Associations of IL6 polymorphisms with lung function decline and COPD

Jian-Qing He ¹, Marilyn G Foreman ², Karey Shumansky ¹, Xuekui Zhang ¹, Loubna Akhabir ¹, Don D Sin ¹, S F Paul Man ³, Dawn L Demeo ², Augusto A Litonjua ², Ed Silverman ⁴, John E Connett ⁵, Nicholas R Anthonisen ⁶, Robert Wise ⁷, Peter Pare ¹ and Andrew J Sandford ^1*

¹ James Hogg iCAPTURE Centre for Cardiovascular and Pulmonary Research, University of British Columbia, Canada
² Channing Laboratory, United States
³ St Pauls' hospital, Vancouver, BC, Canada
⁴ Brigham and Women's Hospital, Boston, United States
⁵ University of Minnesota, United States
⁶ University of Manitoba, Canada
⁷ Johns Hopkins University, United States

^* To whom correspondence should be addressed. E-mail: asandford{at}mrl.ubc.ca.

Accepted 17 March 2009

Abstract

Background: Interleukin-6 (IL6) is a pleiotropic pro-inflammatory and immunomodulatory cytokine which likely plays an important role in the pathogenesis of COPD. There is a functional single nucleotide polymorphism (SNP), -174G/C, in the promoter region of IL6. We hypothesized that IL6 SNPs influence susceptibility for impaired lung function and COPD in smokers.

Methods: Seven and 5 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 one second (FEV₁) over 5 years and baseline FEV₁ at the beginning of the LHS. Serum IL6 concentrations were measured for all subjects. A partially overlapping panel of 9 IL6 SNPs was genotyped in 389 COPD cases 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 FEV1 decline (0.023 P 0.041 in additive models). Among them the IL6_-174C allele was associated with rapid decline of 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: Our results suggested that the IL6_-174G/C SNP is associated with rapid decline of FEV1 and susceptibility to COPD in smokers.