observed in persons with primary and secondary upper aerodigestive tract cancers (Cloos et al., 1996), multiple primary cancers (Cloos et al., 1994), and lung cancer (Li et al., 1996; Spitz et al., 1995; Wei et al., 1996).

Genetic susceptibilities for genes other than those involved in carcinogen metabolism and DNA repair are also being investigated (Jin et al., 1995; Sjalander et al., 1996). There has been less study of genetic susceptibilities for coronary artery disease (Gealy et al, 1999). It is likely that these genes also will play a role in modifying disease risk (see Chapter 13).


The greatest contributors to smoking addiction are the availability of tobacco and cultural acceptance of tobacco smoking. Genetics plays a lesser role. The tobacco smoking epidemic has occurred only over the last 50 to 70 years, and it is unlikely that human genetics have evolved in that amount of time. Nonetheless, twin studies indicate a genetic role for both smoking initiation and smoking persistence (Carmelli et al., 1992; Heath et al., 1993a, b).

People smoke in ways that will maintain a desired blood nicotine level. Nicotine in turn stimulates reward mechanisms in the brain. Presynaptic nicotinic acetylcholine receptors stimulate the secretion of dopamine into neuronal synapses. There also are effects on other pathways, such as those that involve serotonin. For dopamine, synaptic dopamine stimulates dopamine receptors; five subtypes have been identified, which are considered to be D1- or D2-like. Synaptic dopamine levels are governed by presynaptic release and the presynaptic dopamine transporter protein. In humans, there are different types of data supporting the link between nicotine and dopamine. Nicotine self-administration through tobacco smoking may reduce the adverse consequences of Parkinson’s disease, attention deficit disorder, and schizophrenia (Bannon et al., 1995; Olincy et al., 1997; Seeman, 1995), diseases thought to be related to dopamine abnormalities. Also, smoking probably relieves depression (Gilbert and Gilbert, 1995), and the dopamine transporter inhibitor antidepressants (e.g., bupropion SR) are now used to treat nicotine addiction (Hurt et al., 1997; Jorenby et al., 1999).

The genes that code for dopamine receptors (e.g., DRD2, DRD4), dopamine transporter reuptake (SL6A3), and dopamine synthesis (e.g., dopamine hydroxylase, tyrosine hydroxylase, tryptophan hydroxylase, catechol-O-methyltransferase, monoamine oxidase) are polymorphic. Some of the polymorphisms result in altered protein function. Persons with higher levels of synaptic dopamine, or “more stimulation” of dopamine receptors may have less rewarding effects of nicotine and so would be

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