IL6 and CRP haplotypes are associated with COPD risk and systemic inflammation: a case-control study.
BACKGROUND
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). 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).


METHODS
Eighteen 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.


RESULTS
Raised 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.


CONCLUSIONS
Our findings suggest that common genetic variation in CRP and IL6 genes may contribute to heterogeneity of COPD population associated with systemic inflammation.
Yanbaeva
Dilyara G
DG
Department of Respiratory Medicine, Nutrition and Toxicology Research Institute Maastricht (NUTRIM), Maastricht University Medical Centre, Maastricht, The Netherlands. d.yanbaeva@pul.unimaas.nl
Dentener
Mieke A
MA
Spruit
Martijn A
MA
Houwing-Duistermaat
Jeanine J
JJ
Kotz
Daniel
D
Passos
Valéria Lima
VL
Wouters
Emiel F M
EF
D000328:Adult; D000368:Aged; D002097:C-Reactive Protein / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D005340:Fibrinogen / Q000235:genetics; D055106:Genome-Wide Association Study; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D007249:Inflammation / Q000097:blood / Q000235:genetics; D018836:Inflammation Mediators / Q000097:blood; D015850:Interleukin-6 / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D029424:Pulmonary Disease, Chronic Obstructive / Q000097:blood / Q000235:genetics*
D018836:Inflammation Mediators; D015850:Interleukin-6; D005340:Fibrinogen; D002097:C-Reactive Protein