This Article Full Text Full Text (PDF) All Versions of this Article: 0008-5472.CAN-09-0786v1 69/17/6848    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Saccone, N. L. Articles by Bierut, L. J. PubMed PubMed Citation Articles by Saccone, N. L. Articles by Bierut, L. J.

The CHRNA5-CHRNA3-CHRNB4 Nicotinic Receptor Subunit Gene Cluster Affects Risk for Nicotine Dependence in African-Americans and in European-Americans

Departments of ¹ Genetics, ² Psychiatry, ³ Medicine, and ⁴ Anesthesiology, Washington University, St. Louis, Missouri; ⁵ Department of Epidemiology, Michigan State University, East Lansing, Michigan; ⁶ Research Triangle Institute International, Research Triangle Park, North Carolina; and ⁷ Department of Psychiatry, University of Minnesota, Minneapolis, Minnesota

Requests for reprints: Nancy L. Saccone, Department of Genetics, Washington University School of Medicine, Box 8232, St. Louis, MO 63110. Phone: 314-747-3263; Fax: 314-747-2489; E-mail: nlims{at}wustl.edu.

Key Words: genetic association • smoking • cholinergic nicotinic receptors • nicotinic acetylcholine receptors

Genetic association studies have shown the importance of variants in the CHRNA5-CHRNA3-CHRNB4 cholinergic nicotinic receptor subunit gene cluster on chromosome 15q24-25.1 for the risk of nicotine dependence, smoking, and lung cancer in populations of European descent. We have carried out a detailed study of this region using dense genotyping in both European-Americans and African-Americans. We genotyped 75 known single nucleotide polymorphisms (SNPs) and one sequencing-discovered SNP in an African-American sample (N = 710) and in a European-American sample (N = 2,062). Cases were nicotine-dependent and controls were nondependent smokers. The nonsynonymous CHRNA5 SNP rs16969968 is the most significant SNP associated with nicotine dependence in the full sample of 2,772 subjects [P = 4.49 x 10^–8; odds ratio (OR), 1.42; 95% confidence interval (CI), 1.25–1.61] as well as in African-Americans only (P = 0.015; OR, 2.04; 1.15–3.62) and in European-Americans only (P = 4.14 x 10^–7; OR, 1.40; 1.23–1.59). Other SNPs that have been shown to affect the mRNA levels of CHRNA5 in European-Americans are associated with nicotine dependence in African-Americans but not in European-Americans. The CHRNA3 SNP rs578776, which has a low correlation with rs16969968, is associated with nicotine dependence in European-Americans but not in African-Americans. Less common SNPs (frequency 5%) are also associated with nicotine dependence. In summary, multiple variants in this gene cluster contribute to nicotine dependence risk, and some are also associated with functional effects on CHRNA5. The nonsynonymous SNP rs16969968, a known risk variant in populations of European-descent, is also significantly associated with risk in African-Americans. Additional SNPs contribute to risk in distinct ways in these two populations. [Cancer Res 2009;69(17):6848–56]