Alpha-5 and -3 nicotinic receptor gene variants predict nicotine dependence but not cessation: findings from the COMMIT cohort.
Smoking many cigarettes per day (CPD) and short interval to first cigarette (TTF) after waking are two of the most heritable smoking phenotypes and comprise the Heavy Smoking Index (HSI). These phenotypes are often used as proxies for nicotine dependence (ND) and are associated with smoking cessation outcomes. Case-control and genome-wide association studies have reported links between single nucleotide polymorphisms (SNPs) in the alpha-5 and -3 nicotinic receptor subunit (CHRNA5 and CHRNA3) genes and CPD but few have examined TTF or cessation outcomes. In this study we longitudinally assessed 1301 European-American smokers at four time-points from 1988 to 2005. One CHRNA5 (rs16969968) and two CHRNA3 (rs1051703, rs6495308) SNPs were examined for their ability to predict smokers who "ever" reported ND based on three phenotypic classifications: (1) 25+ CPD, (2) TTF < 10 min, and (3) HSI ≥ 4. In a subsample of 1157 quit attempters, we also examined each SNP's ability to predict "ever" quitting for a period of >6 months. Demographically adjusted logistic regressions showed significant allelic and genotypic associations between all three SNPs and CPD but not TTF, HSI, or smoking cessation. Carriers of both the rs16969968-AA and rs6495308-TT genotypes had approximately twofold greater odds for ND defined using CPD or TTF. Results suggest nicotinic receptor variants are associated with greater odds of ND according to CPD and to a lesser extent TTF. Research examining the effect of nicotinic receptor genetic variation on ND phenotypes beyond CPD is warranted.
Department of Psychiatry, The University of Melbourne, Parkville, Victoria, Australia.
Chad A
CA
Bousman
Cheryl
C
Rivard
Jason Den
JD
Haese
Christine
C
Ambrosone
Andrew
A
Hyland
D000293:Adolescent; D000328:Adult; D015331:Cohort Studies; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis; D011978:Receptors, Nicotinic / Q000235:genetics*; D012907:Smoking / Q000235:genetics*; D016540:Smoking Cessation; D014029:Tobacco Use Disorder / Q000235:genetics*; D055815:Young Adult
D009419:Nerve Tissue Proteins; D011978:Receptors, Nicotinic; C447158:CHRNA5 protein, human