Nicotinic receptor gene variants influence susceptibility to heavy smoking.
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 alpha5 nicotinic receptor in heavy smoking.
Stevens
Victoria L
VL
Department of Epidemiology and Surveillance Research, American Cancer Society, 250 Williams Street Northwest, Atlanta, GA 30303-1002, USA. Victoria.Stevens@cancer.org
Bierut
Laura J
LJ
Talbot
Jeffrey T
JT
Wang
Jen C
JC
Sun
Juzhong
J
Hinrichs
Anthony L
AL
Thun
Michael J
MJ
Goate
Alison
A
Calle
Eugenia E
EE
D000368:Aged; D000483:Alleles; D016009:Chi-Square Distribution; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D011978:Receptors, Nicotinic / Q000235:genetics*; D012307:Risk Factors; D011795:Surveys and Questionnaires; D014029:Tobacco Use Disorder / Q000235:genetics*
D009419:Nerve Tissue Proteins; D011978:Receptors, Nicotinic; C447158:CHRNA5 protein, human; C447159:CHRNB4 protein, human