Tobacco and Public Health - TCSC Indonesia

MICHAEL MURPHY ET AL.
risk associated with possession of increasing numbers of alleles at increasing numbers
of loci and their increases in prevalence both mean that an increasing proportion of
the population starts to be at an important level of liability, e.g. to acquisition of nicotine
dependence, but comparatively few are at very low or very high risk, which might
be a reasonable, but entirely hypothetical, description of the population’s liability. If so
it would suggest the numbers of genes to be interested in are numbered in the tens if
not hundreds when assessing genetic contribution.
Thus all of the usual difficulties of investigating a complex genetic trait to define the
quantitative trait loci (QTL) which contribute to the phenotype are evident in the
study of smoking behaviour. Nevertheless the strength of the evidence that genes are
important, the potential rewards from identifying even some of the factors which contribute
to variation in smoking behaviour, the grip exerted by tobacco use, and the
ways in which it might be lessened, are potent incentives to regard the problem of
understanding the genetics of smoking behaviour as a potentially tractable one
Identifying genes contributing to smoking behaviour
The usual approaches to identify the potential genes of interest in smoking—familial
clustering, pedigree-based linkage studies, affected relative (usually sibling) pair studies,
and candidate gene association studies have all contributed though most effort has been
concentrated on the latter. Results from only four genome scan studies have so far been
published (in some shape or form), dealing with different smoking phenotypes. A fifth
(the largest to date and conducted amongst female non-identical twin pairs) has recently
been conducted but is, as yet, unpublished (Munafò et al.personal communication).
Duggirala et al. (1999) looked at the phenotype ‘cigarettes per day’ and found some
evidence of linkage on chromosomes 4, 5,15, and 17. Bergen et al. (1999) contrasted
‘ever/never smokers’ and found evidence for linkage to 6, 9, and 14. Straub et al. (1999)
studied ‘nicotine dependence’ and incriminated regions on chromosomes 2, 10, 16, and
17. Wang et al. (1997) reported weak evidence for linkage of ‘smoking behaviour’ to genes
on chromosomes 1, 9, 10, 13, 14, and 20. Unpublished findings (Munafò et al.personal
communication) suggest no strong evidence of linkage for ‘ever/never’ smokers (i.e. initiation)
or for ‘ex-/current’ smokers (i.e. cessation), but quite good evidence of linkage to
chromosomes 7 and 8 for, ‘age at initiation’ and to 7, 8, and also 18 for ‘cigarettes/day’.
There is not obviously a lot of consistency between these findings, and in none of the
individual studies was the strength of the evidence for linkage absolutely compelling for
any of the regions identified, though some of the measures of association were certainly
sufficiently strong to be hypothesis generating. Some further progress might be made by
meta-analytic pooling of the datasets to maximize the power to detect linkage, but the
variation in definition of the phenotypes considered may argue against the value of this.
Table 35.2 shows the human chromosomal map location of the genes controlling
expression of the major components of the dopaminergic, serotonergic, and
noradrenergic pathways, the nicotinic acetyl cholinergic receptor subunits and the
629