APOM and high-density lipoprotein cholesterol are associated with lung function and per cent emphysema

Manichaikul, Ani; Wilk, Jemma B.; Ahmed, Firas S.; Burke, Gregory L.; Enright, Paul; Hansel, Nadia N.; Haynes, Demondes; Heckbert, Susan R.; Hoffman, Eric A.; Kaufman, Joel D.; Kurai, Jun; Loehr, Laura R.; London, Stephanie J.; Meng, Yang; O’Connor, George T.; Oelsner, Elizabeth C.; Petrini, Marcy F.; Pottinger, Tess D.; Powell, Charles A.; Redline, Susan; Rotter, Jerome I.; Smith, Lewis J.; Artigas, María Soler; Tobin, Martin D.; Tsai, Michael Y.; Watson, Karol E.; White, Wendy B.; Young, Taylor; Rich, Stephen S.; Barr, R. Graham

doi:10.1183/09031936.00147612

Cited by 38 publications

(45 citation statements)

References 97 publications

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“…In turn, HDL might increase inflammation by its protein cargo, including serum amyloid A1, a major apolipoprotein in HDL during inflammation . Interestingly, recent large epidemiological study has demonstrated that higher HDL is associated with lower FEV 1 /FVC ratio and greater percent of emphysema in COPD . Our report lines this observation, indicating HDL as a potent determinant of RBM thickening and higher LAA%.…”

Section: Discussionsupporting

confidence: 85%

The relationship of airway structural changes to blood and bronchoalveolar lavage biomarkers, and lung function abnormalities in asthma

Koźlik

Zuk

Bartyzel

et al. 2019

Clin Experimental Allergy

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Background: Airway structural changes are important in asthma pathology and require further investigations.Objective: We sought to evaluate which computed tomography (CT) indices, bronchial histological traits, or blood and bronchoalveolar lavage (BAL) biomarkers correlate best with lung function abnormalities in asthma. Methods:In 105 white adult asthmatics (53 with a component of fixed airflow obstruction), we determined airway cross-sectional geometry of two proximal (the right upper lobe apical segmental and the left apicoposterior) and two distal (the right and the left basal posterior) bronchi, quantified the low-attenuation lung area (LAA%), and analysed clusters based on airway CT-metrics. We also performed bronchofiberoscopy with BAL and endobronchial biopsy, assessed blood and BAL biomarkers, including interleukin (IL)-4, IL-5, IL-6, IL-10, IL-12p70, IL-17A, IL-23, interferon (INF)γ and periostin, together with circulating a disintegrin and metalloproteinase domain-containing protein (ADAM)33, and investigated interplays between analysed variables.Results: Patients with fixed airflow limitation were characterized by lower lumen area and increased wall area and wall thickness ratios in distal airways, accompanied by raised LAA%. They had also higher blood neutrophilia, blood and BAL eosinophilia, increased circulating fibrinogen, periostin, and ADAM33. Blood neutrophilia, serum high density lipoproteins, thyroid-stimulating hormone, and shortened activated partial thromboplastin time were determinants of thicker reticular basement membrane (RBM). BAL eosinophilia was the only positive predictor of collagen I accumulation. Surprisingly, we observed a negative correlation between RBM thickening and collagen I deposit. Cluster analysis based on CT-metrics of the right lower lobe basal posterior bronchus revealed three well-separated clusters similar in age, asthma duration, and BMI, but different in RBM thickness, collagen I accumulation, and inflammatory markers.Conclusions and clinical relevance: Airway remodelling traits are mainly related to the Th 2 profile, higher circulating ADAM33, and blood neutrophilia. Lung function

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Section: Discussionsupporting

confidence: 85%

The relationship of airway structural changes to blood and bronchoalveolar lavage biomarkers, and lung function abnormalities in asthma

Koźlik

Zuk

Bartyzel

et al. 2019

Clin Experimental Allergy

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“…Lipoproteins may have pathophysiologic importance in lung disease 82 ; differences in apolipoprotein B have been described in association with lung function and COPD 83,84 , and a recent study identified an association between SNPs near APOM , lung function, and emphysema 85 . Similarly, our GRAIL analysis suggested a role for oncostatin M and its receptor, which may be of interest in COPD and emphysema 86,87 .…”

Section: Discussionmentioning

confidence: 99%

Risk loci for chronic obstructive pulmonary disease: a genome-wide association study and meta-analysis

Cho

McDonald

Zhou

et al. 2014

The Lancet Respiratory Medicine

295

307

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Background The genetic risk factors for susceptibility to chronic obstructive pulmonary disease (COPD) are still largely unknown. Additional genetic variants are likely to be identified by genome-wide association studies in larger cohorts or specific subgroups. Methods Genome-wide association analysis in COPDGene (non-Hispanic whites and African-Americans) was combined with existing data from the ECLIPSE, NETT/NAS, and GenKOLS (Norway) studies. Analyses were performed both using all moderate-to-severe cases and the subset of severe cases. Top loci not previously described as genome-wide significant were genotyped in the ICGN study, and results combined in a joint meta-analysis. Findings Analysis of a total of 6,633 moderate-to-severe cases and 5,704 controls confirmed association at three known loci: CHRNA3/CHRNA5/IREB2, FAM13A, and HHIP (10−12 < P < 10−14), and also showed significant evidence of association at a novel locus near RIN3 (overall P, including ICGN = 5•4×10−9). In the severe COPD analysis (n=3,497), the effects at two of three previously described loci were significantly stronger; we also identified two additional loci previously reported to affect gene expression of MMP12 and TGFB2 (overall P = 2•6x10−9 and 8•3×10−9). RIN3 and TGFB2 expression levels were reduced in a set of Lung Tissue Research Consortium COPD lung tissue samples compared with controls. Interpretation In a genome-wide study of COPD, we confirmed associations at three known loci and found additional genome-wide significant associations with moderate-to-severe COPD near RIN3 and with severe COPD near MMP12 and TGFB2. Genetic variants, apart from alpha-1 antitrypsin deficiency, increase the risk of COPD. Our analysis of severe COPD suggests additional genetic variants may be identified by focusing on this subgroup. Funding National Heart, Lung, and Blood Institute; the COPD Foundation through contributions from AstraZeneca, Boehringer Ingelheim, Novartis, and Sepracor; GlaxoSmithKline; Centers for Medicare and Medicaid Services; Agency for Healthcare Research and Quality; US Department of Veterans Affairs.

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“…Another top association was with rs679620 in MMP3, which is in the same region recently associated with severe COPD in a GWAS meta-analysis (6). The variant rs2070600 in AGER is associated with COPD and quantitative computed tomography-identified emphysema, and was first identified as genome-wide significant in GWASs of FEV 1 /FVC ratio (50)(51)(52)(53).…”

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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APOM and high-density lipoprotein cholesterol are associated with lung function and per cent emphysema

Cited by 38 publications

References 97 publications

The relationship of airway structural changes to blood and bronchoalveolar lavage biomarkers, and lung function abnormalities in asthma

The relationship of airway structural changes to blood and bronchoalveolar lavage biomarkers, and lung function abnormalities in asthma

Risk loci for chronic obstructive pulmonary disease: a genome-wide association study and meta-analysis

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

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