title: Desmoplakin Variants Are Associated with Idiopathic Pulmonary Fibrosis.
abstract: Sequence variation, methylation differences, and transcriptional changes in desmoplakin (DSP) have been observed in patients with idiopathic pulmonary fibrosis (IPF).
  
  
  
  To identify novel variants in DSP associated with IPF and to characterize the relationship of these IPF sequence variants with DSP gene expression in human lung.
  
  
  
  A chromosome 6 locus (7,370,061-7,606,946) was sequenced in 230 subjects with IPF and 228 control subjects. Validation genotyping of disease-associated variants was conducted in 936 subjects with IPF and 936 control subjects. DSP gene expression was measured in lung tissue from 334 subjects with IPF and 201 control subjects.
  
  
  
  We identified 23 sequence variants in the chromosome 6 locus associated with IPF. Genotyping of selected variants in our validation cohort revealed that noncoding intron 1 variant rs2744371 (odds ratio = 0.77, 95% confidence interval [CI] = 0.66-0.91, P = 0.002) is protective for IPF, and a previously described IPF-associated intron 5 variant (rs2076295) is associated with increased risk of IPF (odds ratio = 1.36, 95% CI = 1.19-1.56, P < 0.001) after controlling for sex and age. DSP expression is 2.3-fold increased (95% CI = 1.91-2.71) in IPF lung tissue (P < 0.0001). Only the minor allele at rs2076295 is associated with decreased DSP expression (P = 0.001). Staining of fibrotic and normal human lung tissue localized DSP to airway epithelia.
  
  
  
  Sequence variants in DSP are associated with IPF, and rs2076295 genotype is associated with differential expression of DSP in the lung. DSP expression is increased in IPF lung and concentrated in the airway epithelia, suggesting a potential role for DSP in the pathogenesis of IPF.
authors.affiliation: 1 Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, and.
authors.forename: Susan K
authors.initials: SK
authors.lastname: Mathai
authors.affiliation: 2 Department of Genetics, University of Utah, Salt Lake City, Utah.
authors.forename: Brent S
authors.initials: BS
authors.lastname: Pedersen
authors.affiliation: 1 Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, and.
authors.forename: Keith
authors.initials: K
authors.lastname: Smith
authors.affiliation: 3 Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, Colorado.
authors.forename: Pamela
authors.initials: P
authors.lastname: Russell
authors.affiliation: 1 Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, and.
authors.forename: Marvin I
authors.initials: MI
authors.lastname: Schwarz
authors.affiliation: 4 Department of Medicine, National Jewish Health, Denver, Colorado.
authors.forename: Kevin K
authors.initials: KK
authors.lastname: Brown
authors.affiliation: 5 Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee.
authors.forename: Mark P
authors.initials: MP
authors.lastname: Steele
authors.affiliation: 5 Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee.
authors.forename: James E
authors.initials: JE
authors.lastname: Loyd
authors.affiliation: 4 Department of Medicine, National Jewish Health, Denver, Colorado.
authors.forename: James D
authors.initials: JD
authors.lastname: Crapo
authors.affiliation: 6 Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Edwin K
authors.initials: EK
authors.lastname: Silverman
authors.affiliation: 7 Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington; and.
authors.forename: Deborah
authors.initials: D
authors.lastname: Nickerson
authors.affiliation: 8 Center for Genes, Environment and Health, National Jewish Health, Denver, Colorado.
authors.forename: Tasha E
authors.initials: TE
authors.lastname: Fingerlin
authors.affiliation: 1 Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, and.|8 Center for Genes, Environment and Health, National Jewish Health, Denver, Colorado.
authors.forename: Ivana V
authors.initials: IV
authors.lastname: Yang
authors.affiliation: 1 Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, and.
authors.forename: David A
authors.initials: DA
authors.lastname: Schwartz
mesh_terms: D000368:Aged; D051180:Desmoplakins / Q000235:genetics*; D005260:Female; D015870:Gene Expression / Q000235:genetics; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio
chemical_list: C495294:DSP protein, human; D051180:Desmoplakins
keywords: desmoplakin; genetics; idiopathic interstitial pneumonia; idiopathic pulmonary fibrosis; intron