Susan K Mathai1, Brent S Pedersen2, Keith Smith1, Pamela Russell3, Marvin I Schwarz1, Kevin K Brown4, Mark P Steele5, James E Loyd5, James D Crapo4, Edwin K Silverman6, Deborah Nickerson7, Tasha E Fingerlin8, Ivana V Yang1,8, David A Schwartz1. 1. 1 Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, and. 2. 2 Department of Genetics, University of Utah, Salt Lake City, Utah. 3. 3 Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, Colorado. 4. 4 Department of Medicine, National Jewish Health, Denver, Colorado. 5. 5 Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee. 6. 6 Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. 7. 7 Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington; and. 8. 8 Center for Genes, Environment and Health, National Jewish Health, Denver, Colorado.
Abstract
RATIONALE: Sequence variation, methylation differences, and transcriptional changes in desmoplakin (DSP) have been observed in patients with idiopathic pulmonary fibrosis (IPF). OBJECTIVES: 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. METHODS: 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. MEASUREMENTS AND MAIN RESULTS: 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. CONCLUSIONS: 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.
RATIONALE: Sequence variation, methylation differences, and transcriptional changes in desmoplakin (DSP) have been observed in patients with idiopathic pulmonary fibrosis (IPF). OBJECTIVES: 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. METHODS: 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. MEASUREMENTS AND MAIN RESULTS: 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. CONCLUSIONS: 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: Christopher S Carlson; Michael A Eberle; Mark J Rieder; Qian Yi; Leonid Kruglyak; Deborah A Nickerson Journal: Am J Hum Genet Date: 2003-12-15 Impact factor: 11.025
Authors: Michelle G Roy; Alessandra Livraghi-Butrico; Ashley A Fletcher; Melissa M McElwee; Scott E Evans; Ryan M Boerner; Samantha N Alexander; Lindsey K Bellinghausen; Alfred S Song; Youlia M Petrova; Michael J Tuvim; Roberto Adachi; Irlanda Romo; Andrea S Bordt; M Gabriela Bowden; Joseph H Sisson; Prescott G Woodruff; David J Thornton; Karine Rousseau; Maria M De la Garza; Seyed J Moghaddam; Harry Karmouty-Quintana; Michael R Blackburn; Scott M Drouin; C William Davis; Kristy A Terrell; Barbara R Grubb; Wanda K O'Neal; Sonia C Flores; Adela Cota-Gomez; Catherine A Lozupone; Jody M Donnelly; Alan M Watson; Corinne E Hennessy; Rebecca C Keith; Ivana V Yang; Lea Barthel; Peter M Henson; William J Janssen; David A Schwartz; Richard C Boucher; Burton F Dickey; Christopher M Evans Journal: Nature Date: 2013-12-08 Impact factor: 49.962
Authors: Amy L Olson; Jeffrey J Swigris; Dennis C Lezotte; Jill M Norris; Carla G Wilson; Kevin K Brown Journal: Am J Respir Crit Care Med Date: 2007-05-03 Impact factor: 21.405
Authors: Tasha E Fingerlin; Elissa Murphy; Weiming Zhang; Anna L Peljto; Kevin K Brown; Mark P Steele; James E Loyd; Gregory P Cosgrove; David Lynch; Steve Groshong; Harold R Collard; Paul J Wolters; Williamson Z Bradford; Karl Kossen; Scott D Seiwert; Roland M du Bois; Christine Kim Garcia; Megan S Devine; Gunnar Gudmundsson; Helgi J Isaksson; Naftali Kaminski; Yingze Zhang; Kevin F Gibson; Lisa H Lancaster; Joy D Cogan; Wendi R Mason; Toby M Maher; Philip L Molyneaux; Athol U Wells; Miriam F Moffatt; Moises Selman; Annie Pardo; Dong Soon Kim; James D Crapo; Barry J Make; Elizabeth A Regan; Dinesha S Walek; Jerry J Daniel; Yoichiro Kamatani; Diana Zelenika; Keith Smith; David McKean; Brent S Pedersen; Janet Talbert; Raven N Kidd; Cheryl R Markin; Kenneth B Beckman; Mark Lathrop; Marvin I Schwarz; David A Schwartz Journal: Nat Genet Date: 2013-04-14 Impact factor: 38.330
Authors: Max A Seibold; Russell W Smith; Cydney Urbanek; Steve D Groshong; Gregory P Cosgrove; Kevin K Brown; Marvin I Schwarz; David A Schwartz; Susan D Reynolds Journal: PLoS One Date: 2013-03-20 Impact factor: 3.240
Authors: Valérie Besnard; Rania Dagher; Tania Madjer; Audrey Joannes; Madeleine Jaillet; Martin Kolb; Philippe Bonniaud; Lynne A Murray; Matthew A Sleeman; Bruno Crestani Journal: JCI Insight Date: 2018-03-08
Authors: Tsukasa Okamoto; Susan K Mathai; Corinne E Hennessy; Laura A Hancock; Avram D Walts; Adrianne L Stefanski; Kevin K Brown; David A Lynch; Gregory P Cosgrove; Steve D Groshong; Carlyne D Cool; Marvin I Schwarz; Nirmal K Banda; Joshua M Thurman; Ivana V Yang; V Michael Holers; David A Schwartz Journal: Am J Physiol Lung Cell Mol Physiol Date: 2018-03-22 Impact factor: 5.464
Authors: Ezra R Miller; Rachel K Putman; Alejandro A Diaz; Hanfei Xu; Raúl San José Estépar; Tetsuro Araki; Mizuki Nishino; Sergio Poli de Frías; Tomoyuki Hida; James Ross; Harvey Coxson; Josée Dupuis; George T O'Connor; Edwin K Silverman; Ivan O Rosas; Hiroto Hatabu; George Washko; Gary M Hunninghake Journal: Ann Am Thorac Soc Date: 2019-04