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Multiple distinct CHRNB3-CHRNA6 variants are genetic risk factors for nicotine dependence in African Americans and European Americans.

ABSTRACT: AIMS:Studies have shown association between common variants in the ?6-?3 nicotinic receptor subunit gene cluster and nicotine dependence in European ancestry populations. We investigate whether this generalizes to African Americans, whether the association is specific to nicotine dependence and whether this region contains additional genetic contributors to nicotine dependence. DESIGN:We examined consistency of association across studies and race between the ?6?3 nicotinic receptor subunit locus and nicotine, alcohol, marijuana and cocaine dependence in three independent studies. SETTING:United States of America. PARTICIPANTS:European Americans and African Americans from three case-control studies of substance dependence. MEASUREMENTS:Subjects were evaluated using the Semi-Structured Assessment for the Genetics of Alcoholism. Nicotine dependence was determined using the Fagerström Test for Nicotine Dependence. FINDINGS:The single nucleotide polymorphism rs13273442 was associated significantly with nicotine dependence across all three studies in both ancestry groups [odds ratio (OR) = 0.75, P = 5.8 × 10(-4) European Americans; OR = 0.80, P = 0.05 African Americans]. No other substance dependence was associated consistently with this variant in either group. Another SNP in the region, rs4952, remains modestly associated with nicotine dependence in the combined data after conditioning on rs13273442. CONCLUSIONS:The common variant rs13273442 in the CHRNB3-CHNRA6 region is associated significantly with nicotine dependence in European Americans and African Americans across studies recruited for nicotine, alcohol and cocaine dependence. Although these data are modestly powered for other substances, our results provide no evidence that correlates of rs13273442 represent a general substance dependence liability. Additional variants probably account for some of the association of this region to nicotine dependence.

SUBMITTER: Culverhouse RC

PROVIDER: S-EPMC3984604 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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Multiple distinct CHRNB3-CHRNA6 variants are genetic risk factors for nicotine dependence in African Americans and European Americans.

Culverhouse Robert C RC Johnson Eric O EO Breslau Naomi N Hatsukami Dorothy K DK Sadler Brooke B Brooks Andrew I AI Hesselbrock Victor M VM Schuckit Marc A MA Tischfield Jay A JA Goate Alison M AM Saccone Nancy L NL Bierut Laura J LJ

Addiction (Abingdon, England) 20140218 5

<h4>Aims</h4>Studies have shown association between common variants in the α6-β3 nicotinic receptor subunit gene cluster and nicotine dependence in European ancestry populations. We investigate whether this generalizes to African Americans, whether the association is specific to nicotine dependence and whether this region contains additional genetic contributors to nicotine dependence.<h4>Design</h4>We examined consistency of association across studies and race between the α6β3 nicotinic recepto ...[more]

PMID: 24401102

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Project description:Cigarette smoking is a leading cause of preventable death throughout the world. Nicotine, the primary addictive compound in tobacco, plays a vital role in the initiation and maintenance of its use. Nicotine exerts its pharmacological roles through nicotinic acetylcholine receptors (nAChRs), which are ligand-gated ion channels consisting of five membrane-spanning subunits. Besides the CHRNA4, CHRNB2 and CHRNA5/A3/B4 cluster on chromosome 15, which has been investigated intensively, recent evidence from both genome-wide association studies and candidate gene-based association studies has revealed the crucial roles of the CHRNB3-CHRNA6 gene cluster on chromosome 8 in nicotine dependence (ND). These studies demonstrate two distinct loci within this region. The first one is tagged by rs13277254, upstream of the CHRNB3 gene, and the other is tagged by rs4952, a coding single nucleotide polymorphism in exon 5 of that gene. Functional studies by genetic manipulation in mice have shown that ?6*-nAChRs, located in the ventral tegmental area (VTA), are of great importance in controlling nicotine self-administration. However, when the ?6 subunit is selectively re-expressed in the VTA of the ?6(-/-) mouse by a lentiviral vector, the reinforcing property of nicotine is restored. To further determine the role of ?6*-nAChRs in the process of nicotine-induced reward and withdrawal, genetic knock-in strains have been examined, which showed that replacement of Leu with Ser in the 9' residue in the M2 domain of ?6 produces nicotine-hypersensitive mice (?6 L9'S) with enhanced dopamine release. Moreover, nicotine-induced upregulation may be another ingredient in the pathology of nicotine addiction although the effect of chronic nicotine exposure on the expression of ?6-containing receptors is controversial. To gain a better understanding of the pathological processes underlying ND and ND-related behaviors and to promote the development of effective smoking cessation therapies, we here present the most recent studies concerning the genetic effects of the CHRNB3-CHRNA6 gene cluster in ND.

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Multiple distinct CHRNB3-CHRNA6 variants are genetic risk factors for nicotine dependence in African Americans and European Americans.

Publications

Multiple distinct CHRNB3-CHRNA6 variants are genetic risk factors for nicotine dependence in African Americans and European Americans.

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