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Multicenter Study
. 2009 Sep 1;69(17):6848-56.
doi: 10.1158/0008-5472.CAN-09-0786. Epub 2009 Aug 25.

The CHRNA5-CHRNA3-CHRNB4 nicotinic receptor subunit gene cluster affects risk for nicotine dependence in African-Americans and in European-Americans

Nancy L Saccone  1 , Jen C Wang, Naomi Breslau, Eric O Johnson, Dorothy Hatsukami, Scott F Saccone, Richard A Grucza, Lingwei Sun, Weimin Duan, John Budde, Robert C Culverhouse, Louis Fox, Anthony L Hinrichs, Joseph Henry Steinbach, Meng Wu, John P Rice, Alison M Goate, Laura J Bierut
Affiliations
Multicenter Study

The CHRNA5-CHRNA3-CHRNB4 nicotinic receptor subunit gene cluster affects risk for nicotine dependence in African-Americans and in European-Americans

Nancy L Saccone et al. Cancer Res. .

Abstract

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 <or= 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.

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Conflict of interest statement

Conflict of Interest statement: Drs. Bierut, Goate, Hinrichs, Rice, S. Saccone and Wang are listed as inventors on a patent, “Markers of Addiction,” held by Perlegen Sciences, Inc., covering the use of certain SNPs, including rs16969968, in diagnosing, prognosing, and treating addiction. Dr. N. Saccone is the spouse of S. Saccone, who is listed on the above patent. Dr. Bierut has served as a consultant to Pfizer.

Figures

Figure 1
Figure 1
Association results and r2 on chromosome 15q24-25.1 for the EA and AA samples.
See this image and copyright information in PMC

References

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