scholarly journals Genetic evidence supports the development of SLC26A9 targeting therapies for the treatment of lung disease

2021 ◽  
Author(s):  
Jiafen Gong ◽  
Gengming He ◽  
Cheng Wang ◽  
Claire Bartlett ◽  
Naim Panjwani ◽  
...  
Keyword(s):  
Lung Function ◽  
Therapeutic Target ◽  
Unmet Need ◽  
Chronic Obstructive ◽  
Improve Lung Function ◽  
Obstructive Pulmonary Disease ◽  
Large Variability ◽  
Cf Transmembrane Conductance Regulator ◽  
The Uk ◽  
Cftr Modulators

Background: Over 400 variants in the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) are CF-causing. CFTR modulators target different variants to improve lung function, but large variability in response exists and current therapies do not address all CF-causing variants highlighting an unmet need. Alternative epithelial ion channels such as SLC26A9 could compensate for CFTR dysfunction, providing a therapeutic target that benefits all individuals with CF. Method: We investigate the relationship between SLC26A9 and lung function pre- and post-treatment with CFTR modulators in Canadian and US CF cohorts, in the general population, and in those with chronic obstructive pulmonary disease (COPD). Results: SLC26A9 rs7512462 CC genotype is associated with greater lung function in individuals with minimal function variants (for which there are currently no approved therapies; p=0.002); and gating (p=0.03) and p.Phe508del/ p.Phe508del (p=0.009) genotypes upon treatment with CFTR modulators. Analogously, p.Phe508del/p.Phe508del human nasal epithelia with CC after triple combination modulator treatment show greatest CFTR function (p=8x10-4). Beyond CF, rs7512462 is associated with lung function in the UK Biobank (meta-p=2.74x10-44) and in COPD (min p=0.007). Conclusion: These findings support SLC26A9 as a therapeutic target to improve lung function for all people with CF and in individuals with other obstructive lung diseases such as COPD.

scholarly journals Whole genome sequence analysis of pulmonary function and COPD in 19,996 multi-ethnic participants

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Xutong Zhao ◽  
◽  
Dandi Qiao ◽  
Chaojie Yang ◽  
Silva Kasela ◽  
...  
Keyword(s):  
Lung Function ◽  
Genome Sequence ◽  
Molecular Mechanisms ◽  
Whole Genome Sequence ◽  
European Ancestry ◽  
Chronic Obstructive ◽  
Whole Genome ◽  
Obstructive Pulmonary Disease ◽  
Family Based ◽  
The Uk

Abstract Chronic obstructive pulmonary disease (COPD), diagnosed by reduced lung function, is a leading cause of morbidity and mortality. We performed whole genome sequence (WGS) analysis of lung function and COPD in a multi-ethnic sample of 11,497 participants from population- and family-based studies, and 8499 individuals from COPD-enriched studies in the NHLBI Trans-Omics for Precision Medicine (TOPMed) Program. We identify at genome-wide significance 10 known GWAS loci and 22 distinct, previously unreported loci, including two common variant signals from stratified analysis of African Americans. Four novel common variants within the regions of PIAS1, RGN (two variants) and FTO show evidence of replication in the UK Biobank (European ancestry n ~ 320,000), while colocalization analyses leveraging multi-omic data from GTEx and TOPMed identify potential molecular mechanisms underlying four of the 22 novel loci. Our study demonstrates the value of performing WGS analyses and multi-omic follow-up in cohorts of diverse ancestry.

scholarly journals SNPs associated withHHIPexpression have differential effects on lung function in males and females

2019 ◽  
Author(s):  
KA Fawcett ◽  
M Obeidat ◽  
CA Melbourne ◽  
N Shrine ◽  
AL Guyatt ◽  
...  
Keyword(s):  
Lung Function ◽  
Lung Tissue ◽  
Forced Expiratory Volume ◽  
Chronic Obstructive ◽  
Interacting Protein ◽  
Obstructive Pulmonary Disease ◽  
Differential Effects ◽  
Genome Wide ◽  
Males And Females ◽  
The Uk

