Chronic Obstructive Pulmonary Disease Susceptibility Research Articles

Mitochondrial Dysfunction in Chronic Obstructive Pulmonary Disease: Unraveling the Molecular Nexus.

Chronic obstructive pulmonary disease (COPD) is a prevalent and debilitating respiratory disorder characterized by persistent airflow limitation and chronic inflammation. In recent years, the role of mitochondrial dysfunction in COPD pathogenesis has emerged as a focal point of investigation. This review endeavors to unravel the molecular nexus between mitochondrial dysfunction and COPD, delving into the intricate interplay of oxidative stress, bioenergetic impairment, mitochondrial genetics, and downstream cellular consequences. Oxidative stress, a consequence of mitochondrial dysfunction, is explored as a driving force behind inflammation, exacerbating the intricate cascade of events leading to COPD progression. Bioenergetic impairment sheds light on the systemic consequences of mitochondrial dysfunction, impacting cellular functions and contributing to the overall energy imbalance observed in COPD patients. This review navigates through the genetic landscape, elucidating the role of mitochondrial DNA mutations, variations, and haplogroups in COPD susceptibility and severity. Cellular consequences, including apoptosis, autophagy, and cellular senescence, are examined, providing insights into the intricate mechanisms by which mitochondrial dysfunction influences COPD pathology. Therapeutic implications, spanning antioxidant strategies, mitochondria-targeted compounds, and lifestyle modifications, are discussed in the context of translational research. Important future directions include identifying novel biomarkers, advancing mitochondria-targeted therapies, and embracing patient-centric approaches to redefine COPD management. This abstract provides a comprehensive overview of our review, offering a roadmap for understanding and addressing the molecular nexus between mitochondrial dysfunction and COPD, with potential implications for precision medicine and improved patient outcomes.

SRAGE levels are decreased in plasma and sputum of COPD secondary to biomass-burning smoke and tobacco smoking: Differences according to the rs3134940 AGER variant

The receptor for advanced glycation end products (RAGE) and its gene (AGER) have been related to lung injury and inflammatory diseases, including chronic obstructive pulmonary disease (COPD). We aimed to evaluate the association of rs2071288, rs3134940, rs184003, and rs2070600 AGER single-nucleotide variants and the soluble-RAGE plasma and sputum levels with COPD secondary to biomass-burning smoke (BBS) and tobacco smoking. Four groups, including 2189 subjects, were analyzed: COPD secondary to BBS exposure (COPD-BBS, n = 342), BBS-exposed subjects without COPD (BBES, n = 774), tobacco smoking-induced COPD (COPD-TS, n = 434), and smokers without COPD (SWOC, n = 639). Allelic discrimination assays determined the AGER variants. The sRAGE was quantified in plasma (n = 240) and induced-sputum (n = 72) samples from a subgroup of patients using the ELISA technique. In addition, a meta-analysis was performed for the association of rs2070600 with COPD susceptibility. None of the studied genetic variants were found to be associated with COPD-BBS or COPD-TS. A marginal association was observed for the rs3134940 with COPD-BBS (p = 0.066). The results from the meta-analysis, including six case-control studies (n = 4149 subjects), showed a lack of association of rs2070600 with COPD susceptibility (p = 0.681), probably due to interethnic differences. The sRAGE plasma levels were lower in COPD-BBS compared to BBS and in COPD-TS compared to SWOC. The sRAGE levels were also lower in sputum samples from COPD-BBS than BBES. Subjects with rs3134940-TC genotypes exhibit lower sRAGE plasma levels than TT subjects, mainly from the COPD-BBS and SWOC groups. The AGER variants were not associated with COPD-BBS nor COPD-TS, but the sRAGE plasma and sputum levels are related to both COPD-BBS and COPD-TS and are influenced by the rs3134940 variant.

GSTP1 rs4147581 C>G and NLRP3 rs3806265 T>C as Risk Factors for Chronic Obstructive Pulmonary Disease: A Case-Control Study.

