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Published ahead of print on August 9, 2007, doi:10.1165/rcmb.2007-0107OC

Am. J. Respir. Cell Mol. Biol., Volume 38, Number 1, January 2008, 114-120

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Submitted on March 23, 2007
Revised on August 8, 2007

IL10 Polymorphisms are Associated with Airflow Obstruction in Severe alpha 1-antitrypsin Deficiency

Dawn L DeMeo1*, Edward J Campbell2, Alan F Barker3, Mark L Brantly4, Edward Eden5, N. Gerard McElvaney6, Stephen I Rennard7, Robert A Sandhaus8, James M Stocks9, James K Stoller10, Charlie Strange11, Gerard Turino5, and Edwin K Silverman1

1 Channing Laboratory and Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, United States, 2 Univeristy of Utah, Salt Lake City, UT, USA, 3 Oregon Health and Science University, Portland, OR, USA, 4 University of Florida, Gainesville, FL, USA, 5 St. Luke's/Roosevelt Hosptial, New York City, NY, USA, 6 Beaumont Hosptial, Dublin, IR, USA, 7 University of Nebraska, Omaha, NB, USA, 8 National Jewish Medical and Research Center, Denver, CO, USA, 9 University of Texas at Tyler, Tyler, TX, USA, 10 Cleveland Clinic, Cleveland, OH, USA, 11 Medical University of South Carolina, Charleston, SC, USA

* To whom correspondence should be addressed. E-mail: dawn.demeo{at}channing.harvard.edu.

Severe alpha 1-antitrypsin (AAT) deficiency is a proven genetic risk factor for chronic obstructive pulmonary disease (COPD), especially in individuals who smoke. There is marked variability in the development of lung disease in individuals homozygous (PI ZZ) for this autosomal recessive condition, suggesting that modifier genes could be important. We hypothesized that genetic determinants of obstructive lung disease may be modifiers of airflow obstruction in individuals with severe AAT deficiency. Methods: To identify modifier genes, we performed family-based association analyses for 10 genes previously associated with asthma and/or COPD, including IL10, TNF, GSTP1, NOS1, NOS3, SERPINA3, SERPINE2, SFTPB, TGFB1 and EPHX1. All analyses were performed in a cohort of 378 PI ZZ individuals from 167 families. Quantitative spirometric phenotypes included forced expiratory volume in one second (FEV1) and the ratio of FEV1 /Forced vital capacity (FVC). A qualitative phenotype of moderate-to-severe COPD was defined for individuals with FEV1 ≤ 50 percent predicted. Six of 11 SNPs in IL10 (p=0.0005-0.05) and 3 of 5 SNPs in TNF (p=0.01-0.05) were associated with FEV1 and/or FEV1/FVC. IL10 SNPs also demonstrated association with the qualitative COPD phenotype. When phenotypes of individuals with a physician diagnosis of asthma were excluded, IL10 SNPs remained significantly associated, suggesting that the association with airflow obstruction was independent of an association with asthma. Haplotype analysis of IL10 SNPs suggested the strongest association with IL10 promoter SNPs. IL10 is likely an important modifier gene for the development of COPD in individuals with severe AAT deficiency.




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