scholarly journals A Systematic Analysis of Protein-altering Exonic Variants in Chronic Obstructive Pulmonary Disease

2021 ◽  
Author(s):  
Matthew Moll ◽  
Victoria E. Jackson ◽  
Bing Yu ◽  
Megan L. Grove ◽  
Stephanie J. London ◽  
...  
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Cell Proliferation ◽  
Pulmonary Disease ◽  
Association Studies ◽  
Meta Analysis ◽  
Effect Sizes ◽  
Chronic Obstructive ◽  
Genome Wide Association Studies ◽  
Obstructive Pulmonary Disease ◽  
Coding Variants

Genome-wide association studies (GWASs) have identified regions associated with chronic obstructive pulmonary disease (COPD). GWASs of other diseases have shown an approximately 10-fold overrepresentation of nonsynonymous variants, despite limited exonic coverage on genotyping arrays. We hypothesized that a large-scale analysis of coding variants could discover novel genetic associations with COPD, including rare variants with large effect sizes. We performed a meta-analysis of exome arrays from 218,399 controls and 33,851 moderate-to-severe COPD cases. All exome-wide significant associations were present in regions previously identified by GWAS. We did not identify any novel rare coding variants with large effect sizes. Within GWAS regions on chromosomes 5q, 6p, and 15q, four coding variants were conditionally significant (p < 0.00015) when adjusting for lead GWAS SNPs. A common GSDMB splice variant (rs11078928) previously associated with decreased risk for asthma, was nominally associated with decreased risk for COPD (MAF = 0.46, p=1.8e-4). Two stop variants in CCHCR1, a gene involved in regulating cell proliferation, were associated with COPD (both p < 0.0001). The SERPINA1 Z allele was associated with a random effects odds ratio of 1.43 for COPD (95% CI: 1.17-1.74), though with marked heterogeneity across studies. Overall, COPD-associated exonic variants were identified in genes involved in DNA methylation, cell-matrix interactions, cell proliferation, and cell death. In conclusion, we performed the largest exome array meta-analysis of COPD to date and identified potential functional coding variants. Future studies are needed to identify rarer variants, and further define the role of coding variants in COPD pathogenesis.

scholarly journals Integrative Omics Reveal Novel Protein Targets For Chronic Obstructive Pulmonary Disease Biomarker Discovery

2021 ◽  
Author(s):  
Ana I Hernandez Cordero ◽  
Stephen Milne ◽  
Chen Xi Yang ◽  
Xuan Li ◽  
Henry Shi ◽  
...  
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Lung Function ◽  
Pulmonary Disease ◽  
Biomarker Discovery ◽  
Association Studies ◽  
Chronic Obstructive ◽  
Genome Wide Association Studies ◽  
Causal Association ◽  
Obstructive Pulmonary Disease ◽  
Integrative Omics

AbstractBackgroundLarge genome-wide association studies (GWAS) and other genetic studies have revealed genetic loci that are associated with chronic obstructive pulmonary disease (COPD). However, the proteins responsible for COPD pathogenesis remain elusive. We used integrative-omics by combining genetics of lung function and COPD with genetics of proteome to identify proteins underlying lung function variation and COPD risk.MethodsWe used summary statistics from the GWAS of human plasma proteome from the INTERVAL cohort (n=3,301) and integrated these data with lung function GWAS results from the UK Biobank cohorts (n=400,102) and COPD GWAS results from the ICGC cohort (35,735 cases and 222,076 controls). We performed in parallel: a proteome-wide Bayesian colocalization, and a proteome-wide Mendelian Randomization (MR) analyses. Next, we selected proteins that colocalized with lung function and/or COPD risk and explored their causal association with lung function and/or COPD using MR analysis (P<0.05).ResultsWe found 537, 607, and 250 proteins that colocalized with force expiratory volume in one second (FEV1), FEV1/forced vital capacity (FVC), or COPD risk, respectively. Of these, 1,051 were unique proteins. The sRAGE protein demonstrated the strongest colocalization with FEV1/FVC and COPD risk, while QSOX2, FAM3D and F177A proteins had the strongest associations with FEV1. Of these, 37 proteins that colocalized with lung function and/or COPD, also had a significant causal association. These included proteins such as PDE4D, QSOX2 and RGAP1, amongst others.ConclusionIntegrative-omics reveals new proteins related to lung function. These proteins may play important roles in the pathogenesis of COPD.

