Abstract
BackgroundElevated circulating levels of C-reactive protein (CRP), interleukin (IL)-6 and fibrinogen (FG) have been repeatedly associated with many adverse outcomes in patients with chronic obstructive pulmonary disease (COPD). To date, it remains unclear whether and to what extent systemic inflammation is primary or secondary in the pathogenesis of COPD.The aim of this study was to examine the association between haplotypes of CRP, IL6 and FGB genes, systemic inflammation, COPD risk and COPD-related phenotypes (respiratory impairment, exercise capacity and body composition).MethodsEighteen SNPs in three genes, representing optimal haplotype-tagging sets, were genotyped in 355 COPD patients and 195 healthy smokers. Plasma levels of CRP, IL-6 and FG were measured in the total study group. Differences in haplotype distributions were tested using the global and haplotype-specific statistics.ResultsRaised plasma levels of CRP, IL-6 and fibrinogen were demonstrated in COPD patients. However, COPD population was very heterogeneous: about 40% of patients had no evidence of systemic inflammation (CRP < 3 mg/uL or no inflammatory markers in their top quartile). Global test for haplotype effect indicated association of CRP gene and CRP plasma levels (P = 0.0004) and IL6 gene and COPD (P = 0.003). Subsequent analysis has shown that IL6 haplotype H2, associated with an increased COPD risk (p = 0.004, OR = 4.82; 1.64 to 4.18), was also associated with very low CRP levels (p = 0.0005). None of the genes were associated with COPD-related phenotypes.ConclusionOur findings suggest that common genetic variation in CRP and IL6 genes may contribute to heterogeneity of COPD population associated with systemic inflammation.
Highlights
Elevated circulating levels of C-reactive protein (CRP), interleukin (IL)-6 and fibrinogen (FG) have been repeatedly associated with many adverse outcomes in patients with chronic obstructive pulmonary disease (COPD)
The COPD population was very heterogeneous: 27.3% of COPD patients had CRP levels > 10 mg/L, which is a significantly higher proportion than in healthy smokers (5.2%), whereas about 40% of COPD patents had no evidence of systemic inflammation as assessed by CRP levels alone (< 3 mg/L) or by the number of inflammatory markers in their top quartiles
We identified two CRP and one Interleukin 6 (IL6) Single Nucleotide Polymorphism (SNP), which were significantly associated with decreased CRP levels
Summary
Elevated circulating levels of C-reactive protein (CRP), interleukin (IL)-6 and fibrinogen (FG) have been repeatedly associated with many adverse outcomes in patients with chronic obstructive pulmonary disease (COPD). Raised levels of acute phase proteins like C-reactive protein (CRP), fibrinogen and pro-inflammatory cytokines such as interleukin (IL)-6 were found in circulation of stable COPD patients [3,6] and have been shown to be associated with impaired functional capacity [7], reduced daily physical activity [8] and decreased health status [5,7,9]. Given the cross-sectional nature of most studies performed so far and possible confounding by a number of lifestyle factors associated with levels of inflammatory biomarkers [10], it is not clear whether these proteins are markers of the inflammatory process accompanying chronic diseases such as COPD or key players in the pathogenesis of disease. Genetic association testing of genotypes, which influence circulating levels of proteins and directly relate to the outcome of interest, was suggested as more accurate unconfounded estimate of whether systemic inflammation levels causally influence outcome [20]
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