Chronic obstructive pulmonary disease (COPD) is a chronic respiratory ailment influenced by a blend of genetic and environmental factors. Inflammatory response and an imbalance in oxidative-antioxidant mechanisms constitute the primary pathogenesis of COPD. Glutathione S-transferase P1(GSTP1) plays a pivotal role as an antioxidant enzyme in regulating oxidative-antioxidant responses in the pulmonary system. The activation of the NOD-like receptor thermal protein domain (NLRP3) inflammatory vesicle can trigger an inflammatory response. Several investigations have implicated GSTP1 and NLRP3 in the progression of COPD; nonetheless, there remains debate regarding this mechanism. Employing a case-control study design, 312 individuals diagnosed with COPD and 314 healthy controls were recruited from Gansu Province to evaluate the correlation between GSTP1 (rs4147581C>G and rs1695A>G) and NLRP3 (rs3806265T>C and rs10754558G>C) polymorphisms and the susceptibility to COPD. The presence of the GSTP1 rs4147581G allele substantially elevated the susceptibility to COPD (CGvs.CC:OR=3.11,95% CI=1.961-4.935, P<0.001;GGvs.CC:OR=2.065,95% CI=1.273-3.350, P=0.003; CG+GGvs.CC:OR=2.594,95% CI=1.718-3.916, P<0.001). Similarly, the NLRP3rs3806265T allele significantly increased the susceptibility to COPD (TC:TT:OR=0.432,95% CI=0.296-0.630; TC+CCvs.TT:OR=2.132,95% CI=1.479-3.074, P<0.001). However, no statistically significant association was discerned between the rs1695A>G and rs10754558G>C polymorphisms and COPD susceptibility (P>0.05). In summary, this study ascertained that the GSTP1 rs4147581C>G polymorphism is associated with increased COPD susceptibility, with the G allele elevating the risk of COPD. Similarly, the NLRP3 rs3806265T>C polymorphism is linked to elevated COPD susceptibility, with the T allele heightening the risk of COPD.

Patient message preferences to promote clinical conversations about chronic obstructive pulmonary disease (COPD): A discrete choice experiment.

The purpose of this study was to identify message features that motivate patients to initiate clinical conversations about Chronic Obstructive Pulmonary Disease (COPD). A secondary aim was to determine whether preferred message features vary by socio-demographic and behavioral characteristics. A discrete choice experiment was conducted in August 2020. Participants were asked to select which messages would motivate them to speak with a clinician about COPD. This included selecting messages across 8 choice sets, or a systematic combination of messages reflecting 6 attributes (e.g., susceptibility, call-to-action, emotion-frame, efficacy, message source, organizational support). The final sample was 928, which included adults (M=62.07; SD=10.14years old) who identified as non-Hispanic, white, and with at least some college experience. Message attributes ranked from most to least important were COPD susceptibility (25.53% [95% CI=24.39, 26.66]), message source (19.32% [95% CI=18.41-20.24]), COPD organization logo (19.13%; [95% CI=18.26, 20.01]), call-to-action (14.12%; [95% CI=13.40, 14.85], emotion-frame (13.24% [95% CI=12.55-13.94]), and efficacy (8.65%; [95% CI=8.20-9.09]). Participants preferred susceptibility messages about COPD signs/symptoms rather than risk behaviors related to smoking tobacco and environmental exposures. They also preferred messages from medical authorities (i.e., clinicians, COPD organization), a call-to-action that supports their autonomy in screening decision-making, and a message that conveys hope for living a healthy life with COPD and builds their self-efficacy to get screened. Differences in message preferences were detected according to age, gender, race, ethnicity, education level, and current vs. former smoking status. This study identified message features that motivate clinical conversations about COPD, especially those from subgroups who are disproportionately at-risk for its late-stage diagnosis.

GST polymorphism as a predictive biomarker for modulating the susceptibility to chronic obstructive pulmonary disease: A North Indian study.

