A Common Haplotype of the Nicotine Acetylcholine Receptor α4 Subunit Gene Is Associated with Vulnerability to Nicotine Addiction in Men

• Published in: American journal of human genetics Vol. 75; no. 1; pp. 112 - 121
• Main Authors: Feng, Yan, Niu, Tianhua, Xing, Houxun, Xu, Xin, Chen, Changzhong, Peng, Shaojie, Wang, Lihua, Laird, Nan, Xu, Xiping
• Format: Journal Article
• Language: English
• Published: Chicago, IL Elsevier Inc 2004; University of Chicago Press; The American Society of Human Genetics
• Subjects: Biological and medical sciences; General aspects. Genetic counseling; Medical genetics; Medical sciences; Human; Cholinergic receptor; Addiction; Gene; Genetics; Subunit; Haplotype; Nicotine
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1086/422194

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.