Nicotinic Receptor Gene Variants Influence Susceptibility to Heavy Smoking

Abstract

Heavy smoking is a strong predictor of nicotine dependence, which is a major impediment to smoking cessation. Although both heavy smoking and nicotine dependence are highly heritable, previous attempts to identify genes influencing these phenotypes have been largely unsuccessful until very recently. We studied 1,452 heavy smokers (defined as smoking at least 30 cigarettes per day for at least 5 years) and 1,395 light smokers (defined as smoking <5 cigarettes per day for at least 1 year) to investigate the association of common variants in nicotinic receptor subunit genes with smoking behavior. Compared with the most common allele, two separate groups of single nucleotide polymorphisms (SNP) in the CHRNA5-CHRNA3-CHRNB4 gene cluster were associated with heavy smoking with a very high statistical significance. One group of eight SNPs, which included a nonsynonymous SNP in the CHRNA5 gene, was in strong linkage disequilibrium and associated with increased risk of heavy smoking. A second group of SNPs not strongly correlated with the first was associated with decreased risk of heavy smoking. Analyses that combined both groups of SNPs found associations with heavy smoking that varied by >2-fold. Our findings identify two loci in the CHRNA5-CHRNA3-CHRNB4 gene cluster that predict smoking behavior and provide strong evidence for the involvement of the A5 nicotinic receptor in heavy smoking. (Cancer Epidemiol Biomarkers Prev 2008;17(12):3517 -25)

Differential contribution of genetic variation in multiple brain nicotinic cholinergic receptors to nicotine dependence: recent progress and emerging open questions

“…82 These predispositions were strongest if smoking began during adolescence. These finding are in correlation to those reported by Stevens et al, 90 who found two groups of SNPs in this cluster; one increased risk for heavy smoking, while the other was protective. 90 CHRNA5-CHRNA3-CHRNB4 and other substance abuse.…”

“…These finding are in correlation to those reported by Stevens et al, 90 who found two groups of SNPs in this cluster; one increased risk for heavy smoking, while the other was protective. 90 CHRNA5-CHRNA3-CHRNB4 and other substance abuse. Comorbidity of nicotine and alcohol use is well documented but a common biological mechanism or genetic background has not been shown.…”

“…All associations withstand Bonferonni correction for multiple testing. 90 As reported previously, 88 the correlation between the two separate SNP groups is low. 90 On the other hand, no association of this gene cluster with smoking cessation was found in a large, well-powered retrospective cohort study from Germany.…”

“…90 As reported previously, 88 the correlation between the two separate SNP groups is low. 90 On the other hand, no association of this gene cluster with smoking cessation was found in a large, well-powered retrospective cohort study from Germany. 91 Seven SNPs which are related to other ND phenotypes were genotyped (rs684513, rs637137, rs16969968, rs578776, rs1051730, rs3743078, rs3813567) in a sample of 1446 heavy smoking individuals ( > 20 CPD).…”

“…89 In agreement with Bierut et al study, 88 two different groups of SNPs were associated with ND in a case-control sample of 1452 heavy smokers (CPD > 30) and 1395 light smokers (CPD < 5) of EA. 90 Eight SNPs which are in high LD (including rs16969968 and rs1051730) were associated with increased smoking risk (See Table 3), while 11 SNPs (including rs578776) were protective and associated with decreased risk of heavy smoking (See Table 3). All associations withstand Bonferonni correction for multiple testing.…”