Chronic obstructive pulmonary disease (COPD) is commonly characterized by shortness of breath, coughing or expectoration. Smoking is the leading cause of COPD development, but only a small percentage of smokers develop symptoms, implying a genetic component. Glutathione S-transferase enzymes are responsible for detoxifying cigarette smoke components. The role of glutathione S-transferase T1 (GSTT1) and glutathione S-transferase M1 (GSTM1) gene polymorphism was assessed with COPD susceptibility and associated clinical parameters in the North Indian population. This was a cross-sectional study involving 200 COPD patients and 200 healthy individuals, with peripheral blood sampling and adequate questionnaires. Multiplex PCR was used for genotyping GSTT1 and GSTM1 gene polymorphism. Logistic regression was used to calculate the odds ratio and 95% confidence intervals to assess the COPD risk and GST polymorphisms. The GSTT1 gene deletion rate was higher in COPD cases (34.5%) than in healthy individuals (20.5%). A statistical relationship between the GSTT1(-) null genotype and COPD risk was observed (odds ratio=2.04, 95% CI=1.30-3.20, P=0.0019). After adjusting for covariates like age, sex and smoking status, a significant association was found for GSTT1(-) null genotype and COPD risk (adjusted odds ratio=2.90, 95% CI=1.43-5.87, P=0.003). The GSTT1(-) genotype was also significantly correlated with clinical parameters for COPD risk. Another primary observation was that females with the GSTT1(-) null genotype were more vulnerable to COPD than males with the same gene deletion. The GSTT1(-) null genotype strongly correlates with COPD development, while no association was observed in the GSTM1(-) null genotype in the North Indian population.

FAM13A regulates cellular senescence marker p21 and mitochondrial reactive oxygen species production in airway epithelial cells.

Inhalation of noxious gasses induces oxidative stress in airway epithelial cells (AECs), which may lead to cellular senescence and contribute to the development of Chronic Obstructive Pulmonary Disease (COPD). FAM13A, a well-known COPD susceptibility gene, is highly expressed in airway epithelium. We studied whether its expression is associated with aging and cellular senescence and affects airway epithelial responses to paraquat, a cellular senescence inducer. The association between age and FAM13A expression was investigated in two datasets of human lung tissue and bronchial brushings from current/ex-smokers with/without COPD. Protein levels of FAM13A and cellular senescence marker p21 were investigated using immunohistochemistry in lung tissue from COPD patients. In vitro, FAM13A and P21 expression was assessed using qPCR in air-liquid-interface (ALI)-differentiated AECs in absence/presence of paraquat. Additionally, FAM13A was overexpressed in human bronchial epithelial 16HBE cells and the effect on P21 expression (qPCR) and mitochondrial ROS production (MitoSOX staining) was assessed. Lower FAM13A expression was significantly associated with increasing age in lung tissue and bronchial epithelium. In airway epithelium of COPD patients, we found a negative correlation between FAM13A and p21 protein levels. In ALI-differentiated AECs, the paraquat-induced decrease in FAM13A expression was accompanied by increased P21 expression. In 16HBE cells, the overexpression of FAM13A significantly reduced paraquat-induced P21 expression and mitochondrial ROS production. Our data suggest that FAM13A expression decreases with aging, resulting in higher P21 expression and mitochondrial ROS production in the airway epithelium, thus facilitating cellular senescence and as such potentially contributing to accelerated lung aging in COPD.

EPO rs1617640 A>C is a Protective Factor for Chronic Obstructive Pulmonary Disease: A Case Control Study.

The occurrence and development of chronic obstructive pulmonary disease (COPD) are regulated by environmental and genetic factors. In hypoxia, Erythropoietin (EPO) satisfies the body's need for oxygen by promoting the production of red blood cells. Hypoxia was proven to be a common physiological condition in COPD progression and associated with many complications. Some studies have found that EPO is involved in the development of COPD. But the mechanism has not been fully proven. We conducted a case-control study enrolled 1095 COPD patients and 1144 healthy controls in Guangdong Province to evaluate the association between EPO polymorphisms (rs1617640 A>C, rs507392 A>G, rs564449 G>T) and COPD susceptibility. 872 participants from southern Gansu Province were recruited to verify the effect of EPO polymorphisms on lung function. EPO rs1617640 C allele reduced COPD susceptibility in southern Chinese significantly (AC vs. AA: adjusted Odds ratio (OR) = 0.805, 95% CI = 0.669-0.969; AC+CC vs. AA: adjusted OR = 0.822, 95% CI = 0.689-0.980). However, there was no association between rs507392 A>G and rs564449 G>T polymorphisms and COPD susceptibility (p > 0.05). We further observed that the rs1617640 C allele was associated with higher FEV1 and FVC in Guangdong and Gansu populations significantly (both p < 0.05). In brief, the level of FEV1 and FVC increased with the C allele number. We modeled the relative risk for men and women, in which the population-attributable risks chances were 0.449 (0.258-0.641) and 0.262 (0.128-0.396) respectively. In this model, smoking status, coal as fuels, education level, and rs1617640 A>C were finally retained for males, while smoking status, biomass as fuels, and1617640 A>C were retained for females. In the end, using the method developed by Gail and Bruzzi, we fitted a 10-year absolute risk model for southern Chinese with different individual relative risks, which was presented as a table. In conclusion, this study found that EPO rs1617640 A>C polymorphism is associated with COPD susceptibility in southern Chinese, and the C allele was associated with better lung function. In addition, it could also be considered a genetic marker associated with environmental factors to predict the absolute 10-year risk of COPD in southern Chinese.

