br Sources of Funding Conflicts of Interest This study

Sources of Funding/Conflicts of Interest This study was funded by grants from the R.J. Fasenmeyer Center for Clinical Immunology at the Cleveland Clinic, Case Western Reserve University Rottman Fund, ASTMH Benjamin H. Kean Fellowship, IDSA Medical Scholars Program, the NIH-NIAIDR01 AI090118, R01 A1068063, the American College of Rheumatology Research and Education Foundation Within Our Reach campaign, the National Institutes of Health (K23 HL123341), a Wolf Family Foundation Scholars Grant, and Medtronic Philanthropy. All natural autoantibody assays were performed at NYU. Funding sources did not have any role in the design of implementation of this study.
Author Contributions
Introduction Chronic obstructive pulmonary disease (COPD), characterized by progressive and irreversible airflow limitation, is a growing public health burden and might become the third leading cause of death worldwide by 2020 (Raherison and Girodet, 2009). Various risk factors, including environmental factors (mainly cigarette smoking), infection, and genetic susceptibility are involved in the occurrence of COPD. The lung pathology of this disease is featured by abnormal inflammation, small airway wall structural remodeling, mucus hypersecretion and/or flap inhibitor (Rabe et al., 2007; Arinir et al., 2009). Imbalanced inflammation and anti-inflammation, proteases and antiproteases, and oxidation and antioxidation are thought to be the primary pathological mechanisms underlying COPD, and abnormal inflammation has been suggested to play the central role. Therefore, identifying the genetic determinants to inflammation will eventually benefit the early diagnosis and prevention of this disease. Bone morphogenetic protein receptor type 2 (BMPR2), a member of the transforming growth factor β receptor superfamily of the transmembrane serine/threonine kinase receptors, is expressed at high level in various tissues including pulmonary vasculature and airway epithelium (Favre et al., 2003; Atkinson, 2002). Signaling through BMPR2 is essential for embryonic development, pulmonary vascular cell growth and differentiation, angiogenesis, organogenesis, endothelial cell and smooth muscle cell interaction (Shiraishi, 2012; Teichert-Kuliszewska et al., 2006; Yang et al., 2005). Bone morphogenetic protein (BMP) signaling pathway is not only involved in maintaining normal vascular morphology, but also in regulating pro-inflammatory responses in vasculature (Teichert-Kuliszewska et al., 2006; Nohe et al., 2002). A recent report by Kim et al. found that BMPR2 had unique anti-inflammatory functions among BMP receptors (Kim et al., 2013). Another study demonstrated that BMPR2 expression was decreased in lung tissue samples from healthy smokers and COPD patients (Llinàs et al., 2011). Yet, the exact role of BMPR2 on COPD development and progression are unknown. The human BMPR2 gene is located at chromosome 2q33, encoding a 12,086bp messenger RNA (mRNA) and 13 exons with 1038 amino acids. BMPR2 is highly polymorphic with 3317 identified single-nucleotide polymorphisms (SNPs) (Fig. 1A). Although BMPR2 mutations are well defined to be responsible for the occurrence of majority of heritable pulmonary arterial hypertension (PAH) and idiopathic PAH cases (Rosenzweig et al., 2008; Sztrymf et al., 2008; Guo et al., 2011; Wang et al., 2013; Yang et al., 2012), their relationship to COPD has not been identified. The 3′-untranslated region (3′UTR) of gene generally plays important roles in regulating mRNA stability, thus affecting the translation efficacy and protein expression by interacting with other post-transcriptional regulatory factors such as microRNAs (miRNAs). SNPs in 3′UTR could modulate the function of 3′UTR if they are located in the binding sites for miRNAs. In this study, we hypothesized that the presence of SNPs in 3′UTR of BMPR2 may regulate BMPR2 expression, and therefore contribute to COPD risk by interacting with environmental factors such as cigarette smoking. Therefore, we selected two SNPs in the 3′UTR of BMPR2, rs6435156C>T and rs1048829G>T, genotyped them in a southern Chinese population, and assessed their functional association with miRNA, level of BMPR2 expression and risk of COPD.