Interferon gamma polymorphisms and their interaction with smoking are associated with lung function

He, Jian‐Qing; Burkett, Kelly; Connett, John E.; Anthonisen, Nicholas R.; Paré, Peter D.; Sandford, Andrew J.

doi:10.1007/s00439-006-0143-z

Cited by 11 publications

(8 citation statements)

References 53 publications

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“…Both animal and human studies have shown increased inflammatory proteins in the presence of cigarette smoke [30], [31], [32] and prior groups have found smoking-dependent differential associations between inflammatory proteins and markers of disease severity [33]. Relevant to our finding of a direct association of IFN-γ and IL-13 with WA% in current, but not former, smokers, others have also demonstrated interactions between smoking and both IFN-γ [34] and IL-13 [35] polymorphisms in association with lung function. We have further defined specific associations with CT measures of airway thickening independent of airflow obstruction.…”

Section: Discussionsupporting

confidence: 67%

The Influence of Radiographic Phenotype and Smoking Status on Peripheral Blood Biomarker Patterns in Chronic Obstructive Pulmonary Disease

et al. 2009

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BackgroundChronic obstructive pulmonary disease (COPD) is characterized by both airway remodeling and parenchymal destruction. The identification of unique biomarker patterns associated with airway dominant versus parenchymal dominant patterns would support the existence of unique phenotypes representing independent biologic processes. A cross-sectional study was performed to examine the association of serum biomarkers with radiographic airway and parenchymal phenotypes of COPD.Methodology/Principal FindingsSerum from 234 subjects enrolled in a CT screening cohort was analyzed for 33 cytokines and growth factors using a multiplex protein array. The association of serum markers with forced expiratory volume in one second percent predicted (FEV1%) and quantitative CT measurements of airway thickening and emphysema was assessed with and without stratification for current smoking status. Significant associations were found with several serum inflammatory proteins and measurements of FEV1%, airway thickening, and parenchymal emphysema independent of smoking status. The association of select analytes with airway thickening and emphysema was independent of FEV1%. Furthermore, the relationship between other inflammatory markers and measurements of physiologic obstruction or airway thickening was dependent on current smoking status.Conclusions/SignificanceAirway and parenchymal phenotypes of COPD are associated with unique systemic serum biomarker profiles. Serum biomarker patterns may provide a more precise classification of the COPD syndrome, provide insights into disease pathogenesis and identify targets for novel patient-specific biological therapies.

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Section: Discussionsupporting

confidence: 67%

The Influence of Radiographic Phenotype and Smoking Status on Peripheral Blood Biomarker Patterns in Chronic Obstructive Pulmonary Disease

et al. 2009

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“…In contrast with our previous studies,5,6 there was no association of any polymorphism with the rate of decline of lung function (Table 3). Similarly, there was no association of the polymorphisms with measures of baseline lung function in the same subset of individuals (Table 3).…”

Section: Resultscontrasting

confidence: 99%

Effect of gene environment interactions on lung function and cardiovascular disease in COPD

Hackett

Stefanowicz

Aminuddin

et al. 2011

COPD

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Background:The objective of this study was to determine if gene-environment interactions between cigarette smoking and interleukin-6 (IL6), interferon-γ (IFNG), interleukin-1β (IL1B), or interleukin-1 receptor antagonist (IL1RN) single nucleotide polymorphisms are associated with lung function decline and cardiovascular disease in chronic obstructive pulmonary disease (COPD).Methods:Single nucleotide polymorphisms (SNPs) in IL6, IFNG, IL1B, and IL1RN were genotyped in the Lung Health Study and correlated with rate of decline of forced expiratory volume in 1 second (FEV1) over 5 years, baseline FEV1, serum protein levels, cardiovascular disease, and interactions with smoking.Results:The IL6 rs2069825 single nucleotide polymorphism was associated with the rate of decline of prebronchodilator FEV1 (P = 0.049), and was found to have a significant interaction (P = 0.004) with mean number of cigarettes smoked per day. There was also a significant interaction of IFNG rs2069727 with smoking on prebronchodilator (P = 0.008) and postbronchodilator (P =0.01) FEV1. The IL6 polymorphism was also associated with cardiovascular disease in heterozygous individuals (P = 0.044), and was found to have a significant interaction with smoking (P = 0.024). None of the genetic variants were associated with their respective serum protein levels.Conclusion:The results suggest interactions of IL6 rs2069825 and IFNG rs2069727 single nucleotide polymorphisms with cigarette smoking on measures of lung function. The IL6 rs2069825 single nucleotide polymorphism also interacted with smoking to affect the risk of cardiovascular disease in COPD patients.

