Chrna3, encoding the Alpha-3 subunit of the nicotinic acetylcholine receptor, is crucial for fast synaptic transmission in the autonomic ganglia [4]. The nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels, and Chrna3, along with other subunits like α5 and β4 encoded by the CHRNA5-CHRNA3-CHRNB4 gene cluster, are involved in the regulation of nicotine-related behaviors [1,2].

Genetic variation in the CHRNA5-CHRNA3-CHRNB4 gene cluster has been associated with increased vulnerability to tobacco dependence, smoking-associated diseases such as lung cancer, chronic obstructive pulmonary disease, and nicotine addiction [1,3,5]. In a Mexican population, the A allele of CHRNA3 rs1051730 was associated with heavy smoking, and risk of lung cancer and COPD [3]. In a study on nicotine-addicted subjects, the T/T genotype of the rs1051730 polymorphism of the CHRNA3 gene was more frequent in nicotine-dependent subjects, and novel haplotypes in CHRNA3 were associated with nicotine addiction [5]. In addition, rare pathologic variants in the CHRNA3 gene were found in patients with familial autonomic ganglionopathy presenting with severe neurogenic orthostatic hypotension, small non-reactive pupils, and constipation [4]. A patient with neurogenic bladder, vesicoureteral reflux, mydriasis, and gastrointestinal dysmotility was found to have novel compound heterozygous variants in CHRNA3 [6].

In conclusion, Chrna3 plays a significant role in nicotine-related behaviors and is associated with various smoking-related diseases and some rare genetic disorders affecting the autonomic nervous system. The study of Chrna3 through genetic variation analysis in human populations has provided insights into its functions and implications in disease, highlighting its potential as a target for understanding and treating nicotine-related disorders and certain genetic autonomic diseases.