Anti-Tissue Antibodies Are Related to Lung Function in Chronic Obstructive Pulmonary Disease

Núñez, Belén; Sauleda, Jaume; Antó, Josep M.; Juliá, M. R.; Orozco, Mauricio; Monsó, Eduard; Noguera, Aina; Gómez, Federico P.; Garcia‐Aymerich, Judith; Agustí, Àlvar

doi:10.1164/rccm.201001-0029oc

Cited by 94 publications

(60 citation statements)

References 36 publications

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“…The variant rs181206 is a missense variant in which the minor allele (and COPD risk allele) G results in a leucine-to-proline amino acid change in the IL-27 subunit a-protein (54). Of interest, variants at 16p11.2 have previously been identified in GWASs of early-onset inflammatory bowel disease (33), Crohn's disease (34), type 1 diabetes mellitus (35), and type 1 diabetes autoantibodies (36), adding to existing evidence of pleiotropy in GWASs (55) and to a potential biological link between autoimmune disease and COPD (56)(57)(58). Interestingly, effects at this variant appear to be discordant between diabetes and inflammatory bowel disease; the direction of effect that we found at this locus in COPD seems to be concordant with inflammatory bowel disease but discordant with risk to diabetes (59).…”

Section: Discussionmentioning

confidence: 99%

Exome Array Analysis Identifies a Common Variant in IL27 Associated with Chronic Obstructive Pulmonary Disease

Hobbs

Parker²,

Chen

et al. 2016

Am J Respir Crit Care Med

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Rationale: Chronic obstructive pulmonary disease (COPD) susceptibility is in part related to genetic variants. Most genetic studies have been focused on genome-wide common variants without a specific focus on coding variants, but common and rare coding variants may also affect COPD susceptibility.Objectives: To identify coding variants associated with COPD.Methods: We tested nonsynonymous, splice, and stop variants derived from the Illumina HumanExome array for association with COPD in five study populations enriched for COPD. We evaluated single variants with a minor allele frequency greater than 0.5% using logistic regression. Results were combined using a fixed effects meta-analysis. We replicated novel single-variant associations in three additional COPD cohorts.Measurements and Main Results: We included 6,004 control subjects and 6,161 COPD cases across five cohorts for analysis. Our top result was rs16969968 (P = 1.7 3 10 214 ) in CHRNA5, a locus previously associated with COPD susceptibility and nicotine dependence. Additional top results were found in AGER, MMP3, and SERPINA1. A nonsynonymous variant, rs181206, in IL27 (P = 4.7 3 10 26 ) was just below the level of exome-wide significance but attained exome-wide significance (P = 5.7 3 10 28 ) when combined with results from other cohorts. Gene expression datasets revealed an association of rs181206 and the surrounding locus with expression of multiple genes; several were differentially expressed in COPD lung tissue, including TUFM. Conclusions:In an exome array analysis of COPD, we identified nonsynonymous variants at previously described loci and a novel exome-wide significant variant in IL27. This variant is at a locus previously described in genome-wide associations with diabetes, inflammatory bowel disease, and obesity and appears to affect genes potentially related to COPD pathogenesis.

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Section: Discussionmentioning

confidence: 99%

Exome Array Analysis Identifies a Common Variant in IL27 Associated with Chronic Obstructive Pulmonary Disease

Hobbs

Parker²,

Chen

et al. 2016

Am J Respir Crit Care Med

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“…3). 16,21,29,30 A sensitivity analysis was performed to explore the heterogeneity among studies: this was conducted by sequential omission of individual studies in each group. The pooled FIGURE 2: Meta-analysis of 17 studies that investigated the association between serum C-reactive protein concentration and chronic obstructive pulmonary disease (COPD).…”

Section: 2128 -30mentioning

confidence: 99%

Association between C-reactive Protein Concentration and Chronic Obstructive Pulmonary Disease: A Systematic Review and Meta-analysis

et al. 2012

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“…5) Why does the inflammation in COPD persist even after smoking cessation? For example, the theory of stepwise activation of the immune response suggests the involvement of an autoimmune response as the reason why inflammation persists after smoking cessation; unfortunately, the research performed to date has provided inconsistent results [1,2,[9][10][11][12]. We believe an alternate mechanism that addresses the above-mentioned questions may depend on DNA damage, and not simply on the stepwise activation of the immune response.…”

Section: Introductionmentioning

confidence: 95%

The danger signal plus DNA damage two-hit hypothesis for chronic inflammation in COPD

et al. 2013

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Inflammation in chronic obstructive pulmonary disease (COPD) is thought to originate from the activation of innate immunity by a danger signal (first hit), although this mechanism does not readily explain why the inflammation becomes chronic. Here, we propose a two-hit hypothesis explaining why inflammation becomes chronic in patients with COPD. A more severe degree of inflammation exists in the lungs of patients who develop COPD than in the lungs of healthy smokers, and the large amounts of reactive oxygen species and reactive nitrogen species released from inflammatory cells are likely to induce DNA double-strand breaks (second hit) in the airways and pulmonary alveolar cells, causing apoptosis and cell senescence. The DNA damage response and senescence-associated secretory phenotype (SASP) are also likely to be activated, resulting in the production of pro-inflammatory cytokines. These pro-inflammatory cytokines further stimulate inflammatory cell infiltration, intensifying cell senescence and SASP through a positive-feedback mechanism. This vicious cycle, characterised by mutually reinforcing inflammation and DNA damage, may cause the inflammation in COPD patients to become chronic. Our hypothesis helps explain why COPD tends to occur in the elderly, why the inflammation worsens progressively, why inflammation continues even after smoking cessation, and why COPD is associated with lung cancer. @ERSpublications A vicious cycle, involving mutually reinforcing inflammation and DNA damage, may cause chronic inflammation in COPD http://ow.ly/nYW4u

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Anti-Tissue Antibodies Are Related to Lung Function in Chronic Obstructive Pulmonary Disease

Abstract: Between a quarter and a third of patients with clinically stable COPD present abnormal titers of circulating ANA and AT. The observed relationship between AT and lung function supports a role for autoimmunity in the pathogenesis of COPD.

Cited by 94 publications

References 36 publications

Exome Array Analysis Identifies a Common Variant in IL27 Associated with Chronic Obstructive Pulmonary Disease

Exome Array Analysis Identifies a Common Variant in IL27 Associated with Chronic Obstructive Pulmonary Disease

Association between C-reactive Protein Concentration and Chronic Obstructive Pulmonary Disease: A Systematic Review and Meta-analysis

The danger signal plus DNA damage two-hit hypothesis for chronic inflammation in COPD

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