Epidemiological evidence for associations between variants in CHRNA genes and risk of lung cancer and chronic obstructive pulmonary disease

Abstract

BackgroundGenetic studies have previously reported that single-nucleotide polymorphisms (SNPs) in CHRNA genes (such as CHRNA3, CHRNA4, CHRNA5, or CHRNA3-CHRNA5-CHRNB4 clusters) are linked to the risk of neoplastic and non-neoplastic diseases. However, these conclusions were controversial and no systematic research synopsis has been available. We aimed to synthesize current knowledge of variants in the CHRNA genes on the risk of diseases.MethodsWe systematically searched for publications using PubMed, Medline, and Web of Science on or before 25 August 2021. A total of 1,818 publications were identified, of which 29 were deemed eligible for inclusion that could be used to perform meta-analysis based on at least three data sources to assess whether the morbidity associated with neoplastic and non-neoplastic diseases can be attributed to SNPs in CHRNA genes. To further evaluate the authenticity of cumulative evidence proving significant associations, the present study covered the Venice criteria and false-positive report probability tests. Through the Encyclopedia of DNA Elements (ENCODE) project, we created functional annotations for strong associations.ResultsMeta-analyses were done for nine genetic variants with two diseases {chronic obstructive pulmonary disease (COPD) and lung cancer (LC)}that had at least three data sources. Interestingly, eight polymorphisms were significantly related to changes in the susceptibility COPD and LC (p < 0.05). Of these, strong evidence was assigned to six variants (28 significant associations): CHRNA3 rs1051730, CHRNA3 rs6495309, and CHRNA5 rs16969968 with COPD risk, and CHRNA3 rs1051730, CHRNA3 rs578776, CHRNA3 rs6495309, CHRNA3 rs938682, CHRNA5 rs16969968, and CHRNA5 rs588765 with LC risk; moderate evidence was assigned to five SNPs (12 total associations) with LC or COPD risk. Data from ENCODE and other public databases showed that SNPs with strong evidence may be located in presumptive functional regions.ConclusionsOur study summarized comprehensive evidence showing that common mutations in CHRNA genes are strongly related to LC and COPD risk. The study also elucidated the vital function of CHRNA genes in genetic predispositions to human diseases.

Genome-wide association study identifies novel susceptible loci and evaluation of polygenic risk score for chronic obstructive pulmonary disease in a Taiwanese population

“…Furthermore, these genes have been linked to changes in lung function even in patients without COPD. Variations in CHRNA3 and CHRNA5 levels are associated with reduced lung function, FEV 1 and FVC, which may contribute to the development of COPD [ 69 ]. AFAP1 is involved in actin cytoskeleton organization and cell motility.…”

The rs16969968 Tobacco Smoking-Related Single-Nucleotide Variant Is Associated with Clinical Markers in Patients with Severe COVID-19

“…A meta-analysis of nine genetic variants with two respiratory diseases (COPD and lung cancer) identified eight polymorphisms significantly related to changes in disease susceptibility. Strong evidence was assigned to six variants, including CHRNA5 rs16969968 with COPD and lung cancer risk [ 27 ]. The genotype (AA) was associated with increased risk and earlier diagnosis of lung cancer, but the beneficial effects of smoking cessation were very similar in those with and without the risk genotype [ 28 ].…”

“…Data from ENCODE and other public databases showed that SNPs with strong evidence might be in presumptive functional regions [ 27 ].…”

PLEK2 mediates metastasis and invasion via α5‐nAChR activation in nicotine‐induced lung adenocarcinoma

“…nAChR is a nicotine‐dependent receptor, and its expression level plays an important role in the development of smoking‐related diseases, especially respiratory diseases, 9 such as chronic obstructive pulmonary disease (COPD) and lung cancer. Genome‐wide association studies have shown that CHRNA5 gene (encoding α5‐nAChRs [α5‐nAChR]) polymorphisms are significantly related to the occurrence and development of cancer, especially lung cancer 10,11 ; it is highly expressed in esophageal cancer, gastric cancer and lung cancer and plays an important role in tumor cell proliferation, invasion and metastasis 12 . Our previous studies have shown that α5‐nAChR mediates the development and progression of nicotine‐induced lung cancer, activates Hif‐1α/VEGF, JAK2/STAT3, and Jab/Csn5 signaling, and promotes the proliferation and migration of lung cancer cells 13–15 .…”