Journal article
Whole exome sequencing identifies novel candidate genes that modify chronic obstructive pulmonary disease susceptibility
Human genomics, Vol.10(1), pp.1-1
01/07/2016
DOI: 10.1186/s40246-015-0058-7
PMCID: PMC4705629
PMID: 26744305
Abstract
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.
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.
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.
Details
- Title: Subtitle
- Whole exome sequencing identifies novel candidate genes that modify chronic obstructive pulmonary disease susceptibility
- Creators
- Shannon Bruse - Lovelace Respiratory Research Institute, 2425 Ridgecrest Drive SE, Albuquerque, NM, 87108, USAMichael Moreau - Department of Genetics, Rutgers, The State University of New Jersey, 145 Bevier Road, Piscataway, NJ, 08854, USAYana Bromberg - Department of Biochemistry and Microbiology, Rutgers, the State University of New Jersey, Piscataway, NJ, USAJun-Ho Jang - Department of Internal Medicine, University of New Mexico and New Mexico VA Health Care System, Albuquerque, NM, USANan Wang - Department of Genetics, Rutgers, The State University of New Jersey, 145 Bevier Road, Piscataway, NJ, 08854, USAHongseok Ha - Department of Genetics, Rutgers, The State University of New Jersey, 145 Bevier Road, Piscataway, NJ, 08854, USAMaria Picchi - Lovelace Respiratory Research Institute, 2425 Ridgecrest Drive SE, Albuquerque, NM, 87108, USAYong Lin - Lovelace Respiratory Research Institute, 2425 Ridgecrest Drive SE, Albuquerque, NM, 87108, USARaymond J Langley - Lovelace Respiratory Research Institute, 2425 Ridgecrest Drive SE, Albuquerque, NM, 87108, USAClifford Qualls - Biomedical Research Institute of New Mexico, Albuquerque, NM, USAJulia Klensney-Tait - Department of Medicine, University of Iowa, Iowa City, IA, USAJoseph Zabner - Department of Medicine, University of Iowa, Iowa City, IA, USAShuguang Leng - Lovelace Respiratory Research Institute, 2425 Ridgecrest Drive SE, Albuquerque, NM, 87108, USAJenny Mao - Department of Internal Medicine, University of New Mexico and New Mexico VA Health Care System, Albuquerque, NM, USASteven A Belinsky - Lovelace Respiratory Research Institute, 2425 Ridgecrest Drive SE, Albuquerque, NM, 87108, USAJinchuan Xing - Department of Genetics, Rutgers, The State University of New Jersey, 145 Bevier Road, Piscataway, NJ, 08854, USA. xing@biology.rutgers.eduToru Nyunoya - Department of Internal Medicine, University of New Mexico and New Mexico VA Health Care System, Albuquerque, NM, USA. nyunoya.toru@gmail.com
- Resource Type
- Journal article
- Publication Details
- Human genomics, Vol.10(1), pp.1-1
- DOI
- 10.1186/s40246-015-0058-7
- PMID
- 26744305
- PMCID
- PMC4705629
- NLM abbreviation
- Hum Genomics
- ISSN
- 1473-9542
- eISSN
- 1479-7364
- Grant note
- P30 CA118100 / NCI NIH HHS R00 HG005846 / NHGRI NIH HHS U01 CA097356 / NCI NIH HHS CA097356 / NCI NIH HHS I01 CX001048 / CSRD VA R01 CA097356 / NCI NIH HHS R00HG005846 / NHGRI NIH HHS U01 GM115486 / NIGMS NIH HHS P30 DK054759 / NIDDK NIH HHS
- Language
- English
- Date published
- 01/07/2016
- Academic Unit
- Pulmonary, Critical Care, and Occupational Medicine; Internal Medicine
- Record Identifier
- 9984094569302771
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