Association of mannose binding lectin with chronic obstructive pulmonary disease susceptibility and its clinical outcomes.

The physiological interactions of MBL suggest its contribution towards the pathogenesis of COPD. The present case-control study was undertaken to elucidate the role of MBL with COPD risk and clinical outcomes in north Indian cohort. Patients were enrolled as per GOLD criteria. MBL2 variants were selected based on the literature and their putative functional significance. Genotyping of six single nucleotide polymorphisms of MBL2 comprising of two coding (rs1800450, rs1800451) and four non-coding variants (rs11003125, rs7096206, rs11003123 and rs7095891) was done by using PCR-RFLP and ARMS-PCR. Serum MBL levels were analysed by sandwich ELISA. Overall findings of the molecular genetic analysis of MBL2 indicated significant difference in frequency of three of the six studied variants, between patients and controls or among different disease severity stages. Heterozygous genotype of rs7095891 showed significant protective association towards severity of disease. Linkage disequilibrium (LD) analysis indicated a strong LD between rs1800450 and rs7095891 while intermediate LD was observed for rs11003123/rs11003125 and rs7096206/rs11003125. Haplotype analysis revealed 17.14-fold risk of developing exacerbations conferred by GGGTGG haplotype. Significantly low serum MBL levels observed in COPD patients as compared to controls. Significant difference in MBL deficiency levels were also observed for homozygous wild and variant genotypes of rs11003125 and rs7096206 respectively, as well as for all genotypes of rs11003123 than respective controls. The present study reinforces the role played by MBL in the susceptibility, protection and clinical outcomes of COPD. Therefore, including the reported associations at diagnostic, prognostic and therapeutic interventions may prove helpful.

Application of mendelian randomization to study the causal relationship between smoking and the risk of chronic obstructive pulmonary disease.

Smoking is a risk factor for chronic obstructive pulmonary disease (COPD). Few studies have assessed the causal relationship between smoking and COPD using Mendelian randomization. Exposure and outcome datasets were obtained from the IEU Open GWAS project (https://gwas.mrcieu.ac.uk/). The exposure data set includes smoking (ever smoke, smoking/smokers in household, exposure to tobacco smoke at home). The outcome data set includes COPD susceptibility and acute COPD admissions. The main methods of Mendelian randomization analysis are weighted median method and MR-Egger method. Heterogeneity and polymorphism analyses were performed to ensure the accuracy of the results. ever smoke increased the risk of COPD prevalence, and ever smoke and smoking/smokers in household increased the risk of acute COPD admission. Conclusion Therefore, we should enhance the management of nonpharmacological prescription of COPD to reduce the individual incidence.

Association of IL4RA polymorphism in predicting susceptibility towardchronic obstructive pulmonary disease.

Background: The cytokine IL-4 plays vital role in the intercellular signalling network during immune responses to allergen exposure. Methods: This cross-sectional study involved 202 chronic obstructive pulmonary disease (COPD) patientsand 203 healthy individuals. The genotyping of IL4RAQ576R gene polymorphism was determined using PCR restriction fragment length polymorphism analysis. Results: Significant association between mutant genotype (GG) and combined (AA+AG) genotype for the risk of COPD was found (odds ratio [OR]: 4.32;p=0.04). A significant protective effect was observed between the IL4RAQ576R polymorphism and Global Strategy for Obstructive Lung Disease (GOLD) stage fourpatients in a recessive model (AA+AG vs GG; p=0.002). In GOLD A, asubstantial relationship was found between theAG and wild-type genotypes (AA) for COPD risk (OR: 2.38;p=0.03). A strong association was found for COPD duration of 5-10years (OR: 8.80;p=0.01). Conclusion: IL4RAQ576R polymorphism is associated with COPD susceptibility.

