Risk Of Idiopathic Pulmonary Fibrosis Research Articles

Gene polymorphisms and risk of idiopathic pulmonary fibrosis: a systematic review and meta-analysis.

Idiopathic pulmonary fibrosis (IPF) has been widely hypothesized to occur as a result of an interplay between a nexus of environmental and genetic risk factors. However, not much is known about the genetic aspect of this disease. The objective of this review was to identify the genetic polymorphisms associated with the risk of developing IPF. We searched PubMed, EBSCO CINAHL Plus, Web of Science, and Wiley Cochrane Library databases for studies on risk factors of IPF published between March 2000 and November 2023. Studies with an IPF diagnosis based only on the American Thoracic Society and the European Respiratory Society guidelines were included. Thirty-one case-control studies were included with 3997 IPF and 20,925 non-IPF subjects. Two of the studies enrolled biopsy-proven IPF patients; 13 studies diagnosed IPF on the basis of clinical and high-resolution computed tomography (HRCT) findings; and 14 studies diagnosed based on both biopsy and clinical and HRCT findings. 16 studies with MUC5B rs35705950, IL-4 rs2243250, IL-4 rs2070874, and tumor necrosis factor α (TNFα)-308 were eligible for meta-analysis. The allele contrast model (T versus G) for MUC5B rs35705950 revealed statistically significant association of T allele with the risk of IPF [odds ratio (OR) 3.84, 95% confidence interval (CI) 3.20 to 4.61, adjusted p<0.0001), as was the allele contrast model for Asian (OR 2.83, 95% CI 1.51 to 5.32, adjusted p=0.009) and Caucasian (OR 4.11, 95% CI 3.56 to 4.75, adjusted p<0.0001). The allele contrast models for IL-4 rs2243250, IL-4 rs2070874, and TNFα-308 did not demonstrate any significant association with IPF. This review suggests an association of MUC5B rs35705950 T allele with the risk of developing IPF. To our knowledge, this study is the first to aggregate several genetic polymorphisms associated with IPF.

Contemporary Concise Review 2023: Interstitial lung disease.

In this review, we have discussed several important developments in 2023 in Interstitial Lung Disease (ILD). The association of pollution with genetic predispositions increased the risk of Idiopathic Pulmonary Fibrosis (IPF). An interesting comorbidity of malnutrition was not adequately recognized in ILD. Novel genes have been identified in IPF involving predominantly short telomere length and surfactant protein production leading to alveolar epithelial cell dysfunction. Genetics also predicted progression in IPF. Crosstalk between vascular endothelial cells and fibroblasts in IPF mediated by bone morphogenic protein signalling may be important for remodelling of the lung. A novel modality for monitoring of disease included the 4-min gait speed. New treatment modalities include inhaled pirfenidone, efzofitimod, for sarcoidosis, and earlier use of immunosuppression in connective tissue disease-ILD.

Exploring the Mechanisms and Preventive Strategies for the Progression from Idiopathic Pulmonary Fibrosis to Lung Cancer: Insights from Transcriptomics and Genetic Factors.

Background: Idiopathic pulmonary fibrosis (IPF) leads to excessive fibrous tissue in the lungs, increasing the risk of lung cancer (LC) due to heightened fibroblast activity. Advances in nucleotide point mutation studies offer insights into fibrosis-to-cancer transitions. Methods: A two-sample Mendelian randomization (TSMR) approach was used to explore the causal relationship between IPF and LC. A weighted gene co-expression network analysis (WGCNA) identified shared gene modules related to immunogenic cell death (ICD) from transcriptomic datasets. Machine learning selected key genes, and a multi-layer perceptron (MLP) model was developed for IPF prediction and diagnosis. SMR and PheWAS were used to assess the expression of key genes concerning IPF risk. The impact of core genes on immune cells in the IPF microenvironment was explored, and in vivo experiments were conducted to examine the progression from IPF to LC. Results: The TSMR approach indicated a genetic predisposition for IPF progressing to LC. The predictive model, which includes eight ICD key genes, demonstrated a strong predictive capability (AUC = 0.839). The SMR analysis revealed that the elevated expression of MS4A4A was associated with an increased risk of IPF (OR = 1.275, 95% CI: 1.029-1.579; p = 0.026). The PheWAS did not identify any significant traits linked to MS4A4A expression. The rs9265808 locus in MS4A4A was identified as a susceptibility site for the progression of IPF to LC, with mutations potentially reprogramming lung neutrophils and increasing the LC risk. In vivo studies suggested MS4A4A as a promising therapeutic target. Conclusions: A causal link between IPF and LC was established, an effective prediction model was developed, and MS4A4A was highlighted as a therapeutic target to prevent IPF from progressing to LC.