AbstractAdult lung function is highly heritable and 279 genetic loci were recently reported as associated with spirometry-based measures of lung function. Though lung development and function differ between males and females throughout life, there has been no genome-wide study to identify genetic variants with differential effects on lung function in males and females. Here, we present the first genome-wide genotype-by-sex interaction study on four lung function traits in 303,612 participants from the UK Biobank. We detected five SNPs showing genome-wide significant (P<5 × 10−8) interactions with sex on lung function, as well as 21 suggestively significant interactions (P<1 × 10−6). The strongest sex interaction signal came from rs7697189 at 4:145436894 on forced expiratory volume in 1 second (FEV1) (P = 3.15 × 10−15), and was replicated (P = 0.016) in 75,696 individuals in the SpiroMeta consortium. Sex-stratified analyses demonstrated that the minor (C) allele of rs7697189 increased lung function to a greater extent in males than females (untransformed FEV1β = 0.028 [SE 0.0022] litres in males vs β = 0.009 [SE 0.0014] litres in females), and this effect was not accounted for by differential effects on height, smoking or age at puberty. This SNP resides upstream of the gene encoding hedgehog-interacting protein (HHIP) and has previously been reported for association with lung function andHHIPexpression in lung tissue. In our analyses, whileHHIPexpression in lung tissue was significantly different between the sexes with females having higher expression (most significant probeset P=6.90 × 10−6) after adjusting for age and smoking, rs7697189 did not demonstrate sex differential effects on expression. Establishing the mechanism by whichHHIPSNPs have different effects on lung function in males and females will be important for our understanding of lung health and diseases, such as chronic obstructive pulmonary disease (COPD), in both sexes.

Screening of High-risk Patients for Chronic Obstructive Pulmonary Disease in Primary Care: A Narrative Review (Preprint)

2020 ◽  
Author(s):  
Ponrathi Athilingam ◽  
Andrew Bugajski ◽  
Usha Menon
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Lung Function ◽  
Pulmonary Disease ◽  
Current Knowledge ◽  
Screening Tools ◽  
Chronic Obstructive ◽  
Early Screening ◽  
Obstructive Pulmonary Disease ◽  
Impaired Lung Function ◽  
Risk Patients

UNSTRUCTURED Chronic obstructive pulmonary disease (COPD) predominantly affects older adults, and claimed 3 million lives in 2016, making it the third leading cause of death worldwide. Over 35 million Americans aged 40 or older have lung function consistent with diagnosable COPD. COPD and cardiovascular disease (CVD) have a bidirectional relationship, in that one is a risk factor for developing the other. National and international consortiums recommend early screening of adults at risk of COPD, such as those with CVD. Recommended screening strategies include screening tools to assess symptoms, medical history, and handheld spirometry. Handheld spirometry has high diagnostic accuracy and if impaired lung function is indicated, these patients are referred for pulmonary function testing (PFT), the diagnostic gold standard for COPD. However, there is no clinical consensus for pulmonary screening in people with CVD. Current knowledge relating to the prevalence and incidence of CVD in people with COPD and the mechanisms that underlie their coexistence is key in combating the global burden of COPD.

scholarly journals Prognostic and functional impact of perioperative LAMA/LABA inhaled therapy in patients with lung cancer and chronic obstructive pulmonary disease

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Yoko Azuma ◽  
Atsushi Sano ◽  
Takashi Sakai ◽  
Satoshi Koezuka ◽  
Hajime Otsuka ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Chronic Obstructive Pulmonary Disease ◽  
Postoperative Complications ◽  
Lung Function ◽  
Retrospective Review ◽  
Forced Expiratory Volume ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Inhaled Therapy ◽  
Long Acting

Abstract Background Chronic obstructive pulmonary disease (COPD) is an important risk factor for postoperative complications and mortality. To determine the effects of perioperative combination therapy, using a long-acting muscarinic antagonist (LAMA) and a long-acting β2 agonist (LABA), on preoperative lung function, postoperative morbidity and mortality, and long-term outcome in COPD patients. Methods Between January 2005 and October 2019, 130 consecutive patients with newly diagnosed COPD underwent surgery for lung cancer. We conducted a retrospective review of their medical record to evaluate that LAMA/LABA might be an optimal regimen for patients with COPD undergoing surgery for lung cancer. All patients were received perioperative rehabilitation and divided into 3 groups according to the type of perioperative inhaled therapy and management: LAMA/LABA (n = 64), LAMA (n = 23) and rehabilitation only (no bronchodilator) (n = 43). We conducted a retrospective review of their medical records. Results Patients who received preoperative LAMA/LABA therapy showed significant improvement in lung function before surgery (p < 0.001 for both forced expiratory volume in 1 s (FEV1) and percentage of predicted forced expiratory volume in 1 s (FEV1%pred). Compared with patients who received preoperative LAMA therapy, patients with LAMA/LABA therapy had significantly improved lung function (ΔFEV1, LAMA/LABA 223.1 mL vs. LAMA 130.0 mL, ΔFEV1%pred, LAMA/LABA 10.8% vs. LAMA 6.8%; both p < 0.05). Postoperative complications were lower frequent in the LAMA/LABA group than in the LAMA group (p = 0.007). In patients with moderate to severe air flow limitation (n = 61), those who received LAMA/LABA therapy had significantly longer overall survival and disease-free survival compared with the LAMA (p = 0.049, p = 0.026) and rehabilitation-only groups (p = 0.001, p < 0.001). Perioperative LAMA/LABA therapy was also associated with lower recurrence rates (vs. LAMA p = 0.006, vs. rehabilitation-only p = 0.008). Conclusions We believe this treatment combination is optimal for patients with lung cancer and COPD.