Genetic biomarkers for risk prediction of chronic obstructive pulmonary disease (COPD) in smokers and non-smokers

Chronic Obstructive Pulmonary Disease (COPD) is a progressive disease and not fully reversible. It is the 3rd major cause of death worldwide and ranks 2nd in India. Although the primary etiopathogenic factor is chronic exposure to tobacco smoke, it has been observed that all smokers do not develop COPD and many non-smokers suffer from the disease. This difference in susceptibility can be attributed to individual genetic variations. Therefore, the present study was conducted to analyze the association of genetic variants in candidate genes with COPD susceptibility among smokers and non-smokers. A total of 500 subjects were enrolled in the study (250 each of controls and cases) after ethical approval and informed consent. Fifteen single nucleotide polymorphisms (SNPs) in eight genes viz.IL-1RN, IL-1B, IL-6, TNF-A, SOD2, CAT, ADAM33 and AQP5 were genotyped by Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR–RFLP). Data was analyzed using SPSS (ver 21.0) and association with smoking status was determined. Among 250 healthy controls enrolled, 119 were non-smokers and 131 were smokers. Out of 250 COPD cases, only 34 were non-smokers and rest 216 were smokers. The genotypic frequencies of IL-1RN intron2 86 bp VNTR (I,II), IL-1β -511 T/C, IL-6 -597A/G, TNF-α -308G/A, SOD2 + 47C/T, CAT − 21A/T and AQP5 promoter G/A were significantly associated with smoking. Among 07 ADAM33 SNPs, the genotype frequencies of V4exon22C/G and F + 1intron6C/T were significantly associated in smokers, while V1exon22G/T, S2exon19G/C, S1exon19A/G and Q1intron16A/G were associated with non-smokers. The genetic variants (SNPs) in smokers and non-smokers showing differential association with the risk of COPD can be identified as predictive biomarkers.

Suggestive evidence of genetic association of IL23R polymorphisms with chronic obstructive pulmonary disease risk in the Chinese population.

Chronic obstructive pulmonary disease (COPD) is a worldwide public health problem. Previous genetic association studies have identified several susceptibility loci in the interleukin genes that may participate in the nosogenesis of COPD. This study aimed to evaluate the relationship between IL23R loci and COPD susceptibility in the Chinese population. Agena MassARRAY technology was applied to genotype five single nucleotide polymorphisms (SNPs) in the IL23R gene in 498 COPD patients and 498 healthy people. The association between IL23R SNPs and COPD risk was calculated by logistic regression analysis, with odds ratios and 95% confidence intervals. The false-positive report probability analysis was noteworthy for evaluating the significant results. Also, haplotype analysis was performed among IL23R variants, and multifactor dimensionality reduction analysis was performed to assess the SNP-SNP interactions to predict the risk of COPD. Overall analysis showed that rs7517847 had a significant association with an increased risk of COPD. Age-stratified analysis revealed that rs7517847 was significantly related to an increased risk of COPD in people aged over 68 years old. Sex-stratified analysis illustrated a significant association between rs2295359 and rs7517847 and COPD risk in the female population. The significant association of COPD risk with IL23R SNPs was assessed by false-positive report probability values. Additionally, we observed that the haplotypes AAC and GGA formed by rs2201841, rs12743974 and rs10889677 were associated with a reduced risk of COPD (p = 0.009, p = 0.026). Also, the five-loci interaction model formed by rs2295359, rs7517847, rs2201841, rs12743974 and rs10889677 became the best predictor of COPD, with 10/10 cross-validation consistency and 52.4% testing balance accuracy. The research indicated a remarkable association between IL23R variants and COPD susceptibility in the Chinese population. Larger samples and functional research are required to ascertain the relationship between IL23R variants and COPD susceptibility.

Iron and mitochondria in the susceptibility, pathogenesis and progression of COPD.