FAM13A polymorphism is associated with a usual interstitial pneumonia pattern in patients with systemic sclerosis-associated interstitial lung disease.

The MUC5B promoter single nucleotide polymorphism (SNP) rs35705950 has been associated with idiopathic pulmonary fibrosis (IPF) and rheumatoid arthritis (RA)-related interstitial lung disease (ILD), but not with systemic sclerosis (SSc)-ILD. We hypothesized that the MUC5B promoter polymorphism or other IPF susceptibility loci are associated with an increased risk for the uncommon SSc-usual interstitial pneumonia (UIP) endophenotype, rather than SSc-ILD in general. We performed a cross-sectional study of SSc-ILD patients from 4 US Scleroderma Programs to investigate the frequency of MUC5B rs35705950 and 12 additional IPF susceptibility loci. SSc-ILD patients were stratified by high resolution chest CT (HRCT) imaging findings into UIP and non-UIP groups. Analysis of HRCTs performed by a thoracic radiologist blinded to participants' characteristics classified each scan as definite UIP, probable UIP, indeterminate, or alternative diagnosis, according to American Thoracic Society criteria. Four-hundred eighty-nine SSc-ILD patients were included; 80% were female and 75% were White. Twenty-three (4.7%) patients had a definite UIP pattern. The MUC5B SNP rs35705950 was not associated with a definite UIP pattern in SSc-ILD. In contrast, patients carrying 2 copies of the IPF risk gene FAM13A minor allele rs2609255 had significantly higher odds of a definite UIP pattern compared with the other patterns (OR 3.40, 95% CI 1.19-9.70), and compared with an alternative diagnosis (OR 3.65, 95% CI 1.25-10.65). We demonstrated a novel association between FAM13A and SSc-UIP. Contrary to IPF and RA-ILD, the MUC5B promoter polymorphism was not associated with a definite UIP pattern in SSc-ILD.

Rare variants and survival of patients with idiopathic pulmonary fibrosis.

The clinical course of idiopathic pulmonary fibrosis (IPF) is highly variable and unpredictable, with multiple genetic variants influencing IPF outcomes. Notably, rare pathogenic variants in telomere-related genes are associated with poorer clinical outcomes in these patients. Here we assessed whether rare qualifying variants (QVs) in monogenic adult-onset pulmonary fibrosis (PF) genes are associated with IPF survival. Using polygenic risk scores (PRS), we also evaluated the influence of common IPF risk variants in individuals carrying these QVs. We identified QVs in telomere and non-telomere genes linked to monogenic PF forms using whole-genome sequences (WGS) from 888 Pulmonary Fibrosis Foundation Patient Registry (PFFPR) individuals. We also derived a PRS for IPF (PRS-IPF) from 19 previously published common sentinel IPF variants. Using regression models, we then examined the mutual relationships of QVs and PRS-IPF and their association with survival. Validation of results was sought in WGS from an independent IPF study (PROFILE, n=472), and results from the two cohorts were meta-analyzed. Carriers of QVs in monogenic adult-onset PF genes, representing nearly 1 out of 6 IPF patients, were associated with lower PRS-IPF (Odds Ratio [OR]: 1.79; 95% Confidence Interval [CI]: 1.15-2.81; p=0.010) and shorter survival (Hazard Ratio [HR]: 1.53; 95% CI: 1.12-2.10; p=7.3×10 -3 ). Notably, carriers of pathogenic variants at telomere genes showed the strongest association with survival (HR: 1.76; 95% CI: 1.13-2.76; p=0.013). The meta-analysis of the results showed a consistent direction of effect across both cohorts. We revealed the opposite effects of QVs and PRS-IPF on IPF survival. Thus, a distinct IPF molecular subtype might be defined by QVs in monogenic adult-onset PF genes. Assessing the carrier status for QVs and modelling PRS-IPF promises to further contribute to predicting disease progression among IPF patients.

