Whole exome sequencing identifies novel candidate genes that modify chronic obstructive pulmonary disease susceptibility

Abstract

BackgroundChronic 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.ResultsWe 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.ConclusionsOur 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s40246-015-0058-7) contains supplementary material, which is available to authorized users.

fuNTRp: Identifying protein positions for variation driven functional tuning

“…Preferred residues for metal binding are C, H, D, and E (Cao, et al, 2017), which is also confirmed by our data ( Supplementary Fig. S10).…”

“…The recent decades have seen significant advances in high-throughput experimentation and growing sophistication in the analyses of the results. Unfortunately, our ability to perform these experimental analyses cannot keep up with the current pace of sequencing for research and medical purposes (Bruse, et al, 2016;Ellinghaus, et al, 2013;Turner, et al, 2016). On the other hand, advanced computational techniques are enabled by, and crucial for, dealing with this onslaught of data.…”

Cigarette smoke exposure enhances transforming acidic coiled-coil–containing protein 2 turnover and thereby promotes emphysema

“…Our recent human studies using both genomic and functional analyses identified TACC2 as a COPD candidate gene (9). Whole exome sequencing (WES) among 62 smokers with severe COPD and 30 resistant smokers identified 7 rare deleterious variants of TACC2 that cause nonsense or nonsynonymous mutations in 8 COPD subjects (12.9%), in contrast to none in resistant smokers (9). Furthermore, suppression of TACC2 by siRNA transfection markedly enhanced CS-induced apoptotic cell death in cultured immortalized human bronchoepithelial cells (HBECs) (9).…”

Genetic Risk for Developing Chronic Obstructive Pulmonary Disease

“…An exome sequencing study examining resistance to the detrimental effects of the cigarette smoke, identified a variant in CCDC38, previously associated with FEV 1 /FVC ratio, and cilia-related pathways in heavy smokers (n=100, > 20 packyears) with normal lung function 83 . Another case-control study, integrating exome sequencing and airway gene expression of sensitive (n=62) and resistant smokers (n=30), identified two candidate genes (TACC2 and MYO1E) which, when silenced in in vitro studies, augmented cigarette smoke toxicity 84 . To investigate the genetic factors underlying cigarette smoking, GWAS and exome sequencing analysis were combined to examine common and rare variants, respectively.…”