Tasnim Eghbal Eftekhaari - PHD Student, Molecular Medicine, Cardiovascular Research Center, Hormozgan University of Medical Sciences, Bandar Abbas, Iran. Tasnim
Soghra Fallahi - PHD by Research, Reproductive Biology, Molecular Medicine Research Center, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
Mirza Ali Nazar Nejhad - PHD Student, Infectious Disease, Infectious and Tropical Disease Research Center, Hormozgan University of Medical Sciences, Bandar Abbas, Iran.
Rahman Mehdizadeh - PHD Student, Biochemistry, Molecular Medicine Research Center, Hormozgan University of Medical Sciences, Bandar Abbas, Iran

Smoking is one of the most harmful behaviors linked with harmful health conditions in smokers and passive smokers. Smoking has ۳ stages: initiating, current smoking and smoking cessation. This behavior is a multistep process with genetic influences. Current review focuses on loci associated with smoking behavior and predictive epigenetic biomarkers for smoking status. NTRK۲ is associated with smoking initiation and dependence. BDNF binds with NTRK and reinforces nicotine dependence and smoking behavior. The tobacco and genetics (TAG) consortium reports variants at the BDNF locus influence smoking initiation. A region on chromosome ۱۵ (۱۵q۲۵) including the nicotinic receptor subunit genes CHRNA۵, CHRNA۳ and CHRNB۴ (encoding NAChr receptors) was associated with cigarettes consumed per day (CPD), a measure of smoking dependence. The TAG and european network for genetic and genomic epidemiology (ENGAGE) consortia also identified the CHRNA۶–CHRNB۳ cluster on chromosome ۸p۱۱, as well as loci found near CYP۲A۶ on ۱۹q۱۳ and in a region containing noncoding RNAs on chromosome ۱۰q۲۳ and ۱۰q۲۵, as associated with CPD with unknown function. Association of CHRNA۶ with smoking behavior was reported previously in a candidate gene study and is consistent with the gene’s high expression in dopamine-releasing neurons (which have a key role in smoking). For smoking cessation, the TAG consortium identified a region on chromosome ۹ near the gene encoding dopamine β-hydroxylase (DBH) which catalyzes the conversion of dopamine to norepinephrine. Polymorphisms of cytochrome p۴۵۰۲A۶ (encoded by CYP۲A۶) strongly influence the catabolism of nicotine into inactive metabolites, and individuals with rapid metabolism require higher levels of smoking to maintain the same nicotine level than do individuals whose genotypes confer slower metabolism. Epigenome-wide association studies (EpWAS) in Europe revealed that LRRN۳ (among CpG cites) had increased expression and methylation and could be a biomarker for smoking status. EpWAS results in comparing nonsmokers and smokers show ۳ different loci on the AHRR gene (chromosome ۵) (P-values from ۱۰−۱۰۶ to ۱۰−۱۴), ۴ CpG sites in a non-annotated region on chromosome ۲ (۲q۳۷.۱), ۵ sites on chromosome ۱ (including ۴ sites on GFI۱ and ۱ on GNG۱۲), ۱ CpG site on chromosome ۱۹ (F۲RL۳), ۱ CpG site in a non-annotated region on chromosome ۶ (۶p۲۱.۳۳) and ۳ CpG sites on chromosome ۱۱ (KCNQ۱OT۱), ۱۲ (RARG) and ۱۶ (ADCY۹), respectively. Hypomethylation at CpG sites on AHRR and GFI۱ in new-born cord blood related is related to maternal smoking. Several hypermethylated CpG sites, including three sites on MYO۱G, as already reported in several studies, and two sites on CNTNAP۲ were also detected in smokers. The two strongest hypermethylated CpG sites were located on the MYO۱G (chromosome ۷) and these findings suggest epigenetic biomarkers for smoking. According to this review, probable epigenetic biomarkers in smokers and possible pathways inducing smoking behavior are suggested which have potential future in pharmacogenetics.

Smoking, Gene, Expression, Biomarker, Epigenetics