Physical activity and idiopathic pulmonary fibrosis: A prospective cohort study in UK Biobank and Mendelian randomization analyses

IntroductionThe impact of physical activity on the incidence of idiopathic pulmonary fibrosis (IPF) remains less well studied. This study aimed to investigate the relationship between moderate-to-vigorous physical activity (MVPA) and the risk of developing IPF. MethodsWe analyzed data from a prospective cohort study within the UK Biobank involving 502,476 participants. Participants were categorized as meeting or not meeting the 2017 UK Physical Activity Guidelines (150 min of moderate activity or 75 min of vigorous activity per week). The cumulative incidence and hazard ratios (HRs) for IPF were analyzed using the Kaplan–Meier method, log-rank test, and Cox regression. Two-sample Mendelian randomization (MR) analyses were performed to identify potential causal links between physical activity and IPF risk. ResultsOver a median of 12.2 y follow-up, we identified 1,639 incident IPF cases and 395,172 controls. Individuals who met the physical activity guidelines had a significantly lower risk of IPF than those who did not meet the guidelines (adjusted HR = 0.843, 95 % confidence interval [CI] = 0.765–0.930).The cumulative incidence of IPF was lower in the meeting guideline group than in the nonmeeting guideline group (Log-rank P = 0.0019). Two-sample MR analysis revealed that a 1-standard deviation increase in moderate-to-vigorous physical activity was linked to a reduced IPF risk (odds ratio [OR] = 0.17, 95 % CIs = 0.04 to 0.81, P = 0.026). Moreover, an increase in the number of days per week of moderate physical activity was genetically correlated with decreased IPF risk (OR = 0.32, 95 % CIs = 0.15–0.70, P = 0.003). ConclusionHigher levels of moderate-to-vigorous physical activity are causally associated with a significant reduction in the risk of developing IPF.

The association between testosterone, estradiol, estrogen sulfotransferase and idiopathic pulmonary fibrosis: a bidirectional mendelian randomization study

BackgroundThe causal relationships between testosterone, estradiol, estrogen sulfotransferase, and idiopathic pulmonary fibrosis (IPF) are not well understood. This study employs a bidirectional two-sample Mendelian Randomization (MR) approach to explore these associations.MethodsAll genetic data utilized in our study were obtained from the IEU Open GWAS project. For the MR analysis, we employed the inverse variance weighted (IVW), MR-Egger, and weighted median methods to assess the causal relationships. We also conducted a multivariate MR (MVMR) analysis, with adjustments made for smoking. To ensure the robustness of our findings, sensitivity analyses were conducted using Cochran’s Q test, MR-Egger regression, the MR-PRESSO global test, and the leave-one-out method.ResultsGenetically predicted increases in serum testosterone levels by one standard deviation were associated with a 58.7% decrease in the risk of developing IPF (OR = 0.413, PIVW=0.029, 95% CI = 0.187 ∼ 0.912), while an increase in serum estrogen sulfotransferase by one standard deviation was associated with a 32.4% increase in risk (OR = 1.324, PIVW=0.006, 95% CI = 1.083 ∼ 1.618). No causal relationship was found between estradiol (OR = 1.094, PIVW=0.735, 95% CI = 0.650 ∼ 1.841) and the risk of IPF. Reverse MR analysis did not reveal any causal relationship between IPF and testosterone (OR = 1.001, PIVW=0.51, 95% CI = 0.998 ∼ 1.004), estradiol (OR = 1.001, PIVW=0.958, 95% CI = 0.982 ∼ 1.019), or estrogen sulfotransferase (OR = 0.975, PIVW=0.251, 95% CI = 0.933 ∼ 1.018). The MVMR analysis demonstrated that the association between testosterone (OR = 0.442, P = 0.037, 95% CI = 0.205 ∼ 0.953) and estrogen sulfotransferase (OR = 1.314, P = 0.001, 95% CI = 1.118 ∼ 1.545) and the risk of IPF persisted even after adjusting for smoking.ConclusionsIncreased serum levels of testosterone are associated with a reduced risk of IPF, while increased levels of serum estrogen sulfotransferase are associated with an increased risk. No causal relationship was found between estradiol and the development of IPF. No causal relationship was identified between IPF and testosterone, estradiol, or estrogen sulfotransferase.

