required to increase risk, and in Model E, the exposure and the genotype each have
some effect on disease risk, and when they occur together risk is higher or lower than
when they occur alone. For testing these models, individuals must be categorized
based on the presence or absence of both the exposure and the high-risk genotype.
Several strategies can be employed for testing these models such as testing for an
identified susceptibility gene, measurement of candidate genes or ecogenetic
markers (Perera and Whyatt 1994), using a genetic marker that is associated with
the disease as a surrogate for the high-risk genotype (Saunders et al. 1993), linking of
agenetic marker to a disease susceptibility gene, though the actual disease-causing
mutation has not been identified and use of family history data as a surrogate for the
genotype.
In the case of cancers, the model assumes that there is an association between
cancer and the environmental factors such as tobacco smoking, and without the
exposure, the genetic risk factors do not have a role in disease development. The
genetic factors can modulate the association between exposure and cancer and in
case of tobacco smoke, the relationship becomes more complex as the interaction is
not linear but has a dose response (Taioli et al. 1998). There are also other important
factors which need to be considered in taking smoking as an exposure. Some
important factors are age when smoking started, smoking amount, type, duration,
and number of quitting attempts (Vineis 2007). In case of breast cancer, age of
starting smoking is crucial as young breast tissue is more prone to carcinogenesis
compared to the more matured tissue. Moreover, age also plays a role in females as
the sex hormone levels vary according to the age due to which the interaction
between smoking and estrogen levels may play a significant role. The other important factor to consider is the interplay between causative factors of different cancer
types and their interaction. For example, there is an effect of smoking on cancers
which are caused by changes in hormone levels as tobacco smoking inhibits the
aromatization of androgens into estrogens. Another area which also needs careful
attention is epigenetic modifications. Environmental factors may trigger epigenetic
changes which are independent of genetic variations as seen in case of
hypermethylation of metabolic and DNA repair genes in several cancers (Russo
et al. 2005). Studies have reported an association between methylation of genes and
smoking, and, interestingly in one case, methylation of the p16 gene promoter was
associated with early onset of smoking (Jarmalaite et al. 2003; Chang et al. 2004).
10.4.2 Interaction of Genetic Variations with Tobacco
Several studies have been conducted to decipher the association between genetic
variations and cancer in relation to tobacco consumption. A number of meta- and
pooled analysis have been done to study the association between several Phase I and
Phase II metabolic gene polymorphisms and lung cancer (Schwartz et al. 2007). A
study conducted by Singh et al. (2010) reported an increased risk of lung cancer in
smokers who carried variant genotypes of CYP1A2. Similarly, an increased risk to
lung cancer in cases who were regular tobacco chewers and carried variant
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M. Ruwali and R. Shukla
some effect on disease risk, and when they occur together risk is higher or lower than
when they occur alone. For testing these models, individuals must be categorized
based on the presence or absence of both the exposure and the high-risk genotype.
Several strategies can be employed for testing these models such as testing for an
identified susceptibility gene, measurement of candidate genes or ecogenetic
markers (Perera and Whyatt 1994), using a genetic marker that is associated with
the disease as a surrogate for the high-risk genotype (Saunders et al. 1993), linking of
agenetic marker to a disease susceptibility gene, though the actual disease-causing
mutation has not been identified and use of family history data as a surrogate for the
genotype.
In the case of cancers, the model assumes that there is an association between
cancer and the environmental factors such as tobacco smoking, and without the
exposure, the genetic risk factors do not have a role in disease development. The
genetic factors can modulate the association between exposure and cancer and in
case of tobacco smoke, the relationship becomes more complex as the interaction is
not linear but has a dose response (Taioli et al. 1998). There are also other important
factors which need to be considered in taking smoking as an exposure. Some
important factors are age when smoking started, smoking amount, type, duration,
and number of quitting attempts (Vineis 2007). In case of breast cancer, age of
starting smoking is crucial as young breast tissue is more prone to carcinogenesis
compared to the more matured tissue. Moreover, age also plays a role in females as
the sex hormone levels vary according to the age due to which the interaction
between smoking and estrogen levels may play a significant role. The other important factor to consider is the interplay between causative factors of different cancer
types and their interaction. For example, there is an effect of smoking on cancers
which are caused by changes in hormone levels as tobacco smoking inhibits the
aromatization of androgens into estrogens. Another area which also needs careful
attention is epigenetic modifications. Environmental factors may trigger epigenetic
changes which are independent of genetic variations as seen in case of
hypermethylation of metabolic and DNA repair genes in several cancers (Russo
et al. 2005). Studies have reported an association between methylation of genes and
smoking, and, interestingly in one case, methylation of the p16 gene promoter was
associated with early onset of smoking (Jarmalaite et al. 2003; Chang et al. 2004).
10.4.2 Interaction of Genetic Variations with Tobacco
Several studies have been conducted to decipher the association between genetic
variations and cancer in relation to tobacco consumption. A number of meta- and
pooled analysis have been done to study the association between several Phase I and
Phase II metabolic gene polymorphisms and lung cancer (Schwartz et al. 2007). A
study conducted by Singh et al. (2010) reported an increased risk of lung cancer in
smokers who carried variant genotypes of CYP1A2. Similarly, an increased risk to
lung cancer in cases who were regular tobacco chewers and carried variant
224
M. Ruwali and R. Shukla