Genome-Wide Association Study Identification of Novel Loci Associated with Airway Responsiveness in Chronic Obstructive Pulmonary Disease

Hansel, Nadia N.; Paré, Peter D.; Rafaels, Nicholas; Sin, Don D.; Sandford, Andrew J.; Daley, Denise; Vergara, Candelaria; Huang, Lili; Elliott, W. Mark; Pascoe, Chris D.; Arsenault, Bryna A.; Postma, Dirkje S.; Boezen, H. Marike; Bossé, Yohan; Berge, Maarten van den; Hiemstra, Pieter S.; Cho, Michael H.; Litonjua, Augusto A.; Sparrow, David; Ober, Carole; Wise, Robert A.; Connett, John E.; Neptune, Enid; Beaty, Terri H.; Ruczinski, Ingo; Mathias, Rasika A.; Barnes, Kathleen C.

doi:10.1165/rcmb.2014-0198oc

Cited by 27 publications

(23 citation statements)

References 40 publications

(45 reference statements)

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“…Furthermore, some of the other genes with suggestively associated SNPs could be biologically relevant for the BPD phenotype. As an example, variants near the SGCD gene (encoding sarcoglycan delta) are known to be associated with airway responsiveness, a process that is linked to decline in lung function in subjects with COPD 41 . Larger studies are required to assess the potential role of these genes in BPD.…”

Section: Discussionmentioning

confidence: 99%

Genome-wide association study of bronchopulmonary dysplasia: a potential role for variants near the CRP gene

Mahlman

Karjalainen

Huusko

et al. 2017

Sci Rep

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Bronchopulmonary dysplasia (BPD), the main consequence of prematurity, has a significant heritability, but little is known about predisposing genes. The aim of this study was to identify gene loci predisposing infants to BPD. The initial genome-wide association study (GWAS) included 174 Finnish preterm infants of gestational age 24–30 weeks. Thereafter, the most promising single-nucleotide polymorphisms (SNPs) associated with BPD were genotyped in both Finnish (n = 555) and non-Finnish (n = 388) replication cohorts. Finally, plasma CRP levels from the first week of life and the risk of BPD were assessed. SNP rs11265269, flanking the CRP gene, showed the strongest signal in GWAS (odds ratio [OR] 3.2, p = 3.4 × 10−6). This association was nominally replicated in Finnish and French African populations. A number of other SNPs in the CRP region, including rs3093059, had nominal associations with BPD. During the first week of life the elevated plasma levels of CRP predicted the risk of BPD (OR 3.4, p = 2.9 × 10–4) and the SNP rs3093059 associated nominally with plasma CRP levels. Finally, SNP rs11265269 was identified as a risk factor of BPD (OR 1.8, p = 5.3 × 10−5), independently of the robust antenatal risk factors. As such, in BPD, a potential role for variants near CRP gene is proposed.

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Section: Discussionmentioning

confidence: 99%

Genome-wide association study of bronchopulmonary dysplasia: a potential role for variants near the CRP gene

Mahlman

Karjalainen

Huusko

et al. 2017

Sci Rep

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“…Genome wide association study (GWAS) data show Lingo2 genetic polymorphisms in human patients with cancer 19 , asthma 20 , chronic obstructive pulmonary disease 21 , Parkinson's 22 , and Inflammatory bowel disease 23 . Therefore, to understand the spatial pattern of TFF3 and LINGO2 interactions that might be relevant to some of these disease states, human rectal tissues were immunostained with fluorescent antibodies against TFF3 and LINGO2.…”

Section: Discussionmentioning

confidence: 99%

TFF3 is a ligand for LINGO2 that de-represses EGFR to control disease outcome during colitis and gastrointestinal nematode infection