Genetic Underpinnings of Pulmonary Fibrosis: An Overview.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive disorder, in which genetic and environmental factors are involved in disease onset. Although, by definition, the disease is considered idiopathic in nature, evidence-based studies have indicated familial cases of pulmonary fibrosis, in which genetic factors contribute to IPF pathogenesis. Both common as well as rare genetic variants are associated with sporadic as well as familial forms of IPF. Although clinical inferences of the genetic association have still not been explored properly, observation-based studies have found a genotypic influence on disease development and outcome. Based on genetic studies, individuals with a risk of IPF can be easily identified and can be classified more precisely. Identification of genetic variants also helps to develop more effective therapeutic approaches. Further comprehensive research is needed to get a blueprint of IPF pathogenesis. The rapidly evolving field of genetic engineering and molecular biology, along with the bioinformatics approach, will possibly explore a new horizon very soon to achieve this goal.

Deciphering the role of oxidative stress genes in idiopathic pulmonary fibrosis: a multi-omics mendelian randomization approach.

Oxidative stress (OS) is crucial in idiopathic pulmonary fibrosis (IPF) pathogenesis, with its genes potentially acting as both causes and consequences of the disease. We identified OS-related genes from GeneCards and performed a meta-analysis on pulmonary transcriptome datasets to discover differentially expressed genes (DEGs) related to OS in IPF. We integrated this data with the largest available IPF GWAS summaries, expression quantitative trait loci (eQTLs), and DNA methylation QTLs (mQTLs) from blood. This approach aimed to identify blood OS genes and regulatory elements linked to IPF risk, incorporating the latest pulmonary eQTLs and bronchoalveolar lavage fluid microbial QTLs (bmQTLs) for a comprehensive view of gene-lung microbiota interactions through SMR and colocalization analyses. Sensitivity analyses were conducted using two additional mendelian randomization (MR) methods. Meta-analysis revealed 1090 differentially expressed OS genes between IPF patients and controls. Integration with IPF GWAS, eQTL, and mQTL data identified key genes and regulatory elements involved in IPF pathogenesis, highlighting the role of specific genes such as KCNMA1 and SLC22A5 in modulating IPF risk through epigenetic mechanisms. Colocalization analysis further identified potential interactions between gene expression and lung microbiota. Our findings elucidate the complex interplay between OS genes and IPF, suggesting potential therapeutic targets and highlighting the importance of considering epigenetic and microbial interactions in the disease's etiology and progression.

IL6 receptor inhibitors: exploring the therapeutic potential across multiple diseases through drug target Mendelian randomization.

High interleukin-6 levels correlate with diseases like cancer, autoimmune disorders, and infections. IL-6 receptor inhibitors (IL-6Ri), used for rheumatoid arthritis and COVID-19, may have wider uses. We apply drug-target Mendelian Randomization (MR) to study IL-6Ri's effects. To simulate the effects of genetically blocking the IL-6R, we selected single nucleotide polymorphisms (SNPs) within or near the IL6R gene that show significant genome-wide associations with C-reactive protein. Using rheumatoid arthritis and COVID-19 as positive controls, our primary research outcomes included the risk of asthma, asthmatic pneumonia, cor pulmonale, non-small cell lung cancer, small cell lung cancer, Parkinson's disease, Alzheimer's disease, ulcerative colitis, Crohn's disease, systemic lupus erythematosus, type 1 diabetes, and type 2 diabetes. The Inverse Variance Weighted (IVW) method served as our principal analytical approach, with the hypotheses of MR being evaluated through sensitivity and colocalization analyses. Additionally, we conducted Bayesian Mendelian Randomization analyses to minimize confounding and reverse causation biases to the greatest extent possible. IL-6 inhibitors significantly reduced the risk of idiopathic pulmonary fibrosis (OR= 0.278, 95% [CI], 0.138-0.558; P <0.001), Parkinson's disease (OR = 0.354, 95% CI, 0.215-0.582; P <0.001), and positively influenced the causal relationship with Type 2 diabetes (OR = 0.759, 95% CI, 0.637-0.905; P = 0.002). However, these inhibitors increased the risk for asthma (OR = 1.327, 95% CI, 1.118-1.576; P = 0.001) and asthmatic pneumonia (OR = 1.823, 95% CI, 1.246-2.666; P = 0.002). The causal effect estimates obtained via the BWMR method are consistent with those based on the IVW approach. Similarly, sIL-6R also exerts a significant influence on these diseases.Diseases such as Alzheimer's disease, Crohn's disease, pulmonary heart disease, systemic lupus erythematosus, Type 1 diabetes, Non-small cell lung cancer and ulcerative colitis showed non-significant associations (p > 0.05) and were excluded from further analysis. Similarly, Small cell lung cancer were excluded due to inconsistent results. Notably, the colocalization evidence for asthmatic pneumonia (coloc.abf-PPH4 = 0.811) robustly supports its association with CRP. The colocalization evidence for Parkinson's disease (coloc.abf-PPH4 = 0.725) moderately supports its association with CRP. IL-6Ri may represent a promising therapeutic avenue for idiopathic pulmonary fibrosis, Parkinson's disease, and Type 2 diabetes.

