title: Whole exome sequencing identifies novel candidate genes that modify chronic obstructive pulmonary disease susceptibility.
abstract: BACKGROUND
  Chronic obstructive pulmonary disease (COPD) is characterized by an irreversible airflow limitation in response to inhalation of noxious stimuli, such as cigarette smoke. However, only 15-20 % smokers manifest COPD, suggesting a role for genetic predisposition. Although genome-wide association studies have identified common genetic variants that are associated with susceptibility to COPD, effect sizes of the identified variants are modest, as is the total heritability accounted for by these variants. In this study, an extreme phenotype exome sequencing study was combined with in vitro modeling to identify COPD candidate genes.
  
  
  RESULTS
  We performed whole exome sequencing of 62 highly susceptible smokers and 30 exceptionally resistant smokers to identify rare variants that may contribute to disease risk or resistance to COPD. This was a cross-sectional case-control study without therapeutic intervention or longitudinal follow-up information. We identified candidate genes based on rare variant analyses and evaluated exonic variants to pinpoint individual genes whose function was computationally established to be significantly different between susceptible and resistant smokers. Top scoring candidate genes from these analyses were further filtered by requiring that each gene be expressed in human bronchial epithelial cells (HBECs). A total of 81 candidate genes were thus selected for in vitro functional testing in cigarette smoke extract (CSE)-exposed HBECs. Using small interfering RNA (siRNA)-mediated gene silencing experiments, we showed that silencing of several candidate genes augmented CSE-induced cytotoxicity in vitro.
  
  
  CONCLUSIONS
  Our integrative analysis through both genetic and functional approaches identified two candidate genes (TACC2 and MYO1E) that augment cigarette smoke (CS)-induced cytotoxicity and, potentially, COPD susceptibility.
authors.affiliation: Lovelace Respiratory Research Institute, 2425 Ridgecrest Drive SE, Albuquerque, NM, 87108, USA.
authors.forename: Shannon
authors.initials: S
authors.lastname: Bruse
authors.affiliation: Department of Genetics, Rutgers, The State University of New Jersey, 145 Bevier Road, Piscataway, NJ, 08854, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Moreau
authors.affiliation: Department of Biochemistry and Microbiology, Rutgers, the State University of New Jersey, Piscataway, NJ, USA.
authors.forename: Yana
authors.initials: Y
authors.lastname: Bromberg
authors.affiliation: Lovelace Respiratory Research Institute, 2425 Ridgecrest Drive SE, Albuquerque, NM, 87108, USA.|Department of Internal Medicine, University of New Mexico and New Mexico VA Health Care System, Albuquerque, NM, USA.
authors.forename: Jun-Ho
authors.initials: JH
authors.lastname: Jang
authors.affiliation: Department of Genetics, Rutgers, The State University of New Jersey, 145 Bevier Road, Piscataway, NJ, 08854, USA.
authors.forename: Nan
authors.initials: N
authors.lastname: Wang
authors.affiliation: Department of Genetics, Rutgers, The State University of New Jersey, 145 Bevier Road, Piscataway, NJ, 08854, USA.
authors.forename: Hongseok
authors.initials: H
authors.lastname: Ha
authors.affiliation: Lovelace Respiratory Research Institute, 2425 Ridgecrest Drive SE, Albuquerque, NM, 87108, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Picchi
authors.affiliation: Lovelace Respiratory Research Institute, 2425 Ridgecrest Drive SE, Albuquerque, NM, 87108, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Lin
authors.affiliation: Lovelace Respiratory Research Institute, 2425 Ridgecrest Drive SE, Albuquerque, NM, 87108, USA.
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Langley
authors.affiliation: Biomedical Research Institute of New Mexico, Albuquerque, NM, USA.
authors.forename: Clifford
authors.initials: C
authors.lastname: Qualls
authors.affiliation: Department of Medicine, University of Iowa, Iowa City, IA, USA.
authors.forename: Julia
authors.initials: J
authors.lastname: Klensney-Tait
authors.affiliation: Department of Medicine, University of Iowa, Iowa City, IA, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Zabner
authors.affiliation: Lovelace Respiratory Research Institute, 2425 Ridgecrest Drive SE, Albuquerque, NM, 87108, USA.
authors.forename: Shuguang
authors.initials: S
authors.lastname: Leng
authors.affiliation: Department of Internal Medicine, University of New Mexico and New Mexico VA Health Care System, Albuquerque, NM, USA.
authors.forename: Jenny
authors.initials: J
authors.lastname: Mao
authors.affiliation: Lovelace Respiratory Research Institute, 2425 Ridgecrest Drive SE, Albuquerque, NM, 87108, USA.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Belinsky
authors.affiliation: Department of Genetics, Rutgers, The State University of New Jersey, 145 Bevier Road, Piscataway, NJ, 08854, USA. xing@biology.rutgers.edu.
authors.forename: Jinchuan
authors.initials: J
authors.lastname: Xing
authors.affiliation: Lovelace Respiratory Research Institute, 2425 Ridgecrest Drive SE, Albuquerque, NM, 87108, USA. nyunoya.toru@gmail.com.|Department of Internal Medicine, University of New Mexico and New Mexico VA Health Care System, Albuquerque, NM, USA. nyunoya.toru@gmail.com.
authors.forename: Toru
authors.initials: T
authors.lastname: Nyunoya
mesh_terms: D000368:Aged; D002470:Cell Survival / Q000235:genetics; D059472:Exome / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies / Q000379:methods*; D020022:Genetic Predisposition to Disease; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D061251:Primary Cell Culture; D029424:Pulmonary Disease, Chronic Obstructive / Q000235:genetics* / Q000473:pathology; D012907:Smoking / Q000009:adverse effects / Q000235:genetics