PTTG1IP and MAML3, novel genomewide association study genes for severity of hyperresponsiveness in adult asthma

• Published in: Allergy (Copenhagen) 2017-05, Vol.72 (5), p.792-801
• Main Authors: Nieuwenhuis, M. A. E., Vonk, J. M., Himes, B. E., Sarnowski, C., Minelli, C., Jarvis, D., Bouzigon, E., Nickle, D. C., Laviolette, M., Sin, D., Weiss, S. T., Berge, M., Koppelman, G. H., Postma, D. S.
• Format: Article
• Language: English
• Subjects: Adult; Asthma; Asthma - diagnosis; Asthma - genetics; Bronchial Hyperreactivity - diagnosis; Bronchial Hyperreactivity - genetics; Cohort Studies; DNA-Binding Proteins - genetics; Female; Gene Expression; Genetic Predisposition to Disease; genetics; Genome-Wide Association Study; Genotype; Humans; Male; Membrane Proteins - genetics; Nuclear Proteins - genetics; Polymorphism, Single Nucleotide; Quantitative Trait Loci; Respiratory Function Tests; Severity of Illness Index; Transcription Factors - genetics
• ISSN: 0105-4538; 1398-9995
• DOI: 10.1111/all.13062

Background The severity of bronchial hyperresponsiveness (BHR) is a fundamental feature of asthma. The severity of BHR varies between asthmatics and is associated with lack of asthma control. The mechanisms underlying this trait are still unclear. This study aimed to identify genes associated with BHR severity, using a genomewide association study (GWAS) on the slope of BHR in adult asthmatics. Methods We performed a GWAS on BHR severity in adult asthmatics from the Dutch Asthma GWAS cohort (n = 650), adjusting for smoking and inhaled corticosteroid use, and verified results in three other cohorts. Furthermore, we performed eQTL and co‐expression analyses in lung tissue. Results In the discovery cohort, one genomewide significant hit located in phosphodiesterase 4D, cAMP‐specif (PDE4D) and 26 SNPs with P‐values < 1*10−5 were found. None of our findings replicated in adult and childhood replication cohorts jointly. In adult cohorts separately, rs1344110 in pituitary tumour‐transforming 1 interacting protein (PTTG1IP) and rs345983 in Mastermind‐like 3 (MAML3) replicated nominally; minor alleles of rs345983 and rs1344110 were associated with less severe BHR and higher lung tissue gene expression. PTTG1IP showed significant co‐expression with pituitary tumour‐transforming 1, the binding factor of PTTG1lP, and with vimentin and E‐cadherin1. MAML3 co‐expressed significantly with Mastermind‐like 2 (MAML2), both involved in Notch signalling. Conclusions PTTG1IP and MAML3 are associated with BHR severity in adult asthma. The relevance of these genes is supported by the eQTL analyses and co‐expression of PTTG1lP with vimentin and E‐cadherin1, and MAML3 with MAML2.