Tobacco and Public Health - TCSC Indonesia

632
GENES, NICOTINE ADDICTION, SMOKING BEHAVIOUR, AND CANCER
dopamine and noradrenaline within the synapse, terminating their action. It is polymorphic,
the variants are common and functional, increasing the extraneuronal enzyme
activity, and have been linked to substance abuse. Amongst the OXCHECK sample of
smokers, who attended a health check in the early 1990s (mentioned earlier in the chapter),
there was no effect observed in two separate studies. Allele presence did not appear
to influence the number of self-reported cigarettes/day or heavy smoking amongst a random
sample of 226 smokers (McKinney et al. 2000) nor was it associated with smoking
status (current, ex-, never smokers) when three age–sex matched groups of 270 subjects
were compared to one another (David et al. 2002). Should further studies be done?
Candidate genes—false promise?
Dopamine β Hydroxylase (DBH) converts dopamine to noradrenaline, exhibits common
silent polymorphisms which are tightly linked to variants which probably reduce
enzyme activity and has been linked to substance abuse. In the same first OXCHECK
sample of 226 smokers referred to for COMT, allele presence was associated with a significantly
reduced number of self-reported cigarettes per day (especially in women)
(McKinney et al. 2000). When we tried to replicate this finding in all the remaining
1275 smokers for whom we had data in the OXCHECK cohort, allele presence was only
associated with slightly reduced consumption in men and women (Johnstone et al.
2002). However it may be associated with response to NRT particularly in women
(see later) so perhaps there is a case for further studies (Johnstone et al. 2004, In Press;
Yudkin et al.In Press).
Systematic review—hope?
The clearest results from all the studies combined and examined in the systematic
review suggest a relationship between possession of the Dopamine D2 receptor
Taq1A1 allele and polymorphisms in the Dopaminergic Transporter (DAT1), but the
summary estimates of genotypic risk associated with allelic possession are always less
than 2 whatever the hypothesized mode of gene action examined (for which there is
currently little good evidence to choose between, e.g. dominant, codominant, recessive
etc.) (Walton et al. 2001). They reinforce the prevailing notion that the genetic variants
that will be identified may be common (possessed by one person in three, say) but
uniformly of small effect. The results provide a ‘scoping’ study, which allied to advance
in neurobiological understanding should define the principal target of interest (Munafò
et al.In Press).
The levels and types of evidence that these (and many other) genetic variants contribute
to overall genetic liability with respect to smoking behaviour are various. There
is ‘analogy’ in the sense that debate still rages about whether the DRD2 Taq1A1 allele is
related to alcohol use and abuse. Possession of the same allele has also now been linked
to associated or surrogate measures of the smoking behaviour phenotype in (at least) 3