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“…All three studies have relatively small sample sizes. The associations of IL6 SNPs with FEV 1 decline in the current study are novel and are the most significant findings among all the studies we have published utilizing the LHS cohort 13–16,24–27. To strengthen our initial finding in the LHS, we incorporated an association study of IL6 SNPs with COPD in the NETT-NAS.…”

Section: Discussionmentioning

confidence: 77%

“…The LHS cohort provides an excellent opportunity to explore associations between gene polymorphisms and haplotypes with FEV 1 % predicted13,14 as well as the rate of decline in FEV 1 15,16. To validate novel associations between IL6 SNPs with lung function phenotypes, replication of results was sought in COPD cases from the National Emphysema Treatment Trial (NETT) with participants from the Normative Aging Study (NAS) serving as controls 17,18…”

Section: Introductionmentioning

confidence: 99%

Associations of IL6 polymorphisms with lung function decline and COPD

Foreman

Shumansky

et al. 2009

Thorax

109

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Background: Interleukin-6 (IL6) is a pleiotropic proinflammatory and immunomodulatory cytokine which probably plays an important role in the pathogenesis of chronic obstructive pulmonary disease (COPD). There is a functional single nucleotide polymorphism (SNP), -174G/ C, in the promoter region of IL6. It was hypothesised that IL6 SNPs influence susceptibility for impaired lung function and COPD in smokers. Methods: Seven and five SNPs in IL6 were genotyped in two nested case-control samples derived from the Lung Health Study (LHS) based on phenotypes of rate of decline of forced expiratory volume in 1 s (FEV 1 ) over 5 years and baseline FEV 1 at the beginning of the LHS. Serum IL6 concentrations were measured for all subjects. A partially overlapping panel of nine IL6 SNPs was genotyped in 389 cases of COPD from the National Emphysema Treatment Trial (NETT) and 420 controls from the Normative Aging Study (NAS). Results: In the LHS, three IL6 SNPs were associated with decline in FEV 1 (0.023(p(0.041 in additive models). Among them, the IL6_-174C allele was associated with a rapid decline in lung function. The association was more significant in a genotype-based analysis (p = 0.006). In the NETT-NAS study, IL6_-174G/C and four other IL6 SNPs, all of which are in linkage disequilibrium with IL6_-174G/C, were associated with susceptibility to COPD (0.01(p(0.04 in additive genetic models). Conclusion:The results suggest that the IL6_-174G/C SNP is associated with a rapid decline in FEV 1 and susceptibility to COPD in smokers.Interleukin 6 (IL6) is a pleiotropic pro-inflammatory and immunomodulatory cytokine secreted by airway epithelial cells, alveolar macrophages, adipocytes and myocytes as well as other tissues and cells.1 2 The potential importance of IL6 in the pathogenesis of chronic obstructive pulmonary disease (COPD) is suggested by studies showing that high levels of serum or sputum IL6 are associated with impaired lung function or a faster decline in lung function.1 2 IL6 has been related to skeletal muscle weakness in COPD, 3 as well as to exacerbations 4 and pulmonary infections 5 in patients with COPD. In addition, overexpression of IL6 in the murine lung resulted in airway inflammation and emphysema-like airspace enlargement. 6 Furthermore, IL6 is an important mediator of the acute phase response and can upregulate C-reactive protein (CRP) at the transcriptional level.7 CRP has been associated with lung function levels in healthy individuals and/or lung function decline in smoking-induced COPD. Taken together, these data support IL6 as an appealing candidate gene for smoking-induced lung function impairment and COPD.The IL6 gene is located on chromosome 7p21. Previous studies have identified a functional single nucleotide polymorphism (SNP), -174G/C, in the promoter region of IL6.10 Before initiation of the current study, a small study reported no association of an IL6 SNP with COPD.11 Recently, another group showed that the IL6_-572C allele was associated with COPD.12 Large well-designed stu...

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Interferon gamma polymorphisms and their interaction with smoking are associated with lung function

Cited by 11 publications

References 53 publications

The Influence of Radiographic Phenotype and Smoking Status on Peripheral Blood Biomarker Patterns in Chronic Obstructive Pulmonary Disease

The Influence of Radiographic Phenotype and Smoking Status on Peripheral Blood Biomarker Patterns in Chronic Obstructive Pulmonary Disease

Effect of gene environment interactions on lung function and cardiovascular disease in COPD

Associations of IL6 polymorphisms with lung function decline and COPD

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