The impact of psoriasis on idiopathic pulmonary fibrosis: atwo-sample Mendelian randomization study.

The association between psoriasis and pulmonary fibrosis has been reported in observational studies. However, the association is vulnerable to bias from using immunosuppressants such as methotrexate, which can cause fibrosis in multiple organs. The present study is to investigate whether psoriasis could independently increase the risk of idiopathic pulmonary fibrosis (IPF). We conducted a two-sample Mendelian randomization (MR) study using summary statistics from genome-wide association studies. The random-effects inverse variance weighted analysis was used as the primary method. Some secondary analyses were further performed, including a sensitivity analysis using a genetic instrument that excluded extended single nucleotide polymorphisms (SNPs) in the major histocompatibility complex (MHC) gene region. Our study included 9267 cases and 364,071 controls for psoriasis, 2018 cases, and 373,064 controls for IPF of European ancestry, respectively. Genetically predicted psoriasis was associated with a higher risk of IPF (odds ratio (OR), 1.14; 95% confidence interval (CI), 1.08-1.22; P < 0.001). Sensitivity analyses did not uncover any statistically significant evidence of bias resulting from pleiotropy or the genetic instruments, including SNPs in the MHC gene region. These MR analyses support that genetically predicted psoriasis was associated with the risk of IPF, implying that pulmonary fibrosis in patients with psoriasis should not be neglected, even if they are not receiving immunosuppressant therapy.

Exploring the causal effect between lipid-modifying drugs and idiopathic pulmonary fibrosis: a drug-target Mendelian randomization study

BackgroundIdiopathic pulmonary fibrosis (IPF) is a respiratory disorder of obscure etiology and limited treatment options, possibly linked to dysregulation in lipid metabolism. While several observational studies suggest that lipid-lowering agents may decrease the risk of IPF, the evidence is inconsistent. The present Mendelian randomization (MR) study aims to determine the association between circulating lipid traits and IPF and to assess the potential influence of lipid-modifying medications for IPF.MethodsSummary statistics of 5 lipid traits (high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglyceride, apolipoprotein A, and apolipoprotein B) and IPF were sourced from the UK Biobank and FinnGen Project Round 10. The study’s focus on lipid-regulatory genes encompassed PCSK9, NPC1L1, ABCG5, ABCG8, HMGCR, APOB, LDLR, CETP, ANGPTL3, APOC3, LPL, and PPARA. The primary effect estimates were determined using the inverse-variance-weighted method, with additional analyses employing the contamination mixture method, robust adjusted profile score, the weighted median, weighted mode methods, and MR-Egger. Summary-data-based Mendelian randomization (SMR) was used to confirm significant lipid-modifying drug targets, leveraging data on expressed quantitative trait loci in relevant tissues. Sensitivity analyses included assessments of heterogeneity, horizontal pleiotropy, and leave-one-out methods.ResultsThere was no significant effect of blood lipid traits on IPF risk (all P＞0.05). Drug-target MR analysis indicated that genetic mimicry for inhibitor of NPC1L1, PCSK9, ABCG5, ABCG8, and APOC3 were associated with increased IPF risks, with odds ratios (ORs) and 95% confidence intervals (CIs) as follows: 2.74 (1.05–7.12, P = 0.039), 1.36 (1.02–1.82, P = 0.037), 1.66 (1.12–2.45, P = 0.011), 1.68 (1.14–2.48, P = 0.009), and 1.42 (1.20–1.67, P = 3.17×10-5), respectively. The SMR method identified a significant association between PCSK9 gene expression in whole blood and reduced IPF risk (OR = 0.71, 95% CI: 0.50–0.99, P = 0.043). Sensitivity analyses showed no evidence of bias.ConclusionsSerum lipid traits did not significantly affect the risk of idiopathic pulmonary fibrosis. Drug targets MR studies examining 12 lipid-modifying drugs indicated that PCSK9 inhibitors could dramatically increase IPF risk, a mechanism that may differ from their lipid-lowering actions and thus warrants further investigation.

