 3 CpG islands. 625 CpG islands were differentially methylated between IPF and control lungs with an estimated False Discovery Rate less than 5%. The genes associated with the differentially methylated CpG islands are involved in regulation of apoptosis, morphogenesis and cellular biosynthetic processes. The expression of three genes (STK17B, STK3 and HIST1H2AH) with hypomethylated promoters was increased in IPF lungs. Comparison of IPF methylation patterns to lung cancer or control samples, revealed that IPF lungs display an intermediate methylation profile, partly similar to lung cancer and partly similar to control with 402 differentially methylated CpG islands overlapping between IPF and cancer. Despite their similarity to cancer, IPF lungs did not exhibit hypomethylation of long interspersed nuclear element 1 (LINE-1) retrotransposon while lung cancer samples did, suggesting that the global hypomethylation observed in cancer was not typical of IPF. CONCLUSIONS/SIGNIFICANCE:Our results provide evidence that epigenetic changes in IPF are widespread and potentially important. The partial similarity to cancer may signify similar pathogenetic mechanisms while the differences constitute IPF or cancer specific changes. Elucidating the role of these specific changes will potentially allow better understanding of the pathogenesis of IPF.
| S-EPMC3323629 | biostudies-literature
Project description:Idiopathic pulmonary fibrosis (IPF), the most common form of idiopathic interstitial pneumonia (IIP), is characterized by irreversible scarring of the lung parenchyma and progressive decline in lung function leading to eventual respiratory failure. The prognosis of IPF is poor with a median survival of 3-5 years after diagnosis and no curative medical therapies. Although the pathogenesis of IPF is not well understood, there is a growing body of evidence that genetic factors contribute to disease risk. Recent studies have identified common and rare genetic variants associated with both sporadic and familial forms of pulmonary fibrosis, with at least one-third of the risk for developing fibrotic IIP explained by common genetic variants. The IPF-associated genetic loci discovered to date are implicated in diverse biological processes, including alveolar stability, host defense, cell-cell barrier function, and cell senescence. In addition, some common variants have also been associated with distinct clinical phenotypes. Better understanding of how genetic variation plays a role in disease risk and phenotype could identify potential therapeutic targets and inform clinical decision-making. In addition, clinical studies should be designed controlling for the genetic backgrounds of subjects, since clinical outcomes and therapeutic responses may differ by genotype. Further understanding of these differences will allow the development of personalized approaches to the IPF management.
| S-EPMC5622313 | biostudies-literature
Project description:Purpose of reviewGenetics contributes substantially to the susceptibility to idiopathic pulmonary fibrosis (IPF). Genetic studies in sporadic and familial disease have identified several IPF-associated variants, mainly in telomere-related and surfactant protein genes.Here, we review the most recent literature on genetics of IPF and discuss how it may contribute to disease pathogenesis.Recent findingsRecent studies implicate genes involved in telomere maintenance, host defence, cell growth, mammalian target of rapamycin signalling, cell-cell adhesion, regulation of TGF-β signalling and spindle assembly as biological processes involved in the pathogenesis of IPF. Both common and rare genetic variants contribute to the overall risk of IPF; however, while common variants (i.e. polymorphisms) account for most of the heritability of sporadic disease, rare variants (i.e. mutations), mainly in telomere-related genes, are the main contributors to the heritability of familial disease. Genetic factors are likely to also influence disease behaviour and prognosis. Finally, recent data suggest that IPF shares genetic associations - and probably some pathogenetic mechanisms - with other fibrotic lung diseases.SummaryCommon and rare genetic variants are associated with susceptibility and prognosis of IPF. However, many of the reported variants fall in noncoding regions of the genome and their relevance to disease pathobiology remains to be elucidated.
| S-EPMC10470435 | biostudies-literature
Project description:BackgroundIdiopathic pulmonary fibrosis (IPF) is a progressive debilitating lung disease with considerable morbidity. Heterogeneity in epidemiologic studies means the full impact of the disease is unclear.MethodsA targeted literature search for population-based, observational studies reporting incidence and/or prevalence of IPF from January 2009 to April 2020 was conducted. Identified studies were aggregated by country. For countries with multiple publications, a weighted average was determined. Incidence and prevalence data were adjusted for between-study differences where possible. The final model included adjusted estimates of incidence and prevalence per 10,000 of the population with 95% confidence intervals. As prevalence estimates vary depending on the definitions used, estimates were based on a specific case definition of IPF.ResultsOverall, 22 studies covering 12 countries met the inclusion criteria, with 15 reporting incidence and 18 reporting prevalence estimates. The adjusted incidence estimates (per 10,000 of the population) ranged from 0.35 to 1.30 in Asia-Pacific countries, 0.09 to 0.49 in Europe, and 0.75 to 0.93 in North America. Unadjusted and adjusted incidence estimates were consistent. The adjusted prevalence estimates ranged from 0.57 to 4.51 in Asia-Pacific countries, 0.33 to 2.51 in Europe, and 2.40 to 2.98 in North America. South Korea had the highest incidence and prevalence estimates. When prevalence estimates were compared to country-specific rare disease thresholds, IPF met the definition of a rare disease in all countries except South Korea. There were notable geographic gaps for IPF epidemiologic data.ConclusionsDue to differences in study methodologies, there is worldwide variability in the reported incidence and prevalence of IPF. Based on the countries included in our analysis, we estimated the adjusted incidence and prevalence of IPF to be in the range of 0.09-1.30 and 0.33-4.51 per 10,000 persons, respectively. According to these prevalence estimates, IPF remains a rare disease. For consistency, future epidemiologic studies of IPF should take age, sex, smoking status, and the specificity of case definitions into consideration.
| S-EPMC8261998 | biostudies-literature
Project description:Idiopathic Pulmonary Fibrosis (IPF) is a chronic progressive lung disease that affects more than 5 million people worldwide with a steady increase in both incidence and mortality. There is currently no effective therapy and the median survival without transplant is 2-5 years. The etiological factor is unknown, but several observational and pathogenesis studies suggest that environmental agents may cause IPF. DNA methylation is a type of chemical modification of DNA such environmental and occupational factors, that can induced a changes in the regulation of biological processes and link to diseases such as a cancer. We hypothesize that the global changes in methylation patterns of IPF lungs caused by environmental factors. In this study we will identify the global methylation signatures of the IPF lung and to compare to methylation signature of lung cancer. The DNA methylation profiles of IPF lung tissue differs from control lung but it shares great similarity with that of lung cancer.
2012-04-19 | GSE29895 | GEO