Chronic obstructive pulmonary disease (COPD) is a debilitating lung disease characterised by airflow limitation, chronic bronchitis, emphysema and airway remodelling. Cigarette smoke is considered the primary risk factor for the development of COPD; however, genetic factors, host responses and infection also play an important role. Accumulating evidence highlights a role for iron dyshomeostasis and cellular iron accumulation in the lung as a key contributing factor in the development and pathogenesis of COPD. Recent studies have also shown that mitochondria, the central players in cellular iron utilisation, are dysfunctional in respiratory cells in individuals with COPD, with alterations in mitochondrial bioenergetics and dynamics driving disease progression. Understanding the molecular mechanisms underlying the dysfunction of mitochondria and cellular iron metabolism in the lung may unveil potential novel investigational avenues and therapeutic targets to aid in the treatment of COPD.

Quantitative proteomics of differentiated primary bronchial epithelial cells from chronic obstructive pulmonary disease and control identifies potential novel host factors post-influenza A virus infection.

Chronic obstructive pulmonary disease (COPD) collectively refers to chronic and progressive lung diseases that cause irreversible limitations in airflow. Patients with COPD are at high risk for severe respiratory symptoms upon influenza virus infection. Airway epithelial cells provide the first-line antiviral defense, but whether or not their susceptibility and response to influenza virus infection changes in COPD have not been elucidated. Therefore, this study aimed to compare the susceptibility of COPD- and control-derived airway epithelium to the influenza virus and assess protein changes during influenza virus infection by quantitative proteomics. The presence of human- and avian-type influenza A virus receptor was assessed in control and COPD lung sections as well as in fully differentiated primary human bronchial epithelial cells (phBECs) by lectin- or antibody-based histochemical staining. PhBECs were from COPD lungs, including cells from moderate- and severe-stage diseases, and from age-, sex-, smoking, and history-matched control lung specimens. Protein profiles pre- and post-influenza virus infection in vitro were directly compared using quantitative proteomics, and selected findings were validated by qRT-PCR and immunoblotting. The human-type influenza receptor was more abundant in human airways than the avian-type influenza receptor, a property that was retained in vitro when differentiating phBECs at the air-liquid interface. Proteomics of phBECs pre- and post-influenza A virus infection with A/Puerto Rico/8/34 (PR8) revealed no significant differences between COPD and control phBECs in terms of flu receptor expression, cell type composition, virus replication, or protein profile pre- and post-infection. Independent of health state, a robust antiviral response to influenza virus infection was observed, as well as upregulation of several novel influenza virus-regulated proteins, including PLSCR1, HLA-F, CMTR1, DTX3L, and SHFL. COPD- and control-derived phBECs did not differ in cell type composition, susceptibility to influenza virus infection, and proteomes pre- and post-infection. Finally, we identified novel influenza A virus-regulated proteins in bronchial epithelial cells that might serve as potential targets to modulate the pathogenicity of infection and acute exacerbations.

Association of SFTPB Gene Polymorphisms with Chronic Obstructive Pulmonary Disease (COPD) Susceptibility in the Population of Southern Punjab, Pakistan

Association of SFTPB Gene Polymorphisms with Chronic Obstructive Pulmonary Disease (COPD) Susceptibility in the Population of Southern Punjab, Pakistan

IL6R gene polymorphisms and their relation to chronic obstructive pulmonary disease susceptibility in theChinese population.

Background: This work was designedto explore the correlation between IL6R polymorphisms and chronic obstructive pulmonary disease (COPD) susceptibility. Methods: Agena MassARRAY was used to genotype five SNPsof IL6R in 498 patients with COPD and 498 controls. Genetic models and haplotype analysis were used to assess the associations between SNPs and COPD risk. Results: Rs6689306 and rs4845625 increase the risk of COPD. Rs4537545, rs4129267 and rs2228145 were related to a decreased risk of COPD in different subgroups. Haplotype analysis revealed that GTCTC, GCCCA and GCTCA contributed to a reduced risk of COPD after adjustment. Conclusion: IL6R polymorphisms are significantly associated with COPD susceptibility.

