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1 Division of Pulmonary Medicine, Children's Hospital Boston, Massachusetts; 2 Harvard Medical School, Boston, Massachusetts; 3 Channing Laboratory, Brigham and Women's Hospital, Boston, Massachusetts; 4 Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts; 5 Division of Pulmonary and Critical Care Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina; 6 Department of Biostatistics, University of North Carolina School of Public Health, Chapel Hill, North Carolina; 7 Case Western Reserve University, Cleveland, Ohio; and 8 Department of Pediatrics and Critical Care, Children's Hospital of Wisconsin, Milwaukee, Wisconsin
Correspondence and requests for reprints should be addressed to Hara Levy, M.D., Assistant Professor of Pediatrics, Section of Pulmonary and Sleep Medicine, Children's Hospital of Wisconsin, Children's Research Institute, Translational Biomedical Research Center, Medical College of Wisconsin, P.O. Box 26509, Milwaukee, WI 53226. E-mail: hlevy{at}mcw.edu
Variability in pulmonary disease severity is found in patients with cystic fibrosis (CF) who have identical mutations in the CF transmembrane conductance regulator (CFTR) gene. We hypothesized that one factor accounting for heterogeneity in pulmonary disease severity is variation in the family of genes affecting the biology of interleukin-1 (IL-1), which impacts acquisition and maintenance of Pseudomonas aeruginosa infection in animal models of chronic infection. We genotyped 58 single-nucleotide polymorphisms (SNPs) in the IL-1 gene cluster in 808 subjects with CF from the University of North Carolina (UNC) cohort. All were homozygous for 
F508, and categories of "severe" (cases) or "mild" (control subjects) lung disease were defined by the lowest or highest quartile of FEV1 for age. After adjustment for age and sex, genotypic data were tested for association with lung disease severity. Odds ratios comparing severe versus mild CF were also calculated for each genotype (with the homozygote major allele as the reference group) for all 58 SNPs. From these analyses, nine SNPs with a moderate effect size, odds ratio (OR) greater than 1, were selected for further testing. To replicate the case–control study results, we genotyped the same nine SNPs in a second population of CF parent–offspring trios in which the offspring had similar pulmonary phenotypes and were recruited from Children's Hospital, Boston. For the trio analysis, family-based association was performed. SNPs rs1143634 and rs1143639 in the IL1B gene demonstrated a consistent association with lung disease severity categories (P < 0.10) and longitudinal analysis of lung disease severity (P < 0.10) in CF in both the case–control and family-based studies. IL1β is a clinically relevant modulator of CF lung disease.
FOOTNOTES
Conflict of Interest Statement: H.L. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. A.M. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. F.Z. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. C.G. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. B.J.K. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. B.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. R.L. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. K.C.G. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. J.C.C. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. M.D. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. M.K.D. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. M.W.Q. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. M.R.K. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. G.B.P. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. C.L. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. S.T.W. received a grant for $900,065, Asthma Policy Modeling Study, from AstraZeneca from 1997 to 2003. He has been a Co-investigator on a grant from Boehringer Ingelheim to investigate a COPD natural history model which began in 2003. He has received no funds for his involvement in this project. He has been an advisor and chair of the Advisory Board to the TENOR Study for Genentech and has received $10,000 for 2005 to 2006. He received a grant from Glaxo-Wellcome for $500,000 for genomic equipment from 2000 to 2003. He was a consultant for Roche Pharmaceuticals in 2000 and received no financial remuneration for this consultancy. He has also served as a consultant to Pfizer (2000–2003), Schering Plough (1999–2000), Variagenics (2002), Genome Therapeutics (2003), and Merck Frost (2002).
(Received in original form August 31, 2007; accepted in final form October 16, 2007)
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