scholarly journals Pulmonary restriction predicts long-term pulmonary impairment in people with HIV and tuberculosis

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Sara C. Auld ◽  
Hardy Kornfeld ◽  
Pholo Maenetje ◽  
Mandla Mlotshwa ◽  
William Chase ◽  
...  
Keyword(s):  
Lung Function ◽  
Confidence Interval ◽  
Odds Ratio ◽  
Adjusted Odds Ratio ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Logistic Regression Models ◽  
Pulmonary Impairment ◽  
Mixed Pattern

Abstract Background While tuberculosis is considered a risk factor for chronic obstructive pulmonary disease, a restrictive pattern of pulmonary impairment may actually be more common among tuberculosis survivors. We aimed to determine the nature of pulmonary impairment before and after treatment among people with HIV and tuberculosis and identify risk factors for long-term impairment. Methods In this prospective cohort study conducted in South Africa, we enrolled adults newly diagnosed with HIV and tuberculosis who were initiating antiretroviral therapy and tuberculosis treatment. We measured lung function and symptoms at baseline, 6, and 12 months. We compared participants with and without pulmonary impairment and constructed logistic regression models to identify characteristics associated with pulmonary impairment. Results Among 134 participants with a median CD4 count of 110 cells/μl, 112 (83%) completed baseline spirometry at which time 32 (29%) had restriction, 13 (12%) had obstruction, and 9 (7%) had a mixed pattern. Lung function was dynamic over time and 30 (33%) participants had impaired lung function at 12 months. Baseline restriction was associated with greater symptoms and with long-term pulmonary impairment (adjusted odds ratio 5.44, 95% confidence interval 1.16–25.45), while baseline obstruction was not (adjusted odds ratio 1.95, 95% confidence interval 0.28–13.78). Conclusions In this cohort of people with HIV and tuberculosis, restriction was the most common, symptomatic, and persistent pattern of pulmonary impairment. These data can help to raise awareness among clinicians about the heterogeneity of post-tuberculosis pulmonary impairment, and highlight the need for further research into mediators of lung injury in this vulnerable population.

scholarly journals FSTL1 aggravates cigarette smoke-induced airway inflammation and airway remodeling by regulating autophagy

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Ying Liu ◽  
Jiawei Xu ◽  
Tian Liu ◽  
Jinxiang Wu ◽  
Jiping Zhao ◽  
...  
Keyword(s):  
Lung Function ◽  
Airway Inflammation ◽  
Cigarette Smoke ◽  
Airway Remodeling ◽  
Critical Factor ◽  
Lavage Fluid ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Copd Patients ◽  
Impaired Lung Function

Abstract Background Cigarette smoke (CS) is a major risk factor for Chronic Obstructive Pulmonary Disease (COPD). Follistatin-like protein 1 (FSTL1), a critical factor during embryogenesis particularly in respiratory lung development, is a novel mediator related to inflammation and tissue remodeling. We tried to investigate the role of FSTL1 in CS-induced autophagy dysregulation, airway inflammation and remodeling. Methods Serum and lung specimens were obtained from COPD patients and controls. Adult female wild-type (WT) mice, FSTL1± mice and FSTL1flox/+ mice were exposed to room air or chronic CS. Additionally, 3-methyladenine (3-MA), an inhibitor of autophagy, was applied in CS-exposed WT mice. The lung tissues and serum from patients and murine models were tested for FSTL1 and autophagy-associated protein expression by ELISA, western blotting and immunohistochemical. Autophagosome were observed using electron microscope technology. LTB4, IL-8 and TNF-α in bronchoalveolar lavage fluid of mice were examined using ELISA. Airway remodeling and lung function were also assessed. Results Both FSTL1 and autophagy biomarkers increased in COPD patients and CS-exposed WT mice. Autophagy activation was upregulated in CS-exposed mice accompanied by airway remodeling and airway inflammation. FSTL1± mice showed a lower level of CS-induced autophagy compared with the control mice. FSTL1± mice can also resist CS-induced inflammatory response, airway remodeling and impaired lung function. CS-exposed WT mice with 3-MA pretreatment have a similar manifestation with CS-exposed FSTL1± mice. Conclusions FSTL1 promotes CS-induced COPD by modulating autophagy, therefore targeting FSTL1 and autophagy may shed light on treating cigarette smoke-induced COPD.

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