Mendelian randomization study on the causal effect of herpes simplex virus infection on idiopathic pulmonary fibrosis

ABSTRACT Background Previous observational studies have shown that past infection of herpes simplex virus (HSV) is associated with idiopathic pulmonary fibrosis (IPF). The present study aims to identify the causal link between HSV infection (exposure factor) and IPF (outcome factor). Research design and methods To date, the largest publicly available genome-wide association study (GWAS) for HSV infection (1,595 cases and 211,856 controls from Finnish ancestry) and for IPF (1,028 cases and 196,986 controls from Finnish ancestry) were used to perform this two-sample Mendelian randomization (MR) study. Results We found no significant pleiotropy or heterogeneity of all selected nine HSV infection-associated genetic instrumental variants (IVs) in IPF GWAS dataset. Interestingly, we found that as HSV infection genetically increased, IPF risk increased based on an inverse-variance weighted (IVW) analysis (odds ratio [OR] = 1.280, 95% confidence interval [CI]: 1.048–1.563; p = 0.015) and weighted median (OR = 1.321, 95% CI: 1.032–1.692; p = 0.027). Conclusions Our analysis suggests a causal effect of genetically increased HSV infection on IPF risk. Thus, HSV infection may be a potential risk factor for IPF.

Smoking and idiopathic pulmonary fibrosis: A meta-analysis.

In this study, we aimed to systematically explore the relationship between smoking and idiopathic pulmonary fibrosis (IPF). The PubMed, Web of Science and Embase databases were searched to systematically identify eligible studies. The Newcastle‒Ottawa Quality Assessment Scale (NOS) was used to evaluate the quality of the selected studies. The pooled odds ratio (OR) and survival hazard ratio (HR) were calculated with a random effects model using Stata 16.0 software. Thirty studies were enrolled. All of the included studies were considered to have intermediate or high quality. Nine studies were suitable for meta-analysis of ORs, and twenty-one studies were suitable for meta-analysis of survival HR. The pooled analysis revealed a significant difference in the risk of IPF between the smoking group and the never smoking group (OR 1.71, 95% CI 1.27-2.30, P < 0.001), indicating that smoking is a risk factor for IPF. When analyzing pooled survival HRs, never smoking was compared to former smoking or current smoking. Former smoking was shown to be a poor prognostic factor for IPF (HR 1.43, 95% CI 1.18-1.74, P < 0.001), but current smoking was not a significant factor. Our results indicated that smoking is a risk factor for IPF patients. In this study, we mainly concluded that smoking is a risk factor for IPF and that former smoking is a poor prognostic factor for IPF. To our knowledge, this is the first meta-analysis report focusing on the association between smoking per se and IPF. Through our current study, we hope to further raise awareness of the relationship between smoking and IPF.

Mendelian randomisation highlights type 1 diabetes as a causal determinant of idiopathic pulmonary fibrosis

