Abstract
Variants in mannose-binding lectin (MBL2; protein MBL) have shown association with different aspects (eg, lung function, infection, survival) of cystic fibrosis (CF) in some studies but not others. Inconsistent results may be due to confounding among disease variables that were not fully accounted for in each study. To account for these relationships, we derived a modeling framework incorporating CFTR genotype, age, Pseudomonas aeruginosa (Pa) infection, and lung function from 788 patients in the US CF Twin and Sibling Study. This framework was then used to identify confounding variables when testing the effect of MBL2 variation on specific CF traits. MBL2 genotypes corresponding to low levels of MBL associated with Pa infection 1.94 years earlier than did MBL2 genotypes corresponding to high levels of MBL (P=0.0034). In addition, Pa-infected patients with MBL2 genotypes corresponding to low levels of MBL underwent conversion to mucoid Pa 2.72 years earlier than did patients with genotypes corresponding to high levels of MBL (P=0.0003). MBL2 was not associated with the time to transition from infection to conversion or with lung function. Thus, use of a modeling framework that identified confounding among disease variables revealed that variation in MBL2 associates with age at infection with Pa and age at conversion to mucoid Pa in CF.
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Acknowledgements
We thank the North American Cystic Fibrosis Foundation for use of the Cystic Fibrosis Foundation Data Registry; Ase Sewall, Monica Brooks (both from Cystic Fibrosis Foundation), and the staff at the Data Registry; Nulang Wang for CFTR genotyping; Erica Senat for her assistance with MBL2 genotyping; Michael Kulich (Charles University, Prague, Czech Republic), for providing conversion programs for cystic fibrosis-specific percentiles; Rita McWilliams, Julie Hoover-Fong, and Ada Hamosh, all from Johns Hopkins University, for designing questionnaires; and most importantly the patients with cystic fibrosis and their families, research coordinators, nurses, and physicians participating in the Cystic Fibrosis Twin and Sibling Study. This study was supported by the National Heart, Lung, and Blood Institute Grant HL68927. Genotyping reagents were provided by Roche Molecular Systems Inc (Pleasanton, CA, USA).
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GR Cutting is a consultant for Roche Molecular Systems, and received less than US$1000 per year as consulting fees. M Grow and S Cheng are employed by Roche Molecular Systems.
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McDougal, K., Green, D., Vanscoy, L. et al. Use of a modeling framework to evaluate the effect of a modifier gene (MBL2) on variation in cystic fibrosis. Eur J Hum Genet 18, 680–684 (2010). https://doi.org/10.1038/ejhg.2009.226
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DOI: https://doi.org/10.1038/ejhg.2009.226
