Abstract
Tobacco use is one of the leading causes of preventable disease worldwide. Genetic studies have elucidated numerous smoking-associated risk loci in American and European populations. However, genetic determinants for cigarette smoking in Chinese populations are under investigated. In this study, a whole-genome sequencing (WGS)-based genome-wide association study (GWAS) was performed in a Chinese Han population comprising 620 smokers and 564 nonsmokers. Thirteen single-nucleotide polymorphisms (SNPs) of the raftlin lipid linker 1 (RFTN1) gene achieved genome-wide significance levels (P < 5 x 10−8) for smoking initiation. The rs139753473 from RFTN1 and six other suggestively significant loci from CUB and sushi multiple domains 1 (CSMD1) gene were also associated with cigarettes per day (CPD) in an independent Chinese sample consisting of 1,329 subjects (805 smokers and 524 nonsmokers). When treating males separately, associations between smoking initiation and PCAT5/ANKRD30A, two genes involved in cancer development, were identified and replicated. Within RFTN1, two haplotypes (i.e., C-A-C-G and A-G-T-C) formed by rs796812630-rs796584733-rs796349027-rs879511366 and three haplotypes (i.e., T-T-C-C-C, T-T-A-T-T, and C-A-A-T-T) formed by rs879401109-rs879453873-rs75180423-rs541378415-rs796757175 were strongly associated with smoking initiation. In addition, we also revealed two haplotypes (i.e., C-A-G-G and T-C-T-T derived from rs4875371-rs4875372-rs17070935-rs11991366) in the CSMD1 gene showing a significant association with smoking initiation. Further bioinformatics functional assessment suggested that RFTN1 may participate in smoking behavior through modulating immune responses or interactions with the glucocorticoid receptor alpha and the androgen receptor. Together, our results may help understand the mechanisms underlying smoking behavior in the Chinese Han population.
Highlights
Many programs and regulatory policies of tobacco control have been introduced, reducing the smoking prevalence to a satisfactory level remains an unsolved issue in many countries, especially low- and middle-income countries [1]
Associations between genetic variants and cigarette smoking have been largely deciphered for European- and American-ancestry populations [21, 33]
Follow up replication analyses revealed risk alleles in raftlin lipid linker 1 (RFTN1), CUB and sushi multiple domains 1 (CSMD1), and PCAT5/ANKRD30A genes likely contributing to smoking behavior
Summary
Many programs and regulatory policies of tobacco control have been introduced, reducing the smoking prevalence to a satisfactory level remains an unsolved issue in many countries, especially low- and middle-income countries [1]. Cigarette smoking is believed to have a wide range of deleterious health effects, such as cardiovascular and pulmonary diseases, and cancers [3,4,5,6]. The establishment of daily smoking usually consists of three main stages: smoking initiation, transition from experimentation to regular smoking, and development of nicotine dependence (ND) [8, 9]. Both genetic and environmental factors have been shown to influence all smoking-related stages [9]. Smoking initiation, smoking quantity, smoking cessation, and nicotine dependence are commonly studied phenotypes in researches of smoking-related genetic predispositions. In addition to nAChRs, nicotine metabolizing enzymes (e.g., CYP2A6), dopamine receptors and transporters (e.g., DRD2, DRD4, and SLC6A3), and neuregulin signaling pathway proteins (e.g., NRG3) are considered to have high impacts on nicotine addiction [14,15,16,17]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