Synonymous mutations in TLR2 and TLR9 genes decrease COPD susceptibility in the Chinese Han population

IntroductionPrevious studies have found associations between polymorphisms in some candidate genes and chronic obstructive pulmonary disease (COPD) risk. However, the association between TLR2 and TLR9 polymorphisms and COPD risk remains uncertain. MethodsFour variants (rs352140, rs3804099, rs3804100, and rs5743705) of the TLR2 and TLR9 genes in 540 COPD patients and 507 healthy controls were genotyped using the Agena MassARRAY system. Odds ratio (OR) and 95% confidence interval (CI) were calculated to assess the association of TLR2 and TLR9 polymorphisms with COPD risk by logistic regression analysis. ResultsTLR9-rs352140, TLR2-rs3804100, and TLR2-rs5743705 were related to a lower risk of COPD among Chinese people and the significance still existed after Bonferroni correction. Additionally, rs3804099, rs3804100, and rs352140 were found to be associated with COPD development in different subgroups (males, age ≤ 68 years, smokers, BMI < 24 kg/m2, and acute exacerbation). ConclusionsOur findings indicated that TLR9 and TLR2 polymorphisms had protective effects on the development of COPD among Chinese people.

Chronic Obstructive Pulmonary Disease (COPD): Making Sense of Existing GWAS Findings in Indian Context

To date, more than 1456 associations have been identified for Chronic Obstructive Pulmonary Disease (COPD) risk through Genome-Wide Association Studies (GWAS). However, target genes for COPD susceptibility in the Indian population and the mechanism underlying remains largely unexplored and no GWAS studies on COPD are available on the Indian population till now. This study was conducted using the existing public data on GWAS of different parts of the world, and the genetic polymorphisms to understand the possible mechanisms of these polymorphisms using available data from the Genotype-Tissue Expression (GTEx) project. We jotted down 16 important genes and 28 Single Nucleotide Polymorphisms (SNPs) in the Indian population from 1456 variants. Pathway analysis showed that these relevant genes are mostly associated with immune responses and activation, which is a key factor in COPD development. Our investigation revealed possible target genes associated with COPD in the context of the Indian population.

CRISPR interference interrogation of COPD GWAS genes reveals the functional significance of desmoplakin in iPSC-derived alveolar epithelial cells.

Genome-wide association studies (GWAS) have identified dozens of loci associated with chronic obstructive pulmonary disease (COPD) susceptibility; however, the function of associated genes in the cell type(s) affected in disease remains poorly understood, partly due to a lack of cell models that recapitulate human alveolar biology. Here, we apply CRISPR interference to interrogate the function of nine genes implicated in COPD by GWAS in induced pluripotent stem cell–derived type 2 alveolar epithelial cells (iAT2s). We find that multiple genes implicated by GWAS affect iAT2 function, including differentiation potential, maturation, and/or proliferation. Detailed characterization of the GWAS gene DSP demonstrates that it regulates iAT2 cell-cell junctions, proliferation, mitochondrial function, and response to cigarette smoke–induced injury. Our approach thus elucidates the biological function, as well as disease-relevant consequences of dysfunction, of genes implicated in COPD by GWAS in type 2 alveolar epithelial cells.

Identification of genetic variants of the IL-22 gene in association with an altered risk of COPD susceptibility.

The incidence of chronic obstructive pulmonary disease (COPD) is related to the interaction between environmental exposure and genetic factors. Far more than 15% of smokers eventually develop COPD. In addition to smoking, genetic susceptibility may be another factor in the development of COPD. IL‐22 and its receptors are increased in human and experimental COPD and contribute to pathogenesis. Here, we conducted a case–control study to evaluate the association between IL‐22 tag‐single nucleotide polymorphisms (SNPs) and COPD risk. Four tag‐SNPs (rs2227478, rs2227481, rs2227484 and rs2227485) were identified according to linkage disequilibrium (LD) analysis in 30 healthy controls. A total of 513 COPD cases and 504 controls were recruited to perform an association study between these four tag‐SNPs and COPD risk. We found that the “C” allele of rs2227478T>C and the “T” allele of rs2227481C>T were obviously related to decreased COPD susceptibility. Genetic model analysis showed that rs2227478T>C and rs2227481C>T were significantly associated with a decreased risk of COPD under dominant models after adjusting for the above factors. In the recessive model, rs2227485T>C was obviously associated with decreased COPD risk. Our data showed that only rs2227485T>C was associated with a decreased COPD risk after Bonferroni correction. The eQTL analysis showed that rs2227485T>C was significantly associated with IL‐22 expression. The pGL4‐rs2227485‐C gene reporter had a higher promoter activity than pGL4‐rs2227485‐T. In our study, rs2227485T>C, located in the promoter region of IL‐22, was associated with a decreased risk of COPD and increased IL‐22 promoter activity, suggesting that this variant might modulate COPD susceptibility.