BackgroundIt is unclear whether type 1 diabetes (T1D) causes idiopathic pulmonary fibrosis (IPF), despite observational research linking the two conditions. Therefore, our study aimed to examine the causal link between T1D and the likelihood of IPF by employing the Mendelian randomization (MR) technique of two-sample Mendelian randomization.MethodsUsing data from two genome-wide association studies (GWAS) with European ancestry, we performed a two-sample MR analysis. These studies involved 18,856 individuals (6,683 cases and 12,173 controls) for T1D and 198,014 individuals (10,028 cases and 196,986 controls) for IPF. We utilized inverse-variance weighted (IVW) analysis as our main approach to determine the association between the risk of IPF and T1D. To evaluate multidirectionality, the MR-Egger regression test was utilized, whereas heterogeneity was assessed using Cochran’s Q test. Additionally, a leave-one-out analysis was performed to assess the reliability of the results.Results38 SNPs linked to T1D were employed as instrumental variables (IVs). Multiple MR methods yielded consistent results, and the MR analysis reveals a significant and positive causal impact of T1D on IPF (MR-IVW, odds ratio [OR] = 1.128, 95% confidence interval [CI] 1.034–1.230; P = 0.006). The limitations of the study include the lack of data from non-European groups and the inability to rule out the possibility of small links. Larger MR experiments are necessary to investigate minute impacts.ConclusionsThe results of this study provide evidence that T1D contributes to the onset and advancement of IPF. This finding may provide important insights into the cause of IPF and possible treatments in the future.

The causal relationship between genetically predicted blood metabolites and idiopathic pulmonary fibrosis: A bidirectional two-sample Mendelian randomization study.

Numerous metabolomic studies have confirmed the pivotal role of metabolic abnormalities in the development of idiopathic pulmonary fibrosis (IPF). Nevertheless, there is a lack of evidence on the causal relationship between circulating metabolites and the risk of IPF. The potential causality between 486 blood metabolites and IPF was determined through a bidirectional two-sample Mendelian randomization (TSMR) analysis. A genome-wide association study (GWAS) involving 7,824 participants was performed to analyze metabolite data, and a GWAS meta-analysis involving 6,257 IPF cases and 947,616 control European subjects was conducted to analyze IPF data. The TSMR analysis was performed primarily with the inverse variance weighted model, supplemented by weighted mode, MR-Egger regression, and weighted median estimators. A battery of sensitivity analyses was performed, including horizontal pleiotropy assessment, heterogeneity test, Steiger test, and leave-one-out analysis. Furthermore, replication analysis and meta-analysis were conducted with another GWAS dataset of IPF containing 4,125 IPF cases and 20,464 control subjects. Mediation analyses were used to identify the mediating role of confounders in the effect of metabolites on IPF. There were four metabolites associated with the elevated risk of IPF, namely glucose (odds ratio [OR] = 2.49, 95% confidence interval [95%CI] = 1.13-5.49, P = 0.024), urea (OR = 6.24, 95% CI = 1.77-22.02, P = 0.004), guanosine (OR = 1.57, 95%CI = 1.07-2.30, P = 0.021), and ADpSGEGDFXAEGGGVR (OR = 1.70, 95%CI = 1.00-2.88, P = 0.0496). Of note, the effect of guanosine on IPF was found to be mediated by gastroesophageal reflux disease. Reverse Mendelian randomization analysis displayed that IPF might slightly elevate guanosine levels in the blood. Conclusively, hyperglycemia may confer a promoting effect on IPF, highlighting that attention should be paid to the relationship between diabetes and IPF, not solely to the diagnosis of diabetes. Additionally, urea, guanosine, and ADpSGEGDFXAEGGGVR also facilitate the development of IPF. This study may provide a reference for analyzing the potential mechanism of IPF and carry implications for the prevention and treatment of IPF.

Association between statin use and the risk for idiopathic pulmonary fibrosis and its prognosis: a nationwide, population-based study

Given the pleiotropic effects of statins beyond their lipid-lowering effects, there have been attempts to evaluate the role of statin therapy in IPF, but they have shown inconclusive results. Data from the National Health Insurance Service (NHIS) database of South Korea were used to investigate the effects of statin therapy on IPF. The IPF cohort consisted of a total of 10,568 patients who were newly diagnosed with IPF between 2010 and 2017. These patients were then matched in a 1:3 ratio to 31,704 subjects from a control cohort without IPF, with matching based on age and sex. A case–control study was performed to evaluate the association between statin use and the risk for IPF, and the multivariable analysis revealed that statin use was associated with a lower risk for IPF (adjusted OR 0.847, 95% CI 0.800–0.898). Using the IPF cohort, we also evaluated whether statin use at the time of diagnosis was associated with future clinical outcomes. The statin use at the time of IPF diagnosis was associated with improved overall survival (adjusted HR 0.779, 95% CI 0.709–0.856). Further prospective studies are needed to clarify the role of statin therapy in IPF.

