scholarly journals Protective effect of club cell secretory protein (CC-16) on COPD risk and progression: a Mendelian randomisation study

Thorax ◽  
2020 ◽  
Vol 75 (11) ◽  
pp. 934-943
Author(s):  
Stephen Milne ◽  
Xuan Li ◽  
Ana I Hernandez Cordero ◽  
Chen Xi Yang ◽  
Michael H Cho ◽  
...  
Keyword(s):  
Gene Expression ◽  
Lung Tissue ◽  
Causal Effect ◽  
Secretory Protein ◽  
Health Study ◽  
Mendelian Randomisation ◽  
Chronic Obstructive ◽  
Quantitative Trait Locus Study ◽  
Club Cell ◽  
A Genome

BackgroundThe anti-inflammatory pneumoprotein club cell secretory protein-16 (CC-16) is associated with the clinical expression of chronic obstructive pulmonary disease (COPD). We aimed to determine if there is a causal effect of serum CC-16 level on the risk of having COPD and/or its progression using Mendelian randomisation (MR) analysis.MethodsWe performed a genome-wide association meta-analysis for serum CC-16 in two COPD cohorts (Lung Health Study (LHS), n=3850 and ECLIPSE, n=1702). We then used the CC-16-associated single-nucleotide polymorphisms (SNPs) as instrumental variables in MR analysis to identify a causal effect of serum CC-16 on ‘COPD risk’ (ie, case status in the International COPD Genetics Consortium/UK-Biobank dataset; n=35 735 COPD cases, n=222 076 controls) and ‘COPD progression’ (ie, annual change in forced expiratory volume in 1 s in LHS and ECLIPSE). We also determined the associations between SNPs associated with CC-16 and gene expression using n=1111 lung tissue samples from the Lung Expression Quantitative Trait Locus Study.ResultsWe identified seven SNPs independently associated (p<5×10–8) with serum CC-16 levels; six of these were novel. MR analysis suggested a protective causal effect of increased serum CC-16 on COPD risk (MR estimate (SE) −0.11 (0.04), p=0.008) and progression (LHS only, MR estimate (SE) 7.40 (3.28), p=0.02). Five of the SNPs were also associated with gene expression in lung tissue (at false discovery rate <0.1) of several genes, including the CC-16-encoding gene SCGB1A1.ConclusionWe have identified several novel genetic variants associated with serum CC-16 level in COPD cohorts. These genetic associations suggest a potential causal effect of serum CC-16 on the risk of having COPD and its progression, the biological basis of which warrants further investigation.

scholarly journals The protective effect of club cell secretory protein (CC-16) on COPD risk and progression: a Mendelian randomisation study

2019 ◽  
Author(s):  
Stephen Milne ◽  
Xuan Li ◽  
Ana I Hernandez Cordero ◽  
Chen Xi Yang ◽  
Michael H Cho ◽  
...  
Keyword(s):  
Gene Expression ◽  
Protective Effect ◽  
Lung Tissue ◽  
Therapeutic Target ◽  
Causal Effect ◽  
Secretory Protein ◽  
Mendelian Randomisation ◽  
Bottom Line ◽  
Club Cell ◽  
Encoding Gene

