Novel genes for airway wall thickness identified with combined genome-wide association and expression analyses

• Verfasst von: Dijkstra, Akkelies E. [VerfasserIn]
• Verfasst von: Postma, Dirkje S. [VerfasserIn]
• Verfasst von: van Ginneken, Bram [VerfasserIn]
• Verfasst von: Wielpütz, Mark Oliver [VerfasserIn]
• Verfasst von: Schmidt, Michael [VerfasserIn]
• Verfasst von: Becker, Nikolaus [VerfasserIn]
• Verfasst von: Owsijewitsch, Michael [VerfasserIn]
• Verfasst von: Kauczor, Hans-Ulrich [VerfasserIn]
• Verfasst von: de Koning, Harry J. [VerfasserIn]
• Verfasst von: Lammers, Jan W. [VerfasserIn]
• Verfasst von: Oudkerk, Matthijs [VerfasserIn]
• Verfasst von: Brandsma, Corry-Anke [VerfasserIn]
• Verfasst von: Bossé, Yohan [VerfasserIn]
• Verfasst von: Nickle, David C. [VerfasserIn]
• Verfasst von: Sin, Don D. [VerfasserIn]
• Verfasst von: Hiemstra, Pieter S. [VerfasserIn]
• Verfasst von: Wijmenga, Ciska [VerfasserIn]
• Verfasst von: Smolonska, Joanna [VerfasserIn]
• Verfasst von: Zanen, Pieter [VerfasserIn]
• Verfasst von: Vonk, Judith M. [VerfasserIn]
• Verfasst von: van den Berge, Maarten [VerfasserIn]
• Verfasst von: Boezen, H. Marike [VerfasserIn]
• Verfasst von: Groen, Harry J. M. [VerfasserIn]
• Titel: Novel genes for airway wall thickness identified with combined genome-wide association and expression analyses
• Verf.angabe: Akkelies E. Dijkstra, Dirkje S. Postma, Bram van Ginneken, Mark O. Wielpütz, Michael Schmidt, Nikolaus Becker, Michael Owsijewitsch, Hans-Ulrich Kauczor, Harry J. de Koning, Jan W. Lammers, Matthijs Oudkerk, Corry-Anke Brandsma, Yohan Bossé, David C. Nickle, Don D. Sin, Pieter S. Hiemstra, Ciska Wijmenga, Joanna Smolonska, Pieter Zanen, Judith M. Vonk, Maarten van den Berge, H. Marike Boezen, and Harry J.M. Groen
• E-Jahr: 2015
• Jahr: Mar 1, 2015
• Umfang: 10 S.
• Fussnoten: Gesehen am 28.05.2020
• Titel Quelle: Enthalten in: American journal of respiratory and critical care medicine
• Ort Quelle: New York, NY : American Thoracic Society, 1959
• Jahr Quelle: 2015
• Band/Heft Quelle: 191(2015), 5, Seite 547-556
• ISSN Quelle: 1535-4970
• DOI: doi:10.1164/rccm.201405-0840OC
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1698988311

Abstract

Rationale: Airway wall thickness (AWT) is affected by both environmental and genetic factors and is strongly associated with airflow limitation in smaller airways. Objectives: To investigate the genetic component of AWT.Methods: AWT was measured on low-dose computed tomography scans in male heavy smokers participating in a lung cancer screening study (n = 2,640). Genome-wide association studies on AWT were performed under an additive model using linear regression (adjusted for pack-years, lung volume), followed by metaanalysis. An independent cohort was used for validation of the most strongly associated single-nucleotide polymorphisms (SNPs). The functional relevance of significant SNPs was evaluated.Measurements and Main Results: Three significant loci on chromosomes 2q (rs734556; P =  6.2 × 10−7) and 10q (rs10794108, P = 8.6 × 10−8; rs7078439, P = 2.3 × 10−7) were associated with AWT and confirmed in the metaanalysis in cohorts with comparable lung function: P values = 4.6 × 10−8, 7.4 × 10−8, and 7.5 × 10−8, respectively. SNP rs734556 was associated with decreased lung tissue expression of SERPINE2, a susceptibility gene for emphysema. Two nominally significant SNPs showed effects with similar direction: rs10251504 in MAGI2 (P = 5.8 × 10−7) and rs4796712 in NT5C3B (P = 3.1 × 10−6). Higher MAGI2 expression in bronchial biopsies of patients with chronic obstructive pulmonary disease was significantly associated with fewer inflammatory cells. The presence of the NT5C3B risk allele was associated with higher lung tissue expression (P = 1.09 × 10−41). Conclusions: Genetic variants contribute to AWT. Among others, the identified genes are also involved in emphysema, airway obstruction, and bronchial inflammation.