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IL10 Polymorphisms Are Associated with Airflow Obstruction in Severe ₁-Antitrypsin Deficiency

¹ Channing Laboratory and Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts; ² University of Utah, Salt Lake City, Utah; ³ Oregon Health and Science University, Portland, Oregon, ⁴ University of Florida, Gainesville, Florida, ⁵ St. Luke's/Roosevelt Hospital, New York, New York; ⁶ Beaumont Hospital, Dublin, Ireland; ⁷ University of Nebraska, Omaha, Nebraska; ⁸ National Jewish Medical and Research Center, Denver, Colorado; ⁹ University of Texas at Tyler, Tyler, Texas; ¹⁰ Cleveland Clinic, Cleveland, Ohio; and ¹¹ Medical University of South Carolina, Charleston, South Carolina

Correspondence and requests for reprints should be addressed to Dawn L. DeMeo, M.D., M.P.H., Brigham and Women's Hospital, Channing Laboratory, 181 Longwood Avenue, Boston, MA 02115. E-mail: dawn.demeo{at}channing.harvard.edu

Severe 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. 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 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.

Key Words: chronic obstructive pulmonary disease • genetic modifiers • interleukin 10 • family-based association analysis

CLINICAL RELEVANCE The identification of IL10 as a potential modifier gene for chronic obstructive pulmonary disease susceptibility provides insight into additional inflammatory pathways to consider in 1-antitrypsin deficiency, and may result in improved risk assessment and clinical management of individuals who are homozygous for the Z deficiency allele.