ABSTRACTBackgroundThere are currently no robust biomarkers of chronic obstructive pulmonary disease (COPD) risk or progression. Club cell secretory protein-16 (CC-16) is associated with the clinical expression of COPD. We aimed to determine if there is a causal effect of serum CC-16 level on COPD risk and/or progression using Mendelian randomisation (MR) analysis.MethodsWe performed a genome-wide association meta-analysis for serum CC-16 in two COPD cohorts (Lung Health Study [LHS], n=3,850 and ECLIPSE, n=1,702). We then used the CC-16-associated single-nucleotide polymorphisms (SNPs) in MR analysis to estimate the causal effect of serum CC-16 on COPD risk (International COPD Genetics Consortium/UK-Biobank dataset; n=35,735 cases, n=222,076 controls) and progression (change in forced expiratory volume in 1 s [FEV1] in LHS and ECLIPSE). We also determined the associations between SNPs associated with CC-16 and gene expression using n=1,111 lung tissue samples from the Lung eQTL Study.ResultsWe identified 7 SNPs independently associated (p<5×10−8) with serum CC-16 levels; 6 of these were novel. MR analysis suggested a protective causal effect of increased serum CC-16 on COPD risk (p=0.008) and progression (LHS only, p=0.02). Five of the SNPs were also associated with gene expression in lung tissue, including that of the CC-16-encoding gene SCGB1A1 (false discovery rate<0.1).ConclusionWe have identified several novel genetic variants associated with serum CC-16 level in COPD cohorts. These genetic associations suggest a potential causal effect of serum CC-16 on COPD risk and progression. Further investigation of CC-16 as a biomarker or therapeutic target in COPD is warranted.KEY MESSAGESWhat is the key question?Can genetics help uncover a causal effect of serum CC-16 level on COPD risk and/or progression?What is the bottom line?There is a protective effect of genetically-increased serum CC-16 on both COPD risk and progression (as measured by change in FEV1 over time), which may be due to increased expression of the CC-16-encoding gene SCGB1A1 in the lung.Why read on?This is the first study to demonstrate a possible causal effect of serum CC-16 in people with COPD, and highlights the potential for CC-16 as a biomarker or therapeutic target.

scholarly journals No evidence that vitamin D is able to prevent or affect the severity of COVID-19 in individuals with European ancestry: a Mendelian randomisation study of open data

2021 ◽  
pp. bmjnph-2020-000151
Author(s):  
Hasnat A Amin ◽  
Fotios Drenos
Keyword(s):  
Vitamin D ◽  
Vitamin D Deficiency ◽  
Causal Effect ◽  
Infection Risk ◽  
European Ancestry ◽  
Mendelian Randomisation ◽  
Upper Respiratory Tract ◽  
A Genome ◽  
Vitamin D Levels ◽  
Tract Infections

BackgroundUpper respiratory tract infections are reportedly more frequent and more severe in individuals with lower vitamin D levels. Based on these findings, it has been suggested that vitamin D can prevent or reduce the severity of COVID-19.MethodsWe used two-sample Mendelian randomisation (MR) to assess the causal effect of vitamin D levels on SARS-CoV-2 infection risk and COVID-19 severity using publicly available data. We also carried out a genome-wide association analysis (GWA) of vitamin D deficiency in the UK Biobank (UKB) and used these results and two-sample MR to assess the causal effect of vitamin D deficiency on SARS-CoV-2 infection risk and COVID-19 severity.ResultsWe found no evidence that vitamin D levels causally affect the risk of SARS-CoV-2 infection (ln(OR)=0.17 (95% CI −0.22 to 0.57, p=0.39)) nor did we find evidence that vitamin D levels causally affect COVID-19 severity (ln(OR)=0.36 (95% CI −0.89 to 1.61, p=0.57)). Based on our GWA analysis, we found that 17 independent variants are associated with vitamin D deficiency in the UKB. Using these variants as instruments for our two-sample MR analyses, we found no evidence that vitamin D deficiency causally affects the risk of SARS-CoV-2 infection (ln(OR)=−0.04 (95% CI −0.1 to 0.03, p=0.25)) nor did we find evidence that vitamin D deficiency causally affects COVID-19 severity (ln(OR)=−0.24 (95% CI −0.55 to 0.08, p=0.14)).ConclusionsIn conclusion, we found no evidence that vitamin D is protective against SARS-CoV-2 infection or COVID-19 severity. Our data support the recent statement by the National Institute for Health and Care Excellence that the use of vitamin D supplementation to mitigate COVID-19 is not supported by the available data.

scholarly journals Biomarkers in Airway Diseases

2013 ◽  
Vol 20 (3) ◽  
pp. 180-182 ◽  
Author(s):  
Janice M Leung ◽  
Don D Sin
Keyword(s):  
Clinical History ◽  
Surfactant Protein ◽  
Secretory Protein ◽  
Surfactant Protein D ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Club Cell ◽  
Disease Phenotypes ◽  
Airway Diseases ◽  
Steroid Responsiveness