scholarly journals Amerindian Ancestry Influences Genetic Susceptibility to Chronic Obstructive Pulmonary Disease

2020 ◽  
Vol 10 (3) ◽  
pp. 93
Author(s):  
Roberto Díaz-Peña ◽  
Felix Boekstegers ◽  
Rafael S. Silva ◽  
Sergio Jaime ◽  
H. Dean Hosgood ◽  
...  
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Pulmonary Disease ◽  
Association Studies ◽  
Genetic Ancestry ◽  
Chronic Obstructive ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Obstructive Pulmonary Disease ◽  
Genome Wide

The contribution of genetic ancestry on chronic obstructive pulmonary disease (COPD) predisposition remains unclear. To explore this relationship, we analyzed the associations between 754,159 single nucleotide polymorphisms (SNPs) and risk of COPD (n = 214 cases, 193 healthy controls) in Talca, Chile, considering the genetic ancestry and established risk factors. The proportion of Mapuche ancestry (PMA) was based on a panel of 45 Mapuche reference individuals. Five PRDM15 SNPs and two PPP1R12B SNPs were associate with COPD risk (p = 0.05 to 5 × 10−4) in those individuals with lower PMA. Based on linkage disequilibrium and sliding window analyses, an adjacent PRDM15 SNPs were associated with COPD risk in the lower PMA group (p = 10−3 to 3.77 × 10−8). Our study is the first to report an association between PPP1R12B and COPD risk, as well as effect modification between ethnicity and PRDM15 SNPs in determining COPD risk. Our results are biologically plausible given that PPP1R12B and PRDM15 are involved in immune dysfunction and autoimmunity, providing mechanistic evidence for COPD pathogenesis and highlighting the importance to conduct more genome wide association studies (GWAS) in admixed populations with Amerindian descent.

scholarly journals rs6837671A>G in FAM13A Is a Trans-Ethnic Genetic Variant Interacting with Vitamin D Levels to Affect Chronic Obstructive Pulmonary Disease

2021 ◽  
Vol 11 (2) ◽  
pp. 84
Author(s):  
Said El Shamieh ◽  
Ali Salami ◽  
Mirna Fawaz ◽  
Rania Jounblat ◽  
Mirna Waked ◽  
...  
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Vitamin D ◽  
Pulmonary Disease ◽  
Genetic Variant ◽  
Meta Analysis ◽  
Chronic Obstructive ◽  
Genome Wide Association Studies ◽  
Obstructive Pulmonary Disease ◽  
Increased Risk ◽  
Vitamin D Levels

(1) Background and objectives: Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality throughout the world. In addition to genetics, increasing evidence suggests that Vitamin D (VitD) might be involved in different pathogenic mechanisms in COPD. Furthermore, the prevalence of VitD insufficiency is exceptionally high in COPD patients and increases with the severity. Based on the above, we first tested the relation between the top 10 single nucleotide polymorphisms from genome-wide association studies and the risk of COPD. Then, we investigated whether VitD levels might also have a role in COPD. A meta-analysis followed, combining our participants with previously published European and non-European populations (15,716 cases and 48,107 controls). (2) Methods: 631 Lebanese participants were recruited, of which ~28% were affected with COPD. Demographic and clinical data were collected, and DNA was genotyped using Kompetitive allele-specific PCR (KASPTM). Adjusted multiple logistic regression models were used. Bonferroni corrections were also applied. The statistical power was also assessed. (3) Results: Both rs6837671A>G in FAM13A and VitD levels were significantly associated with increased risk of COPD (OR = 1.75, p = 0.01, and OR = 3.10, p < 0.001 respectively). An interaction between rs6837671A>G in FAM13A and VitD levels, which increased COPD risk, was found (OR = 3.35 and p < 0.001). The meta-analysis showed that rs6837671G increases COPD risk in populations from different origins; Europeans, Asians, and now in Middle-Eastern. (4) Conclusions: Our results suggest that rs6837671A>G in FAM13A is a trans-ethnic genetic variant that interact with VitD to affect COPD.

