IL10 polymorphisms are associated with airflow obstruction in severe α1-antitrypsin deficiency

Dawn L. DeMeo, Edward J. Campbell, Alan F. Barker, Mark L. Brantly, Edward Eden, N. Gerard McElvaney, Stephen I. Rennard, Robert A. Sandhaus, James M. Stocks, James K. Stoller, Charlie Strange, Gerard Turino, Edwin K. Silverman

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Abstract

Severe α1-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. 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 FEV 1 ≤ 50 percent predicted. Six of 11 single-nucleotide polymorphisms (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's 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.

Original languageEnglish (US)
Pages (from-to)114-120
Number of pages7
JournalAmerican journal of respiratory cell and molecular biology
Volume38
Issue number1
DOIs
StatePublished - Jan 1 2008

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Keywords

  • Chronic obstructive pulmonary disease
  • Family-based association analysis
  • Genetic modifiers
  • Interleukin 10

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

Cite this

DeMeo, D. L., Campbell, E. J., Barker, A. F., Brantly, M. L., Eden, E., McElvaney, N. G., Rennard, S. I., Sandhaus, R. A., Stocks, J. M., Stoller, J. K., Strange, C., Turino, G., & Silverman, E. K. (2008). IL10 polymorphisms are associated with airflow obstruction in severe α1-antitrypsin deficiency. American journal of respiratory cell and molecular biology, 38(1), 114-120. https://doi.org/10.1165/rcmb.2007-0107OC