The inherent limitations of spirometry and clinical history have prompted clinicians and scientists to search for surrogate markers of airway diseases. Although few biomarkers have been widely accepted into the clinical armamentarium, the authors explore three sources of biomarkers that have shown promise as indicators of disease severity and treatment response. In asthma, exhaled nitric oxide measurements can predict steroid responsiveness and sputum eosinophil counts have been used to titrate anti-inflammatory therapies. In chronic obstructive pulmonary disease, inflammatory plasma biomarkers, such as fibrinogen, club cell secretory protein-16 and surfactant protein D, can denote greater severity and predict the risk of exacerbations. While the multitude of disease phenotypes in respiratory medicine make biomarker development especially challenging, these three may soon play key roles in the diagnosis and management of airway diseases.

scholarly journals Identification of Novel Genes Associated with Chronic Obstructive Pulmonary Disease Using Different Penalized Logistics Regression with High-Dimensional Biological Data from Human Sputum Cells

2021 ◽  
Author(s):  
Kimiya Gohari ◽  
Anoshirvan Kazemnejad ◽  
Shayan Mostafaei ◽  
Ali Sheidaei ◽  
Maryam S Daneshpour ◽  
...  
Keyword(s):  
Gene Expression ◽  
Logistic Regression ◽  
Gene Networks ◽  
Gene Expression Omnibus ◽  
Biological Data ◽  
Chronic Obstructive ◽  
Small Subset ◽  
Differential Analysis ◽  
Absolute Deviation ◽  
A Genome

Abstract Background: Comparison of LASSO, smoothly clipped absolute deviation (SCAD) and minimax concave penalty (MCP) logistic classifiers in order to reconnaissance of related genes with COPD disease and assessing the genes effects on the progression of the disease based on one of the main classes of cells involved in the disease, Sputum Cells. We used a genome-wide expression profiling to define gene networks relevant to the disease. The data retrieved from Gene Expression Omnibus (GEO) with accession numbers "GSE22148". From 143 samples in GOLD stage 2-4 COPD ex-smokers, 54,675 probes primary were assessed. After normalization, LASSO, SCAD and MCP logistic regressions were applied. K-fold cross-validation scheme was used to evaluate the performance of two methods. All of the computational processes were done using "ncvreg", "Affy," "Limma" and "SVA" R packages. Results: The results of LASSO (AUC=0.95, sensitivity= 0.91, specificity= 0.86) and SCAD (AUC=0.97, sensitivity= 0.95, specificity= 0.85) logistic regression were almost similar. There were 23 and 22 significantly associated genes for LASSO and SCAD, respectively. The only difference between these models is related to "stromal interaction molecule 2". Comparing to MCP approach, the most conservative method, we detected only 7 significant genes (AUC= 0.94, sensitivity= 0.94, specificity= 0.82). Conclusions: In the present study, the relative expressions of thousands of the genes were assessed and identified as associated genes with the progression of COPD. Differential analysis of gene expression data is able to reduce the number of genes but in a limited manner. In order to find an efficient and small subset of genes, we should use alternative approaches like logistic regression. Regularization solves the high dimensionality problem in using this kind of regression.

scholarly journals Genetic regulation of gene expression of MIF family members in lung tissue

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Laura Florez-Sampedro ◽  
Corry-Anke Brandsma ◽  
Maaike de Vries ◽  
Wim Timens ◽  
Rene Bults ◽  
...  
Keyword(s):  
Gene Expression ◽  
Lung Tissue ◽  
Splice Variants ◽  
Genetic Regulation ◽  
Regulation Of Gene Expression ◽  
Chronic Obstructive ◽  
Nucleotide Polymorphisms ◽  
Related Factors ◽  
Dopachrome Tautomerase ◽  
Copd Patients