scholarly journals An innate contribution of human nicotinic receptor polymorphisms to COPD-like lesions

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Julie Routhier ◽  
Stéphanie Pons ◽  
Mohamed Lamine Freidja ◽  
Véronique Dalstein ◽  
Jérôme Cutrona ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Chronic Obstructive Pulmonary Disease ◽  
Pulmonary Disease ◽  
Association Studies ◽  
Airway Remodeling ◽  
Chronic Obstructive ◽  
Genome Wide Association Studies ◽  
Obstructive Pulmonary Disease ◽  
Genome Wide

AbstractChronic Obstructive Pulmonary Disease is a generally smoking-linked major cause of morbidity and mortality. Genome-wide Association Studies identified a locus including a non-synonymous single nucleotide polymorphism in CHRNA5, rs16969968, encoding the nicotinic acetylcholine receptor α5 subunit, predisposing to both smoking and Chronic Obstructive Pulmonary Disease. Here we report that nasal polyps from rs16969968 non-smoking carriers exhibit airway epithelium remodeling and inflammation. These hallmarks of Chronic Obstructive Pulmonary Disease occur spontaneously in mice expressing human rs16969968. They are significantly amplified after exposure to porcine pancreatic elastase, an emphysema model, and to oxidative stress with a polymorphism-dependent alteration of lung function. Targeted rs16969968 expression in epithelial cells leads to airway remodeling in vivo, increased proliferation and production of pro-inflammatory cytokines through decreased calcium entry and increased adenylyl-cyclase activity. We show that rs16969968 directly contributes to Chronic Obstructive Pulmonary Disease-like lesions, sensitizing the lung to the action of oxidative stress and injury, and represents a therapeutic target.

scholarly journals Whole-genome analyses reveal gene content differences between nontypeable Haemophilus influenzae isolates from chronic obstructive pulmonary disease compared to other clinical phenotypes

2020 ◽  
Vol 6 (8) ◽  
Author(s):  
Rajendra KC ◽  
Kelvin W.C. Leong ◽  
Nicholas M. Harkness ◽  
Julia Lachowicz ◽  
Sanjay S. Gautam ◽  
...  
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Haemophilus Influenzae ◽  
Pulmonary Disease ◽  
Association Studies ◽  
Cellular Respiration ◽  
Chronic Obstructive ◽  
Genome Wide Association Studies ◽  
Obstructive Pulmonary Disease ◽  
Clinical Phenotypes ◽  
The Core

Nontypeable Haemophilus influenzae (NTHi) colonizes human upper respiratory airways and plays a key role in the course and pathogenesis of acute exacerbations of chronic obstructive pulmonary disease (COPD). Currently, it is not possible to distinguish COPD isolates of NTHi from other clinical isolates of NTHi using conventional genotyping methods. Here, we analysed the core and accessory genome of 568 NTHi isolates, including 40 newly sequenced isolates, to look for genetic distinctions between NTHi isolates from COPD with respect to other illnesses, including otitis media, meningitis and pneumonia. Phylogenies based on polymorphic sites in the core-genome did not show discrimination between NTHi strains collected from different clinical phenotypes. However, pan-genome-wide association studies identified 79 unique NTHi accessory genes that were significantly associated with COPD. Furthermore, many of the COPD-related NTHi genes have known or predicted roles in virulence, transmembrane transport of metal ions and nutrients, cellular respiration and maintenance of redox homeostasis. This indicates that specific genes may be required by NTHi for its survival or virulence in the COPD lung. These results advance our understanding of the pathogenesis of NTHi infection in COPD lungs.

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