Variants of the ADRB2 Gene in COPD: Systematic Review and Meta-Analyses of Disease Risk and Treatment Response
COPD-JOURNAL OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE
Authors: Nielsen, Anne Orholm; Jensen, Camilla Steen; Arredouani, Mohamed Simo; Dahl, Ronald; Dahl, Morten
Abstract
The beta(2)-adrenergic receptor (ADRB(2)) is an important regulator of airway smooth muscle tone in chronic obstructive pulmonary disease (COPD). Variants that impair ADRB(2) function could increase disease risk or reduce the response to endogenous and inhaled adrenergic agonists in COPD. We performed a systematic review and three meta-analyses to assess whether three functional variants (Thr164Ile, Arg16Gly, and Gln27Glu) in the ADRB(2) gene are associated with elevated risk of disease or reduced therapeutic response to inhaled beta(2)-agonists in COPD. We searched the medical literature from 1966 to 2017 and found 16 relevant studies comprising 85381 study subjects. The meta-analyses found no significant association between ADRB(2) genotype and COPD risk. The summary odds ratios (ORs) for COPD in Thr164Ile homozygotes and heterozygotes were 2.57 (95% confidence interval (CI): 0.54-12.4) and 1.17 (95% CI: 0.96-1.44), respectively. Corresponding summary ORs for COPD in Arg16Gly homozygotes and heterozygotes were 0.97 (95% CI: 0.76-1.22) and 1.01 (95% CI: 0.81-1.26), while summary ORs for COPD in Gln27Glu homozygotes and heterozygotes were 1.00 (95% CI: 0.80-1.25) and 0.94 (95% CI: 0.69-1.24), respectively. When stratified by ethnicity, the summary ORs for COPD did not differ from 1.0 for any of the ADRB(2) variants among Asian, Caucasian, or African populations. We found no consistent associations between ADRB(2) genotype and treatment response to inhaled beta(2)-agonists in COPD. This systematic review and meta-analyses found that COPD risk and response to inhaled beta(2)-agonistswere not associated with Thr164Ile, Arg16Gly, and Gln27Glu genotypes. However, identified cases of Thr164Ile were few, and additional studies of rare ADRB(2) genotypes are required.
A functional SNP upstream of the ADRB2 gene is associated with COPD
INTERNATIONAL JOURNAL OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE
Authors: Li, Jin-Xiu; Fu, Wei-Ping; Zhang, Jing; Zhang, Xiao-Hua; Sun, Chang; Dai, Lu-Ming; Zhong, Li; Yu, Li; Zhang, Ya-Ping
Abstract
Background: Previous studies have suggested that beta(2)-adrenergic receptor (ADRB2) is associated with COPD. However, the role of genetic polymorphisms in ADRB2 on COPD has not been evaluated yet. Methods: In this study, SNaPshot genotyping, luciferase assay, chromatin immunoprecipitation and real-time polymerase chain reaction were adopted to investigate the association between ADRB2 genetic polymorphisms and COPD, comprehensively. Results: One single nucleotide polymorphism (rs12654778), located upstream of ADRB2, showed a significant association with COPD by the logistic regression analysis after adjusting for age, sex and smoking history (p=0.04) in 200 COPD patients and 222 controls from southwest Chinese population. Furthermore, the luciferase assay indicated that rs12654778-A allele reduced the relative promoter activity by similar to 26% compared with rs12654778-G allele (p=0.0034). The chromatin immunoprecipitation analysis demonstrated that rs12654778 modulated the binding affinity of transcription factor neurofibromin 1. In addition, a significantly reduced expression of ADRB2 in COPD patients was observed, compared with normal controls (p=0.017). Conclusion: Our findings suggest a previously unknown mechanism linking allele-specific effects of rs12654778 on ADRB2 expression to COPD onset, for the first time.