Novel Genes for Airway Wall Thickness Identified with Combined Genome Wide Association and Expression Analyses
A.E. Dijkstra, D.S. Postma, B. van Ginneken, M.O. Wielpütz, M. Schmidt, N. Becker, M. Owsijewitsch, H.-U. Kauczor, H.J. de Koning, J.W. Lammers, M. Oudkerk, C.-A. Brandsma, Y. Bossé, D.C. Nickle, D.D. Sin, P.S. Hiemstra, C. Wijmenga, J. Smolonska, P. Zanen, J.M. Vonk, M. van den Berge, H.M. Boezen and H.J.M. Groen
American Journal of Respiratory and Critical Care Medicine 2015;191:547-556
Rationale Airway wall thickness (AWT) is affected by both environmental and genetic factors and is strongly associated with airflow limitation in smaller airways. Objectives The aim of our study was to investigate its genetic component. Methods AWT was measured on low-dose CT-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 meta-analysis. 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 = 6.2x10-7) and 10q (rs10794108, p = 8.6x10-8; rs7078439, p = 2.3x10-7) were associated with AWT and confirmed in the meta-analysis in cohorts with comparable lung function: p-values 4.6x10-8, 7.4x10-8 and 7.5x10-8, 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 = 5.8x10-7) and rs4796712 in NT5C3B (p = 3.1x10-6). Higher MAGI2 expression in bronchial biopsies of COPD patients was significantly associated with lower inflammatory cell numbers, lower NT5C3B expression with worse lung function. The NT5C3B risk allele was associated with higher lung tissue expression (p = 1.09x10-41). Conclusions Genetic variants contribute to AWT. Amongst others, the identified genes are involved in emphysema, airway obstruction and bronchial inflammation.
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