title: Gene expression in transformed lymphocytes reveals variation in endomembrane and HLA pathways modifying cystic fibrosis pulmonary phenotypes.
abstract: Variation in cystic fibrosis (CF) phenotypes, including lung disease severity, age of onset of persistent Pseudomonas aeruginosa (P. aeruginosa) lung infection, and presence of meconium ileus (MI), has been partially explained by genome-wide association studies (GWASs). It is not expected that GWASs alone are sufficiently powered to uncover all heritable traits associated with CF phenotypic diversity. Therefore, we utilized gene expression association from lymphoblastoid cells lines from 754 p.Phe508del CF-affected homozygous individuals to identify genes and pathways. LPAR6, a G protein coupled receptor, associated with lung disease severity (false discovery rate q value = 0.0006). Additional pathway analyses, utilizing a stringent permutation-based approach, identified unique signals for all three phenotypes. Pathways associated with lung disease severity were annotated in three broad categories: (1) endomembrane function, containing p.Phe508del processing genes, providing evidence of the importance of p.Phe508del processing to explain lung phenotype variation; (2) HLA class I genes, extending previous GWAS findings in the HLA region; and (3) endoplasmic reticulum stress response genes. Expression pathways associated with lung disease were concordant for some endosome and HLA pathways, with pathways identified using GWAS associations from 1,978 CF-affected individuals. Pathways associated with age of onset of persistent P. aeruginosa infection were enriched for HLA class II genes, and those associated with MI were related to oxidative phosphorylation. Formal testing demonstrated that genes showing differential expression associated with lung disease severity were enriched for heritable genetic variation and expression quantitative traits. Gene expression provided a powerful tool to identify unrecognized heritable variation, complementing ongoing GWASs in this rare disease.
authors: Marsico Lung Institute/UNC CF Research Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address: wanda_o'neal@med.unc.edu.
authors: Wanda K
authors: WK
authors: O'Neal
authors: Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors: Paul
authors: P
authors: Gallins
authors: Marsico Lung Institute/UNC CF Research Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors: Rhonda G
authors: RG
authors: Pace
authors: Marsico Lung Institute/UNC CF Research Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors: Hong
authors: H
authors: Dang
authors: Marsico Lung Institute/UNC CF Research Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors: Whitney E
authors: WE
authors: Wolf
authors: Marsico Lung Institute/UNC CF Research Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors: Lisa C
authors: LC
authors: Jones
authors: Marsico Lung Institute/UNC CF Research Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors: XueLiang
authors: X
authors: Guo
authors: Bioinformatics Research Center and Department of Statistics, North Carolina State University, Raleigh, NC 27695, USA.
authors: Yi-Hui
authors: YH
authors: Zhou
authors: Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors: Vered
authors: V
authors: Madar
authors: State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital affiliated with Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors: Jinyan
authors: J
authors: Huang
authors: Department of Biostatistics, Harvard University, Boston, MA 02115, USA.
authors: Liming
authors: L
authors: Liang
authors: National Heart and Lung Institute, Imperial College London, London SW7 2AZ, UK.
authors: Miriam F
authors: MF
authors: Moffatt
authors: McKusick-Nathans Institute of Genetic Medicine and Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors: Garry R
authors: GR
authors: Cutting
authors: Department of Pediatrics, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.
authors: Mitchell L
authors: ML
authors: Drumm
authors: Program in Genetics and Genome Biology, The Hospital for Sick Children and Department of Molecular Genetics, University of Toronto, Toronto, ON M5G 1X8, Canada.
authors: Johanna M
authors: JM
authors: Rommens
authors: Program in Child Health Evaluative Sciences, The Hospital for Sick Children, and Division of Biostatistics, Dalla Lana School of Public Health, University of Toronto, ON M5G 1X8, Canada.
authors: Lisa J
authors: LJ
authors: Strug
authors: Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors: Wei
authors: W
authors: Sun
authors: Marsico Lung Institute/UNC CF Research Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors: Jaclyn R
authors: JR
authors: Stonebraker
authors: Bioinformatics Research Center and Department of Statistics, North Carolina State University, Raleigh, NC 27695, USA; Department of Biological Sciences, North Carolina State University, Raleigh, NC 27695, USA.
authors: Fred A
authors: FA
authors: Wright
authors: Marsico Lung Institute/UNC CF Research Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors: Michael R
authors: MR
authors: Knowles
mesh_terms: D003550:Cystic Fibrosis / Q000235:genetics* / Q000473:pathology*; D059865:Endoplasmic Reticulum Stress / Q000235:genetics; D020869:Gene Expression Profiling; D005805:Genes, MHC Class I / Q000235:genetics*; D014644:Genetic Variation; D006801:Humans; D016014:Linear Models; D010641:Phenotype; D049368:Receptors, Lysophosphatidic Acid / Q000235:genetics*; D017384:Sequence Deletion / Q000235:genetics
chemical_list: C545560:LPAR6 protein, human; D049368:Receptors, Lysophosphatidic Acid
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