Smoking status and the human dopamine transporter variable number of tandem repeats (VNTR) polymorphism: failure to replicate and finding that never-smokers may be different

Abstract

Cigarette smoking, like many addictive behaviors, has been shown to have a genetic component. The dopamine transporter (DAT) gene (SLC6A3) encodes a protein that regulates synaptic levels of dopamine in the brain and is a candidate gene for addictive behaviors. We have collected smoking information from a national probability sample of 3383 adult volunteers contacted via a random-digit dialing telephone interview. A subset of individuals provided DNA from cheek swabs returned via the mail for subsequent genetic analysis of self-reported smoking behavior. DNA samples were genotyped at a variable number of tandem repeats (VNTR) polymorphism in the 3'-untranslated region of the DAT gene. If we classify smokers as non- (<100 cigarettes), former and current, we fail to replicate both Lerman et al. (Health Psychology 18:14-20, 1999) and Sabol et al. (Health Psychology 18:7-13, 1999) and support the absence of effects found by Jorm et al. (American Journal of Medical Genetics (Neuropsychiatric Genetics) 96:331-334, 2000). When we distinguish between never-smokers (no cigarettes ever) and non-smokers (1-99 in lifetime), we find a reliable trend essentially in the opposite direction from Lerman et al. (1999), with the 10-copy allele being more frequent in never-smokers. Biobehavioral research on cigarette smoking should distinguish between never- and non-smokers. We have also developed an improved set of polymerase chain reaction conditions to increase the frequency of successful amplification of DAT'sw VNTR, which is a long, G+C-rich repeat.

Epistasis between the DAT 3′ UTR VNTR and the COMT Val158Met SNP on cortical function in healthy subjects and patients with schizophrenia

“…Thus, although effects of medication cannot be completely excluded, we could not find any evidence that the findings were attributable to effects of treatment. Because DAT and specifically the 3Ј UTR VNTR has also been implicated, although not consistently, in the vulnerability to substance abuse disorders (78,79), it is possible that the DAT subgroups differed with respect to smoking and alcohol consumption, which might have influenced the fMRI results. In the present study, we excluded subjects who met DSM-IV criteria for a substance misuse disorder, but did not measure the frequency of substance use among those who were included (SI Materials and Methods).…”

Interaction between BDNF Val66Met and Dopamine Transporter Gene Variation Influences Anxiety-Related Traits

“…Furthermore, there is strong evidence for a role of DAT VNTR in alcohol-withdrawal symptoms (Sander et al, 1997;Schmidt et al, 1998;Gorwood et al, 2003). Its relevance to smoking behavior (Lerman et al, 1999;Sabol et al, 1999;Jorm et al, 2000;Vandenbergh et al, 2002;Erblich et al, 2005) is still tentative. With regard to the pathophysiology of stress-related disorders, the role of DAT VNTR in bipolar disorder is inconclusive as well (Souery et al, 1996;GomezCasero et al, 1996;Waldman et al, 1997;Georgieva et al, 2002).…”

Overview of the pharmacogenomics of cigarette smoking

“…88,93 The SLC6A3-9 allele has been associated with a lower risk of current smoking and starting smoking before age 16 years, longer periods of abstinence during previous quit attempts and increased quitting. 94,95 However, these findings have not been replicated, 96,97 and conversely, the SCL6A3-9 allele has also been associated with stronger cue-or stress-induced cravings. 68 Examination of a single-nucleotide polymorphism (SNP) in the 3 0 -UTR of SCL6A3-9 (rs27072G4A) found individuals with the A-allele were more likely to initiate smoking before age 18 years.…”