Summary 161(c) pleitropy is involved (i.e., the same genetic risk factors
may lead to different addictions such as alcoholism in addi-
tion to tobacco dependence in different people); (d) epistasis
refers to the situation in which a genetic risk factor modi“es
the expression of another genetic risk factor to produce to-
bacco dependence; and, (e) the interaction of the environ-
ment with a gene can produce an increased likelihood of
becoming dependent on tobacco.
It is important to use lessons from other areas of biomed-
ical research on complex genetic traits to inform the tobacco
dependence community about problems and pitfalls that
should be avoided over the next decade of research. Initially,
obesity was thought to be a simple characteristic to measure,
but now it is known to be quite complex with many differ-
ent endophenotypes. At least four genetic linkage or associa-
tion designs have been used in obesity research over the past
decade resulting in the identi“cation of more than 17 candi-
date markers. Linkage has been reported for more than
20 genes or markers. Currently there are at least six indepen-
dent genome scanning efforts being conducted around the
world. Unfortunately, there has been no overall coordination
of these efforts. Because obesity has been linked to many
markers with small effect sizes (a plausible situation for
tobacco dependence), researchers have recently recognized
the need to pool their data across studies to have suf“ciently
powerful tests. However, because barriers to collaboration
exist (e.g., dissimilar measures) and the research environ-
ment is highly competitive, the pooling of the data may take
longer than it should. Meanwhile, in spite of the progress on
the genetic front, the obesity rates in the U.S. population
continue to rise (Comuzzie & Allison, 1998). Similarly, the
tobacco-related death toll continues to rise.
The public health challenge of tobacco dependence makes
it fundamentally different from obesity. Three thousand new
smokers per day and over 430,000 premature deaths annually
provide an urgency to conduct a coordinated, large multidis-
ciplinary effort to identify both main and interactive effects
for genetic and environmental risk factors as quickly as pos-
sible so that effective and more powerful preventive efforts
can begin to offset the highly addictive nature of nicotine.
Ethical Considerations
As described previously, genetic in”uences consistently
account, at least partially, for twin and family similarity in
smoking. Recent “ndings point to speci“c molecular genetic
markers that suggest increased susceptibility for smoking.
The implications of such research and its use in clinical prac-
tice, in health promotion and disease prevention, and for
health policy decision making are highly signi“cant and
very broad (Parker, 1995; Plomin & Rutter, 1998; Quaid,
Dinwiddie, Conneally, & Nurnberger, 1996).
Currently, although genetic markers for tobacco use have
been identi“ed, there is no clear scienti“c understanding of
how these markers in”uence smoking initiation and tobacco
dependence nor is there any understanding of the degreeto
which they in”uence smoking behavior. Although research
into the genetic bases for behavior could yield enormous
bene“t for those suf fering from addictions, such research also
creates a danger of reduction, that is, that complex multifac-
torial behavior could be perceived to be genetic or biological
alone (Annas, 1998; Philpott, 1996). At the same time,
concerted efforts at tobacco control have arrived at a multi-
pronged approach that includes •denormalizationŽ of smok-
ing by changing social norms and tolerance for smoking by
nonsmokers.
Research efforts on both of these fronts are making
progress toward a comprehensive and integrative understand-
ing of tobacco dependence, in terms of biological and social
factors. However, it is entirely possible that advances in
both arenas may converge to have undesirable or unintended
effects on the individuals with tobacco dependence, their
families, their employment, and their access to health care
and insurance (American Society of Human Genetics and
the American College of Medical Genetics, 1995; Annas,
Glantz, & Roche, 1995).SUMMARYThis chapter emphasizes the importance of a multidiscipli-
nary approach to understanding the problem of tobacco
dependence. Findings from preclinical animal studies exam-
ining the neurobiology of nicotine and the reinforcing effects
of nicotine have been integrated with human clinical and pop-
ulation studies examining sex and ethnic differences, cogni-
tive effects, various environmental risk factors, complex
genetic traits, and prevention and cessation methods for
tobacco dependence. In many respects, examination of social,
behavioral, and genetic risk factors in humans has developed
independently from basic animal research. Fortunately, there
has been a greater collaboration and exchange of “ndings
between the human and animal “elds of research, prompted
mainly by signi“cant progress at the molecular genetic level.
For example, present and future research is addressing the
following important issues: the study of nicotine pharmaco-
kinetics and gene-environment interactions in families as
they relate to tobacco dependence; the examination of gene-
environment interactions in the development and mainte-
nance of nicotine addiction in well-controlled conditions