Abstract Macrophage migration inhibitory factor (MIF) is a cytokine found to be associated with chronic obstructive pulmonary disease (COPD). However, there is no consensus on how MIF levels differ in COPD compared to control conditions and there are no reports on MIF expression in lung tissue. Here we studied gene expression of members of the MIF family MIF, D-Dopachrome Tautomerase (DDT) and DDT-like (DDTL) in a lung tissue dataset with 1087 subjects and identified single nucleotide polymorphisms (SNPs) regulating their gene expression. We found higher MIF and DDT expression in COPD patients compared to non-COPD subjects and found 71 SNPs significantly influencing gene expression of MIF and DDTL. Furthermore, the platform used to measure MIF (microarray or RNAseq) was found to influence the splice variants detected and subsequently the direction of the SNP effects on MIF expression. Among the SNPs found to regulate MIF expression, the major LD block identified was linked to rs5844572, a SNP previously found to be associated with lower diffusion capacity in COPD. This suggests that MIF may be contributing to the pathogenesis of COPD, as SNPs that influence MIF expression are also associated with symptoms of COPD. Our study shows that MIF levels are affected not only by disease but also by genetic diversity (i.e. SNPs). Since none of our significant eSNPs for MIF or DDTL have been described in GWAS for COPD or lung function, MIF expression in COPD patients is more likely a consequence of disease-related factors rather than a cause of the disease.

scholarly journals Genome-wide methylation and expression analyses reveal the epigenetic landscape of immune-related diseases for tobacco smoking

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Ying Mao ◽  
Peng Huang ◽  
Yan Wang ◽  
Maiqiu Wang ◽  
Ming D. Li ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cigarette Smoke ◽  
Tobacco Smoking ◽  
Molecular Mechanisms ◽  
Functional Enrichment ◽  
Chronic Obstructive ◽  
Rna Seq ◽  
Immune System Diseases ◽  
Genome Wide ◽  
A Genome

Abstract Background Smoking is a major causal risk factor for lung cancer, chronic obstructive pulmonary disease (COPD), cardiovascular disease (CVD), and is the main preventable cause of deaths in the world. The components of cigarette smoke are involved in immune and inflammatory processes, which may increase the prevalence of cigarette smoke-related diseases. However, the underlying molecular mechanisms linking smoking and diseases have not been well explored. This study was aimed to depict a global map of DNA methylation and gene expression changes induced by tobacco smoking and to explore the molecular mechanisms between smoking and human diseases through whole-genome bisulfite sequencing (WGBS) and RNA-sequencing (RNA-seq). Results We performed WGBS on 72 samples (36 smokers and 36 nonsmokers) and RNA-seq on 75 samples (38 smokers and 37 nonsmokers), and cytokine immunoassay on plasma from 22 males (9 smokers and 13 nonsmokers) who were recruited from the city of Jincheng in China. By comparing the data of the two groups, we discovered a genome-wide methylation landscape of differentially methylated regions (DMRs) associated with smoking. Functional enrichment analyses revealed that both smoking-related hyper-DMR genes (DMGs) and hypo-DMGs were related to synapse-related pathways, whereas the hypo-DMGs were specifically related to cancer and addiction. The differentially expressed genes (DEGs) revealed by RNA-seq analysis were significantly enriched in the “immunosuppression” pathway. Correlation analysis of DMRs with their corresponding gene expression showed that genes affected by tobacco smoking were mostly related to immune system diseases. Finally, by comparing cytokine concentrations between smokers and nonsmokers, we found that vascular endothelial growth factor (VEGF) was significantly upregulated in smokers. Conclusions In sum, we found that smoking-induced DMRs have different distribution patterns in hypermethylated and hypomethylated areas between smokers and nonsmokers. We further identified and verified smoking-related DMGs and DEGs through multi-omics integration analysis of DNA methylome and transcriptome data. These findings provide us a comprehensive genomic map of the molecular changes induced by smoking which would enhance our understanding of the harms of smoking and its relationship with diseases.

scholarly journals Elevated plasma level of Pentraxin 3 is associated with emphysema and mortality in smokers

