title: A Functional Variant rs6435156C > T in BMPR2 is Associated With Increased Risk of Chronic Obstructive Pulmonary Disease (COPD) in Southern Chinese Population.
abstract: BACKGROUND
  Bone morphogenetic protein receptor type 2 (BMPR2) signaling is anti-inflammatory. Decreased BMPR2 expression was seen in lung tissue from chronic obstructive pulmonary disease (COPD) patients.
  
  
  METHODS
  The selected single nucleotide polymorphisms (SNPs) in BMPR2 were genotyped with polymerase chain reaction (PCR) ligase detection reaction. The effects of SNPs on gene expression were analyzed with luciferase assays. The mRNA and protein expression levels of BMPR2 in peripheral blood mononuclear cells (PBMCs) from COPD patients were determined by quantitative PCR and western blotting, respectively.
  
  
  RESULTS
  Two SNPs, rs6435156C > T and rs1048829G > T in the 3'-untranslated region (3'UTR) of BMPR2 were selected and genotyped in COPD case and healthy control subjects from southern Chinese population. Both of them were found associated with significantly increased COPD risk (adjusted odds ratio [OR] = 1.58 with 95% confidence interval [CI] = 1.14-2.15, P = 0.0056 for rs6435156C > T; adjusted OR = 1.47 and 95% CI = 1.10-1.97, P = 0.0092 for rs1048829G > T). Older age, cigarette smoking, family history of cancer and COPD were all factors that interacted with rs6435156C > T and rs1048829G > T causing increased COPD risk. Cigarette smokers with rs6435156 (CT + TT) or rs1048829 (GT + TT) were more susceptible to COPD than that with the rs6435156CC or rs1048829GG genotypes. In A549 human alveolar epithelial cells, luciferase reporter assays revealed that introduction of 3'UTR of BMPR2 plasmids carrying rs6435156T allele but not rs1048829T led to lower luciferase activity than the wild-type C or G alleles. Comparing to rs6435156CC, treatment with hsa-miR-20a mimics deceased whereas hsa-miR-20a inhibitor restored the luciferase reporter activity in cells transfected with constructs carrying rs6435156TT. BMPR2 mRNA and protein expressions were significantly lower in PBMCs from COPD smokers than that in non-smokers. COPD patients carrying rs6435156T allele had less BMPR2 expression in PBMCs.
  
  
  CONCLUSIONS
  This study demonstrated that both rs6435156C > T and rs1048829G > T variants in BMPR2 contributed to increased susceptibility to COPD. The T variants of rs6435156 increased COPD risk likely by binding with hsa-miR-20a, thus leading to downregulated BMPR2 expression in lung epithelial and immune cells.
authors.affiliation: State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China; Department of Respiration, Inner Mongolia Autonomous Region People's Hospital, Hohhot 010017, Inner Mongolia, China; Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21224, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
authors.forename: Chenting
authors.initials: C
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
authors.forename: Zili
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
authors.forename: Zeguang
authors.initials: Z
authors.lastname: Zheng
authors.affiliation: Department of Respiration, Inner Mongolia Autonomous Region People's Hospital, Hohhot 010017, Inner Mongolia, China.
authors.forename: Dejun
authors.initials: D
authors.lastname: Sun
authors.affiliation: State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
authors.forename: Quan
authors.initials: Q
authors.lastname: Yang
authors.affiliation: Geisinger Medical Center, 100 North Academy Avenue, Danville, PA 17822, USA.
authors.forename: Cyrus
authors.initials: C
authors.lastname: Hadadi
authors.affiliation: State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
authors.forename: Defu
authors.initials: D
authors.lastname: Li
authors.affiliation: State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
authors.forename: Mingmei
authors.initials: M
authors.lastname: Xiong
authors.affiliation: State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
authors.forename: Qipeng
authors.initials: Q
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
authors.forename: Meihua
authors.initials: M
authors.lastname: Guo
authors.affiliation: State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
authors.forename: Yingfeng
authors.initials: Y
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
authors.forename: Chun
authors.initials: C
authors.lastname: Tang
authors.affiliation: Department of Respiration, Inner Mongolia Autonomous Region People's Hospital, Hohhot 010017, Inner Mongolia, China.
authors.forename: Guihua
authors.initials: G
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
authors.forename: Nanshan
authors.initials: N
authors.lastname: Zhong
authors.affiliation: State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
authors.forename: Wenju
authors.initials: W
authors.lastname: Lu
mesh_terms: D000368:Aged; D000483:Alleles; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000096:biosynthesis / Q000235:genetics*; D002681:China; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D029424:Pulmonary Disease, Chronic Obstructive / Q000235:genetics* / Q000473:pathology; D012307:Risk Factors
chemical_list: C534451:MIRN20a microRNA, human; D035683:MicroRNAs; C498218:BMPR2 protein, human; D052006:Bone Morphogenetic Protein Receptors, Type II
keywords: BMPR2; COPD; Cigarette smoking; hsa-miR-20a; rs6435156