Duplicated copy of CHRNA7 increases risk and worsens prognosis of COPD and lung cancer

Abstract

Recent genome-wide association studies implicated that the nicotinic acetylcholine receptors (nAChRs) are common susceptible genes of two contextual diseases: chronic obstructive pulmonary disease (COPD) and lung cancer. We aimed to test whether the copy number variations (CNVs) in nAChRs have hereditary contributions to development of the two diseases. In two, two-stage, case-control studies of southern and eastern Chinese, a common CNV-3956 that duplicates the cholinergic receptor, nicotinic, α7 (CHRNA7) gene was genotyped in a total of 7880 subjects and its biological phenotype was assessed. The ≥ 4-copy of CNV-3956 increased COPD risk (≥4-copy vs 2/3-copy: OR = 1.44, 95% CI = 1.23-1.68) and caused poor lung function, and it similarly augmented risk (OR = 1.49, 95% CI = 1.29-1.73) and worsened prognosis (hazard ratio (HR) = 1.25, 95% CI = 1.07-1.45) of lung cancer. The ≥ 4-copy was estimated to account for 1.56% of COPD heritability and 1.87% of lung cancer heritability, respectively. Phenotypic analysis further showed that the ≥ 4-copy of CNV-3956 improved CHRNA7 expression in vivo and increased the carriers' smoking amount. The CNV-3956 of CHRNA7 contributed to increased risks and poor prognoses of both COPD and lung cancer, and this may be a genetic biomarker of the two diseases.

Association of nsv823469 copy number loss with decreased risk of chronic obstructive pulmonary disease and pulmonary function in Chinese

“…As described in previously published studies52829, a two-stage case-control study was conducted in the southern Chinese and eastern Chinese population. In brief, 1025 COPD patients and 1061 controls were enrolled from Guangzhou city; 486 COPD patients and 616 controls were recruited from Suzhou city.…”

“…However, these loci by no means cover the complete genetic predisposition of COPD, because they mainly focus on single nucleotide polymorphism (SNP). Copy number variation (CNV)45 also contributes to COPD heritability67. CNVs can hold greater influence over covering genes than SNPs do, because CNVs can cause changes in a large DNA fragment while SNPs can only cause one base change8.…”

β-Cryptoxanthin Reduced Lung Tumor Multiplicity and Inhibited Lung Cancer Cell Motility by Downregulating Nicotinic Acetylcholine Receptor α7 Signaling

“…Because of its high calcium permeability which modulates intracellular signaling molecules (11), the homopentameric α7 type of nAChRs (α7-nAChR) has been implicated in lung tumorigenesis (12–14). A recent study has showed that the copy number variations (CNV-3956) which resulted in a duplicated α7-nAChR conferred to an increased risk of lung cancer and poor survival of lung cancer patients (15). Treatment with NNK, which binds with high affinity to α7-nAChR, increases the expression of α7-nAChR in papillomavirus-immortalized bronchial epithelial cells (13), as well as cell proliferation and cell motility (16, 17).…”

CNVs Associated with Susceptibility to Cancers: A Mini-Review

“…The risk of lung cancer depends on the copy number of the CNV at 16q23 containing oxidoreductase (WWOX); the deletion genotype of the CNV increases the risk of lung cancer (OR = 1.39). Recently, Yang et al have reported that ≥4-copy of CNV in the nicotinic acetylcholine receptors (nAChRs) increase risk of lung cancer [59]. Lung cancers are classified into histological subtypes for the difference in therapeutic regimen.…”