title: A common haplotype of the nicotine acetylcholine receptor alpha 4 subunit gene is associated with vulnerability to nicotine addiction in men.
abstract: Nicotine is the major addictive substance in cigarettes, and genes involved in sensing nicotine are logical candidates for vulnerability to nicotine addiction. We studied six single-nucleotide polymorphisms (SNPs) in the CHRNA4 gene and four SNPs in the CHRNB2 gene with respect to nicotine dependence in a collection of 901 subjects (815 siblings and 86 parents) from 222 nuclear families with multiple nicotine-addicted siblings. The subjects were assessed for addiction by both the Fagerstrom Test for Nicotine Dependence (FTND) and the Revised Tolerance Questionnaire (RTQ). Because only 5.8% of female offspring were smokers, only male subjects were included in the final analyses (621 men from 206 families). Univariate (single-marker) family-based association tests (FBATs) demonstrated that variant alleles at two SNPs, rs1044396 and rs1044397, in exon 5 of the CHRNA4 gene were significantly associated with a protective effect against nicotine addiction as either a dichotomized trait or a quantitative phenotype (i.e., age-adjusted FTND and RTQ scores), which was consistent with the results of the global haplotype FBAT. Furthermore, the haplotype-specific FBAT showed a common (22.5%) CHRNA4 haplotype, GCTATA, which was significantly associated with both a protective effect against nicotine addiction as a dichotomized trait (Z=-3.04, P<.005) and significant decreases of age-adjusted FTND (Z=-3.31, P<.005) or RTQ scores (Z=-2.73, P=.006). Our findings provide strong evidence suggesting a common CHRNA4 haplotype might be protective against vulnerability to nicotine addiction in men.
authors.affiliation: Program for Population Genetics, Harvard School of Public Health, Boston, MA, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Feng
authors.forename: Tianhua
authors.initials: T
authors.lastname: Niu
authors.forename: Houxun
authors.initials: H
authors.lastname: Xing
authors.forename: Xin
authors.initials: X
authors.lastname: Xu
authors.forename: Changzhong
authors.initials: C
authors.lastname: Chen
authors.forename: Shaojie
authors.initials: S
authors.lastname: Peng
authors.forename: Lihua
authors.initials: L
authors.lastname: Wang
authors.forename: Nan
authors.initials: N
authors.lastname: Laird
authors.forename: Xiping
authors.initials: X
authors.lastname: Xu
mesh_terms: D000328:Adult; D004247:DNA / Q000235:genetics; D005260:Female; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009538:Nicotine / Q000009:adverse effects; D009679:Nuclear Family; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011978:Receptors, Nicotinic / Q000235:genetics*; D035781:Siblings; D011795:Surveys and Questionnaires; D014029:Tobacco Use Disorder / Q000209:etiology / Q000235:genetics*
chemical_list: D004247:DNA; D009538:Nicotine; D011978:Receptors, Nicotinic