Mendelian Randomization Study of Interleukin-6 in Chronic Obstructive Pulmonary Disease

Department of Respiratory Medicine, Ghent University and Ghent University Hospital, Ghent, Belgium.
Respiration (Impact Factor: 2.92). 01/2011; 82(6):530-8. DOI: 10.1159/000332336
Source: PubMed

ABSTRACT Cross-sectional studies have demonstrated that increased levels of interleukin-6 (IL6) are present in the airways and blood samples of patients with chronic obstructive pulmonary disease (COPD).
To investigate the association between IL6 and the risk of COPD using a Mendelian randomization approach.
Eight common single-nucleotide polymorphisms (SNPs) in the region of the IL6 gene were genotyped using both TaqMan and Illumina in the Rotterdam Study, a prospective population-based cohort study consisting of 7,983 participants aged 55 years or older, including 928 COPD patients. At baseline, blood was drawn in a random sample of 714 subjects to measure the IL6 plasma level. Analysis of variance, logistic regression, and Cox proportional hazard models--adjusted for age, gender, pack years, and BMI--were used for analyses.
High levels of IL6 (>2.4 pg/ml, the highest tertile) were associated with a three-fold increased risk of developing COPD, in comparison to low levels (<1.4 pg/ml, the lowest tertile). The rs2056576 SNP was associated with a 10% increase in the risk of COPD per additional T allele. However, the association was no longer significant after adjustment. No association was found with other common SNPs in the IL6 gene and COPD.
Although increased IL6 plasma levels at baseline are associated with the risk of developing COPD during follow-up, there was no strong evidence for an association between common variation in the IL6 gene and the risk of COPD.

1 Follower
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background Chronic obstructive pulmonary disease (COPD) is characterized by chronic pulmonary and systematic inflammation. An abnormal adaptive immune response leads to an imbalance between pro- and anti-inflammatory processes. T-helper (Th), T-cytotoxic (Tc) and T-regulatory (Treg) cells may play important roles in immune and inflammatory responses. This study was conducted to clarify the changes and imbalance of cytokines and T lymphocyte subsets in patients with COPD, especially during acute exacerbations (AECOPD). Methods Twenty-three patients with stable COPD (SCOPD) and 21 patients with AECOPD were enrolled in the present study. In addition, 20 age-, sex- and weight-matched non-smoking healthy volunteers were included as controls. The serum levels of selected cytokines (TGF-β, IL-10, TNF-α, IL-17 and IL-9) were measured by enzyme-linked immunosorbent assay (ELISA) kits. Furthermore, the T lymphocyte subsets collected from peripheral blood samples were evaluated by flow cytometry after staining with anti-CD3-APC, anti-CD4-PerCP, anti-CD8- PerCP, anti-CD25-FITC and anti-FoxP3-PE monoclonal antibodies. Importantly, to remove the confounding effects of inflammatory factors, the authors introduced a concept of “inflammation adjustment” and corrected each measured value using representative inflammatory markers, such as TNF-α and IL-17. Results Unlike the other cytokines, serum TGF-β levels were considerably higher in patients with AECOPD relative to the control group regardless of adjustment. There were no significant differences in the percentages of either CD4+ or CD8+ T cells among the three groups. Although Tregs were relatively upregulated during acute exacerbations, their capacities of generation and differentiation were far from sufficient. Finally, the authors noted that the ratios of Treg/IL-17 were similar among groups. Conclusions These observations suggest that in patients with COPD, especially during acute exacerbations, both pro-inflammatory and anti-inflammatory reactions are strengthened, with the pro-inflammatory reactions dominating. Although the Treg/IL-17 ratios were normal, the regulatory T cells were still insufficient to suppress the accompanying increases in inflammation. All of these changes suggest a complicated mechanism of pro- and anti-inflammatory imbalance which needs to be further investigated.
    PLoS ONE 10/2014; 9(10):e111044. DOI:10.1371/journal.pone.0111044 · 3.53 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Abstract Context: Endothelial function is abnormal in chronic obstructive pulmonary disease (COPD); whether endothelial dysfunction causes COPD is unknown. Objective: Test associations of endothelial biomarkers with FEV1 using instrumental variables. Methods: Among 26 907 participants with spirometry, ICAM-1, P-selectin, E-selectin and endothelin-1 were measured in subsets. Results: ICAM-1 and P-selectin were inversely associated with FEV1 among European-Americans (-29 mL and -34 mL per standard deviation of log-transformed biomarker, p < 0.001), as was endothelin-1 among African-Americans (-22 mL, p = 0.008). Genetically-estimated ICAM-1 and P-selectin were not significantly associated with FEV1. The instrumental variable for endothelin-1 was non-informative. Conclusion: Although ICAM-1, P-selectin and endothelin-1 were inversely associated with FEV1, associations for ICAM-1 and P-selectin do not appear causal.
    Biomarkers 04/2013; 18(3). DOI:10.3109/1354750X.2012.762805 · 2.52 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The burden of chronic obstructive pulmonary disease (COPD) is high and rising in the low and middle income countries. The most common risk factor is smoking but COPD is a complex multifactorial disease caused by interaction of genes and other environmental factors in addition to smoking. A genetic basis for COPD is illustrated by the rare genetic syndrome of α1- antitrypsin deficiency. Lung volumes (e.g., force vital capacity and forced expiratory volume in 1 second) are quantitative physiologic and diagnostic measures of COPD and have high heritability. Explaining this high heritability of lung function at genomic scale has only become possible in last few years with the advent of genome-wide association studies. In this review, we discuss standard approaches to the study of genetic causes of COPD, present the latest developments in genomics of COPD, and consider the utility of genetic variants in establishing causal relationships between modifiable environmental exposures and COPD—Mendelian randomization.
    Chronic Obstructive Pulmonary Disease, 1 edited by S.K. Jindal, 01/2013: chapter Genomics of Chronic Obstructive Pulmonary Disease: pages 55-71; World Clin Pulm Crit Care Med.., ISBN: 2319-1260


Available from
May 20, 2014