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SNPs reported in the nicotine receptor CHRNB2 gene
No association found between polymorphisms and smoking or nicotine dependence
Edward R. Winstead

Researchers at Virginia Commonwealth University screened part of the nicotine receptor CHRNB2 gene for polymorphisms and identified five single nucleotide polymorphisms, or SNPs. The researchers found no association between the four SNPs they tested and smoking initiation or nicotine dependence in a population of smokers and non-smokers.

Mice without the receptor gene do not become addicted to nicotine

The nicotine receptor belongs to a relatively large family of genes involved in mediating the transmission of signals between brain cells. CHRNB2 is short for nicotinic acetylcholine receptor b2-subunit gene, and the gene is suspected in epilepsy as well as nicotine addiction. The principal nicotine receptor is formed by the expression of two genes: CHRNB2 and the a4-subunit of the nicotinic acetylcholine receptor, or CHRNA4.

Richard E. Straub, who directs a molecular genetics laboratory at Virginia Commonwealth University, led the study. In May 1999, Straub and colleagues reported evidence that susceptibility genes for nicotine addiction reside on chromosomes 2, 4, 10, 16, 17, and 18; the regions were identified using genome scans.

The scan data support the notion that nicotine addiction is a complex disorder involving many genes. The region of chromosome 1 containing CHRNB2 did not turn up in the 1999 study. But CHRNB2 is of particular interest to smoking researchers, because mice lacking the gene have been studied since the mid-1990s.

"This was by far the most interesting nicotine receptor to begin with because of the work in the mouse," says Straub. Normal mice give themselves doses of nicotine when the drug is available. Nicotine is not habit-forming in mice that lack the primary nicotine receptor, presumably because in these mice the drug never reaches the reward center of the brain.

"This is a nice preliminary study on an important topic by the first group to show genetic linkage in nicotine addiction," says Sherry Leonard, of the University of Colorado Health Sciences Center. Leonard investigates the role of nicotine receptors in schizophrenia and mental illness, and she hopes Straub's group will screen the entire gene.

The four polymorphisms tested in the current study may have functional effects on the gene that the researchers were not able to detect in the sample of some 800 individuals. The researchers compared smoking initiation and progression toward nicotine addiction in nonsmokers, regular smokers with low levels of nicotine addiction, and smokers with high nicotine addiction. The findings appeared recently as a Rapid Communication in the American Journal of Medical Genetics. The issue was devoted to research on substance use and abuse.

Straub emphasizes that these polymorphisms—and undiscovered polymorphisms—may influence nicotine dependence in some individuals. A drawback of the current study is that it included only Caucasians. Finding genes in complex disorders is generally believed to require extremely large samples. "My guess is you could assemble twice as many people and still not see an association between polymorphisms and an increased or decreased risk for dependence," says Straub.

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Silverman, M.A. et al. Haplotypes of four novel single nucleotide polymorphisms in the nicotinic acetylcholine receptor b2-subunit (CHRNB2) gene show no association with smoking initiation or nicotine dependence. Am J Med Genet (Neuropsychiatr Genet) 96, 646-653 (October 9, 2000).
Straub, R.E. et al. Susceptibility genes for nicotine dependence: A genome scan and followup in an independent sample suggest that regions on chromosomes 2, 4, 10, 16, 17 and 18 merit further study. Mol Psychiatry 4, 129-144 (March 1999).

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