Use of a modeling framework to evaluate the effect of a modifier gene ( ) on variation in cystic fibrosis

• Published in: European journal of human genetics : EJHG 2010-06, Vol.18 (6), p.680-684
• Main Authors: McDougal, Kathryn E, Green, Deanna M, Vanscoy, Lori L, Fallin, M Daniele, Grow, Michael, Cheng, Suzanne, Blackman, Scott M, Collaco, J Michael, Henderson, Lindsay B, Naughton, Kathleen, Cutting, Garry R
• Format: Article
• Language: English
• Subjects: 631/208/2489/144; 631/208/457/649; 692/420/254; Adolescent; Adult; Age; Bioinformatics; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Child; Cystic fibrosis; Cystic Fibrosis - complications; Cystic Fibrosis - genetics; Cytogenetics; Epidemiology; Errors of metabolism; Female; Fibrosis; Fundamental and applied biological sciences. Psychology; Gene Expression; General aspects. Genetic counseling; Genes; Genetic Heterogeneity; Genetic Variation - physiology; Genetics; Genetics of eukaryotes. Biological and molecular evolution; Genotypes; Human Genetics; Humans; Infections; Lectins; Lung; Lung diseases; Male; Mannose; Mannose-binding lectin; Mannose-Binding Lectin - genetics; Mannose-Binding Lectin - physiology; Medical genetics; Medical sciences; Metabolic diseases; Miscellaneous hereditary metabolic disorders; Models, Biological; Models, Genetic; Molecular and cellular biology; Patients; Proteins; Pseudomonas aeruginosa; Pseudomonas aeruginosa - physiology; Pseudomonas Infections - complications; Pseudomonas Infections - genetics; Siblings; Studies; Survival; Twin Studies as Topic; Twins; Variables; Variation; Young Adult
• ISSN: 1018-4813; 1476-5438
• DOI: 10.1038/ejhg.2009.226

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.