Wei

Park

et al. 2018

Preprint

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Intestinal epithelial cells (IEC) comprise diverse lineages that serve distinct roles necessary for regulation of nutrient absorption, regeneration, immunity, and homeostasis 1,2 . Goblet cells secrete Trefoil factor 3 (TFF3) to maintain mucus viscosity and drive mucosal healing by inhibiting cell death and influencing tight junction protein expression 3 . However, whether TFF3 signaling relies upon conventional ligand-receptor interactions has been unclear for decades. This study demonstrates that the orphan transmembrane protein leucine rich repeat receptor and nogo-interacting protein 2 (LINGO2) immunoprecipitates with TFF3, that LINGO2 and TFF3 co-localize at the IEC cell surface, and that TFF3/LINGO2 interactions block IEC apoptosis. Loss of function studies show that TFF3-driven STAT3 and EGFR activation are both LINGO2 dependent. Importantly, we demonstrate that TFF3 disrupts LINGO2/EGFR interactions that normally restrict EGFR activity, resulting in enhanced EGFR signaling. Excessive EGFR activation in Lingo2 gene deficient mice exacerbates colitic disease and accelerates host resistance to parasitic nematodes, whereas TFF3 deficiency results in host susceptibility. Thus, our data demonstrating that TFF3 functions through a previously unrecognized ligandreceptor interaction with LINGO2 to de-repress LINGO2-dependent inhibition of EGFR activation provides a novel conceptual framework explaining how TFF3-mediates mucosal wound healing through enhanced activation of the EGFR pathway.3 Although Trefoil factor 3 (TFF3) is well known to drive reparative pathways at respiratory, ocular, genitourinary and gastrointestinal mucosa, the identity of a potential TFF3 receptor has remained elusive for several decades 4-8 . In addition to enhancing mucous viscosity 9 , TFF3 induces epithelial cell survival and proliferation, activates EGFR, β-catenin, and STAT3 signaling pathways, and controls tight junction protein expression through ill-defined mechanisms to protect against gastrointestinal (GI) tissue injury and inflammation 3,10 . Since the anti-inflammatory activity of TFF3 suggested that leukocytes may be directly responsive to TFF3, we utilized a human macrophage/monocyte cell line (U937) to first ask whether cytokine release could be regulated in response to rTFF3 exposure in order to isolate the TFF3 receptor. We found that rhTFF3 caused a dose-dependent reduction in endotoxin-mediated TNF release over a range of 1-100 ng/ml and that TFF3 suppression was lost at a higher range of rhTFF3 (100-1000 ng/ml) ( Figure S1A). TFF3-induced interleukin 10 (IL-10) production was found over several orders of magnitude, but was lost at higher doses of rhTFF3 ( Figure 1A). As the dose response is similar to the established range of activity for most cytokine and growth factor receptors 11 , these observations suggested that TFF3 was interacting with a receptor in a conventional manner.TFF3 was likely to interact with its receptor through low-affinity interactions because glycosylation has been shown critical for biological...

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“…48 Significant association has been found for a number of loci already associated with lung function with COPD diagnosis including FAM13A, TNS1, INTS12/GSTCD/NPNT, HTR4, HHIP, AGER, TSHD4, CHRNA5/CHRNA3 and ADAM19. 34,43,[45][46][47][49][50][51][52][53] A 2017 GWAS using 15 256 COPD cases and 47 936 controls identified 22 loci at genome-wide significance which included 13 new COPD associations, 9 of which have previously been associated with lung function. 44 The remaining four loci (EEFSEC, DSP, MTCL1 and SFTPD) were novel.…”

Section: Gwas In Lung Function and Copdmentioning

confidence: 99%

Genetic risk factors for the development of pulmonary disease identified by genome‐wide association

Hall

Sayers

2018

Respirology

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Chronic respiratory diseases are a major cause of morbidity and mortality. Asthma and chronic obstructive pulmonary disease (COPD) combined affect over 500 million people worldwide. While environmental factors are important in disease progression, asthma and COPD have long been known to be heritable with genetic components playing an important role in the risk of developing disease. Identification of genetic variation contributing to disease progression is important for a number of reasons including identification of risk alleles, understanding underlying disease mechanisms and development of novel therapies. Genome‐wide association studies (GWAS) have been successful in identifying many loci associated with lung function, COPD and asthma. In recent years, meta‐analyses and improved imputation have facilitated the growth of GWAS in terms of numbers of subjects and the number of single nucleotide polymorphisms (SNP) that can be interrogated. As a consequence, there has been a significant increase in the number of signals associated with asthma, COPD and lung function. SNP that have shown association with lung function reassuringly show a significant overlap with SNP associated with COPD giving a glimpse at pathways that may be involved in COPD mechanisms including genes in, for example, developmental pathways. In asthma, association signals are often in or near genes involved in both adaptive and innate immune response pathways, epithelial cell homeostasis and airway structural changes. The challenges now are translating these genetic signals into a new understanding of lung biology, understanding how variants impact health and disease and how they may provide opportunities for therapeutic intervention.

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Genome-Wide Association Study Identification of Novel Loci Associated with Airway Responsiveness in Chronic Obstructive Pulmonary Disease

Cited by 27 publications

References 40 publications

Genome-wide association study of bronchopulmonary dysplasia: a potential role for variants near the CRP gene

Genome-wide association study of bronchopulmonary dysplasia: a potential role for variants near the CRP gene

TFF3 is a ligand for LINGO2 that de-represses EGFR to control disease outcome during colitis and gastrointestinal nematode infection

Genetic risk factors for the development of pulmonary disease identified by genome‐wide association

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