Novel variation at chr11p13 associated with cystic fibrosis lung disease severity.
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ABSTRACT:
SUBMITTER: Dang H
PROVIDER: S-EPMC4935763 | biostudies-literature | 2016
REPOSITORIES: biostudies-literature
Publications
Novel variation at chr11p13 associated with cystic fibrosis lung disease severity.
Dang Hong H Gallins Paul J PJ Pace Rhonda G RG Guo Xue-Liang XL Stonebraker Jaclyn R JR Corvol Harriet H Cutting Garry R GR Drumm Mitchell L ML Strug Lisa J LJ Knowles Michael R MR O'Neal Wanda K WK
Human genome variation 20160707
Published genome-wide association studies (GWASs) identified an intergenic region with regulatory features on chr11p13 associated with cystic fibrosis (CF) lung disease severity. Targeted resequencing in n=377, followed by imputation to n=6,365 CF subjects, was used to identify unrecognized genetic variants (including indels and microsatellite repeats) associated with phenotype. Highly significant associations were in strong linkage disequilibrium and were seen only in Phe508del homozygous CF su ...[more]
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Project description:[This corrects the article DOI: 10.1038/hgv.2016.20.].
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Project description:Although cystic fibrosis (CF) is a monogenic disease, its clinical manifestations are influenced in a complex manner. Severity of lung disease, the main cause of mortality among CF patients, is likely modulated by several genes. The mannose-binding lectin 2 (MBL2) gene encodes an innate immune response protein and has been implicated as a pulmonary modifier in CF. However, reports have been conflicting, and interactions with other modifiers have not been investigated. We therefore evaluated the association of MBL2 with CF pulmonary phenotype in a cohort of 1,019 Canadian pediatric CF patients. MBL2 genotypes were combined into low-, intermediate-, and high-expression groups based on MBL2 levels in plasma. Analysis of age at first infection with Pseudomonas aeruginosa demonstrated that MBL2 deficiency was significantly associated with earlier onset of infection. This MBL2 effect was amplified in patients with high-producing genotypes of transforming growth factor beta 1 (TGFB1). Similarly, MBL2 deficiency was associated with more rapid decline of pulmonary function, most significantly in those carrying the high-producing TGFB1 genotype. These findings provide evidence of gene-gene interaction in the pathogenesis of CF lung disease, whereby high TGF-beta1 production enhances the modulatory effect of MBL2 on the age of first bacterial infection and the rate of decline of pulmonary function.
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Project description:RATIONALE:Cystic fibrosis, like primary ciliary dyskinesia, is an autosomal recessive disorder characterized by abnormal mucociliary clearance and obstructive lung disease. We hypothesized that genes underlying the development or function of cilia may modify lung disease severity in persons with cystic fibrosis. OBJECTIVES:To test this hypothesis, we compared variants in 93 candidate genes in both upper and lower tertiles of lung function in a large cohort of children and adults with cystic fibrosis with those of a population control dataset. METHODS:Variants within candidate genes were tested for association using the SKAT-O test, comparing cystic fibrosis cases defined by poor (n?=?127) or preserved (n?=?127) lung function with population controls (n?=?3,269 or 3,148, respectively). Associated variants were then tested for association with related phenotypes in independent datasets. RESULTS:Variants in DNAH14 and DNAAF3 were associated with poor lung function in cystic fibrosis, whereas variants in DNAH14 and DNAH6 were associated with preserved lung function in cystic fibrosis. Associations between DNAH14 and lung function were replicated in disease-related phenotypes characterized by obstructive lung disease in adults. CONCLUSIONS:Genetic variants within DNAH6, DNAH14, and DNAAF3 are associated with variation in lung function among persons with cystic fibrosis.
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