reports are available regarding the relationship between the GSTP1 polymorphisms
and smoking status in HNSCC though the variant forms of GSTP1 are more efficient
in detoxifying the carcinogenic epoxide of benzo(a)pyrene with high and selective
activity (Saarikoski et al. 1998).
10.4.3 Interaction of Genetic Variations with Alcohol
Similar to tobacco use, significant interaction has been reported between alcohol and
genetic variations in phase I and phase II xenobiotic metabolizing enzymes. Heterozygous or homozygous genotype of CYP1B1*2 either alone or in combination
resulted in high (five to sixfold) or very high (about 20 fold) increase in the risk to
HNSCC (Singh et al. 2008b) though alcohol was not found to interact with CYP1A1
genotypes (Singh et al. 2009). Studies have further shown that individuals with
variant genotypes of CYP2C19*2, CYP2C19*3, CYP2D6*4 and who were regular
alcohol users were at several fold increase in the risk to HNSCC when compared to
the controls, who were regular alcohol drinkers (Yadav et al. 2008, 2010). Similarly,
alcohol consumption was also found to interact with variant CYP2E1 genotypes as
the risk associated with RsaI variant genotypes and DraI variant genotypes was
significantly higher in the HNSCC cases who were regular alcohol users when
compared with the controls (Ruwali et al. 2009a). However, a study by Singh
et al. (2010) found no significant increase in risk to lung cancer in alcohol users
among cases with variant genotypes of CYP1A2 when compared to non-alcohol
users. A study by Shah et al. (2008a) reported about 5-6 fold increase in the risk for
lung cancer in the alcohol users with the variant genotypes of CYP1A1*2A and
CYP1A1*2C. In a pooled analysis of cohort studies, it was found that alcohol
consumption was associated with increased risk to lung cancer in male never
smokers (Freudenheim et al. 2005). Since people who smoke are also alcohol
users, the major concern in the examination of an association between alcohol
consumption and lung cancer has been the failure to control for confounding by
smoking.
Among the phase II xenobiotic metabolizing enzymes, several studies have been
carried out to investigate the association between genetic variations in GSTs and
alcohol use. A higher increase in HNSCC risk was observed in cases who were
regular alcohol users and carried null genotypes of GSTM1 or GSTT1 compared to
non-alcohol users (Singh et al. 2008a). Similarly, strong association in regular
alcohol users carrying GSTT1 null genotype and a higher risk for multiple primary
neoplasmas in UADT cancers was also reported (Soya et al. 2007). The role of
alcohol–tobacco interaction in HNSCC risk was investigated by Peters et al. (2006)
in a study which showed that deletion of GSTM1 markedly increased the alcohol–
tobacco interaction. Homozygous deletion of GSTM1, tobacco, and alcohol exhibit
a tri-modal interaction with the risk being higher among those who were both heavy
smokers and low alcohol consumers with the possibility that alcohol may be
facilitating the entry of tobacco carcinogens into oral tissues (Howie et al. 2001).
Interestingly, there is also report that variants in certain genes lower the risk of
10 Interactions of Environmental Risk Factors and Genetic Variations: Association. . .
227
and smoking status in HNSCC though the variant forms of GSTP1 are more efficient
in detoxifying the carcinogenic epoxide of benzo(a)pyrene with high and selective
activity (Saarikoski et al. 1998).
10.4.3 Interaction of Genetic Variations with Alcohol
Similar to tobacco use, significant interaction has been reported between alcohol and
genetic variations in phase I and phase II xenobiotic metabolizing enzymes. Heterozygous or homozygous genotype of CYP1B1*2 either alone or in combination
resulted in high (five to sixfold) or very high (about 20 fold) increase in the risk to
HNSCC (Singh et al. 2008b) though alcohol was not found to interact with CYP1A1
genotypes (Singh et al. 2009). Studies have further shown that individuals with
variant genotypes of CYP2C19*2, CYP2C19*3, CYP2D6*4 and who were regular
alcohol users were at several fold increase in the risk to HNSCC when compared to
the controls, who were regular alcohol drinkers (Yadav et al. 2008, 2010). Similarly,
alcohol consumption was also found to interact with variant CYP2E1 genotypes as
the risk associated with RsaI variant genotypes and DraI variant genotypes was
significantly higher in the HNSCC cases who were regular alcohol users when
compared with the controls (Ruwali et al. 2009a). However, a study by Singh
et al. (2010) found no significant increase in risk to lung cancer in alcohol users
among cases with variant genotypes of CYP1A2 when compared to non-alcohol
users. A study by Shah et al. (2008a) reported about 5-6 fold increase in the risk for
lung cancer in the alcohol users with the variant genotypes of CYP1A1*2A and
CYP1A1*2C. In a pooled analysis of cohort studies, it was found that alcohol
consumption was associated with increased risk to lung cancer in male never
smokers (Freudenheim et al. 2005). Since people who smoke are also alcohol
users, the major concern in the examination of an association between alcohol
consumption and lung cancer has been the failure to control for confounding by
smoking.
Among the phase II xenobiotic metabolizing enzymes, several studies have been
carried out to investigate the association between genetic variations in GSTs and
alcohol use. A higher increase in HNSCC risk was observed in cases who were
regular alcohol users and carried null genotypes of GSTM1 or GSTT1 compared to
non-alcohol users (Singh et al. 2008a). Similarly, strong association in regular
alcohol users carrying GSTT1 null genotype and a higher risk for multiple primary
neoplasmas in UADT cancers was also reported (Soya et al. 2007). The role of
alcohol–tobacco interaction in HNSCC risk was investigated by Peters et al. (2006)
in a study which showed that deletion of GSTM1 markedly increased the alcohol–
tobacco interaction. Homozygous deletion of GSTM1, tobacco, and alcohol exhibit
a tri-modal interaction with the risk being higher among those who were both heavy
smokers and low alcohol consumers with the possibility that alcohol may be
facilitating the entry of tobacco carcinogens into oral tissues (Howie et al. 2001).
Interestingly, there is also report that variants in certain genes lower the risk of
10 Interactions of Environmental Risk Factors and Genetic Variations: Association. . .
227