Thorax ◽  
2021 ◽  
pp. thoraxjnl-2020-215356
Author(s):  
Yingze Zhang ◽  
John Tedrow ◽  
Mehdi Nouraie ◽  
Xiaoyun Li ◽  
Divay Chandra ◽  
...  
Keyword(s):  
Gene Expression ◽  
Hyaluronic Acid ◽  
Lung Tissue ◽  
Regulatory Gene ◽  
Airflow Obstruction ◽  
Chronic Obstructive ◽  
Pentraxin 3 ◽  
Tobacco Exposure ◽  
Regulatory Variants ◽  
Emphysema Severity

BackgroundPentraxin 3 (PTX3) influences innate immunity and inflammation, host defence, the complement cascade and angiogenesis. PTX3 expression in lung and blood of subjects with tobacco exposure, and its potential relationship with disease pattern and clinical outcome are poorly understood.MethodsUsing independent platforms and cohorts, we identified associations of PTX3 gene expression in lung tissue and plasma from current and former tobacco smokers (with and without chronic obstructive pulmonary disease, COPD) to disease phenotypes including quantitative CT determined emphysema, lung function, symptoms and survival. Two putative regulatory variants of the PTX3 gene were examined for association with COPD manifestations. The relationship between plasma PTX3 and hyaluronic acid levels was further examined.ResultsPTX3 gene expression in lung tissue was directly correlated with emphysema severity (p<0.0001). Circulating levels of PTX3 were inversely correlated with FEV1 (p=0.006), and positively associated with emphysema severity (p=0.004) and mortality (p=0.008). Two PTX3 gene regulatory variants were associated with a lower risk for emphysema and expiratory airflow obstruction, and plasma levels of PTX3 and hyaluronic acid were related.ConclusionsThese data show strong and overlapping associations of lung and blood PTX3 levels, and PTX3 regulatory gene variants, with the severity of airflow obstruction, emphysema and mortality among smokers. These findings have potential implications regarding the pathogenesis of smoking-related lung diseases and warrant further exploration for the use of PTX3 as a predictive biomarker.

Association of genetic variants for plasma LRG1 with rapid decline in kidney function in patients with type 2 diabetes

2021 ◽  
Author(s):  
Resham Lal Gurung ◽  
Rajkumar Dorajoo ◽  
M Yiamunaa ◽  
Jian-Jun Liu ◽  
Sharon Li Ting Pek ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Glomerular Filtration ◽  
Kidney Function ◽  
Genetic Variants ◽  
Genome Wide Association Study ◽  
Causal Effect ◽  
Mendelian Randomisation ◽  
Rapid Decline ◽  
A Genome

Abstract Context Elevated levels of plasma Leucine Rich α-2-Glycoprotein 1 (LRG1), a component of TGF-ß signalling, are associated with development and progression of chronic kidney disease in patients with type 2 diabetes (T2D). However, whether this relationship is causal is uncertain. Objectives To identify genetic variants associated with plasma LRG1 levels and determine whether genetically predicted plasma LRG1 contributes to a rapid decline in kidney function (RDKF) in patients with T2D. Design and participants We performed a genome-wide association study (GWAS) of plasma LRG1 among 3,694 T2D individuals [1,881(983 Chinese, 420 Malay and 478 Indian) discovery from SMART2D cohort and 1,813 (Chinese) validation from DN cohort]. One- sample Mendelian randomization analysis was performed among 1,337 T2D Chinese participants with preserved glomerular filtration function (baseline estimated glomerular filtration rate (eGFR) &gt;60ml/min/1.73m 2). RDKF was defined as an eGFR decline of 3 mL/min/1.73 m 2/year or greater. Results We identified rs4806985 variant near LRG1 locus robustly associated with plasma LRG1 levels (MetaP=6.66x10 -16). Among 1,337 participants, 344 (26%) developed RDKF and the rs4806985 variant was associated with higher odds of RDKF (meta odds ratio =1.23, P=0.030 adjusted for age and sex). Mendelian randomisation analysis provided evidence for a potential causal effect of plasma LRG1 on kidney function decline in T2D (P&lt;0.05). Conclusion We demonstrate that genetically influenced plasma LRG1 increases the risk of RDKF in T2D patients suggesting plasma LRG1 as a potential treatment target. However, further studies are warranted to elucidate underlying pathways to provide insight into DKD prevention.

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