Quantitative Analysis of Lung Shape in Idiopathic Pulmonary Fibrosis: Insights Into Disease- and Age-Associated Patterns

Rationale and objectivesFibrotic scarring in idiopathic pulmonary fibrosis (IPF) typically develops first in the posterior-basal lung tissue before advancing to involve more of the lung. The complexity of lung shape in the costo-diaphragmatic region has been proposed as a potential factor in this regional development. Intrinsic and disease-related shape could therefore be important for understanding IPF risk and its staging. We hypothesised that lung and lobe shape in IPF would have important differences from controls. Materials and MethodsA principal component (PC) analysis was used to derive a statistical shape model (SSM) of the lung for a control cohort aged > 50 years (N=39), using segmented lung and fissure surface data from CT imaging. Individual patient shape models derived for baseline (N=18) and follow-up (N=16) CT scans in patients with IPF were projected to the SSM to describe shape as the sum of the SSM average and weighted PC modes. Associations between the first four PC shape modes, lung function, percentage of fibrosis (fibrosis%) and pulmonary vessel-related structures (PVRS%), and other tissue metrics were assessed and compared between the two cohorts. ResultsShape was different between IPF and controls (p<0.05 for all shape modes), with IPF shape forming a distinct shape cluster. Shape had a negative relationship with age in controls (p = 0.013), but a positive relationship with age in IPF (p = 0.026). Some features of shape changed on follow-up. Shape in IPF was associated with fibrosis% (p<0.05) and PVRS% (p<0.05). ConclusionQuantitative comparison of lung and lobe shape in IPF with controls of a similar age reveals shape differences that are strongly associated with age and percent fibrosis. The clustering of IPF cohort shape suggests that it could be an important feature to describe disease.

Diabetes mellitus and idiopathic pulmonary fibrosis: a Mendelian randomization study

BackgroundThe question as to whether or not diabetes mellitus increases the risk of idiopathic pulmonary fibrosis (IPF) remains controversial. This study aimed to investigate the causal association between type 1 diabetes (T1D), type 2 diabetes (T2D), and IPF using Mendelian randomization (MR) analysis.MethodsWe used two-sample univariate and multivariate MR (MVMR) analyses to investigate the causal relationship between T1D or T2D and IPF. We obtained genome-wide association study (GWAS) data for T1D and T2D from the European Bioinformatics Institute, comprising 29,652 T1D samples and 101,101 T1D single nucleotide polymorphisms (SNPs) and 655,666 T2D samples and 5,030,727 T2D SNPs. We also used IPF GWAS data from the FinnGen Biobank comprising 198,014 IPF samples and 16,380,413 IPF SNPs. All cases and controls in these datasets were derived exclusively from European populations. In the univariate MR analysis, we employed inverse variance-weighted (IVW), weighted median (WM), and MR-Egger regression methods. For the MVMR analysis, we used the multivariate IVW method primarily, and supplemented it with multivariate MR-Egger and multivariate MR- least absolute shrinkage and selection operator methods. Heterogeneity tests were conducted using the MR-IVW and MR-Egger regression methods, whereas pleiotropic effects were assessed using the MR-Egger intercept. The results of MR and sensitivity analyses were visualized using forest, scatter, leave-one-out, and funnel plots.ResultsUnivariate MR revealed a significant causal relationship between T1D and IPF (OR = 1.118, 95% CI = 1.021–1.225, P = 0.016); however, no significant causal relationship was found between T2D and IPF (OR = 0.911, 95% CI = 0.796–1.043, P = 0.178). MVMR analysis further confirmed a causal association between T1D and IPF (OR = 1.133, 95% CI = 1.011–1.270, P = 0.032), but no causal relationship between T2D and IPF (OR = 1.009, 95% CI = 0.790–1.288, P = 0.950). Sensitivity analysis results validated the stability and reliability of our findings.ConclusionUnivariate and multivariate analyses demonstrated a causal relationship between T1D and IPF, whereas no evidence was found to support a causal relationship between T2D and IPF. Therefore, in clinical practice, patients with T1D should undergo lung imaging for early detection of IPF.

Retraction Note: Dietary intake and incidence risk of idiopathic pulmonary fibrosis: a Mendelian randomization study

Retraction Note: Dietary intake and incidence risk of idiopathic pulmonary fibrosis: a Mendelian randomization study