The association of microsomal epoxide hydrolase polymorphisms and lung cancer risk in AfricanAmericans and MexicanAmericans
Xifeng Wu51,2,
Karin Gwyn3,
Christopher I. Amos1,
Nimisha Makan1,
Waun Ki Hong4,4 and
Margaret R. Spitz1
1 Department of Epidemiology,
2 Southwest Center for Occupational Health, School of Public Health, The University of Texas Health Science Center at Houston, 1200 Herman Pressler, Houston, TX 77030, USA
3 Department of Medical Oncology and
4 Department of Thoracic/Head & Neck Medical Oncology, The University of Texas M.D.Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030 and
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Abstract
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This study evaluated the influence of genetic polymorphisms in the microsomal epoxide hydrolase (mEPHX) gene on lung cancer risk in a casecontrol study of two different ethnic groups, MexicanAmericans and AfricanAmericans. There were 138 lung cancer cases (60 MexicanAmerican and 78 AfricanAmerican) and 148 controls (76 MexicanAmerican and 72 AfricanAmerican). There was a significant difference in the distribution of the mEPHX exon 4 polymorphism between the two ethnic groups with AfricanAmericans more likely to be heterozygous and MexicanAmericans to be wild-type. There was no significant difference between the ethnic groups for the allelic distribution of the mEPHX exon 3 polymorphism. When the exon 4 and exon 3 polymorphism distributions in cases and controls were examined by ethnicity, only the MexicanAmerican cases showed a substantial proportion with the exon 4 polymorphism. The exon 4 polymorphism was associated with a significantly increased risk of lung cancer only among the MexicanAmerican cases (adjusted OR 3.6, 95% CI 1.26, 10.42). Younger MexicanAmericans with the exon 4 polymorphism had a greater risk of lung cancer than older members of their groups (adjusted OR 7.4, 95% CI 1.36, 40.23; 1.6, 95% CI 0.33, 7.80, respectively). The exon 3 polymorphism did not appear to significantly increase the risk of lung cancer in all but one study group examined. MexicanAmericans younger than 65 years did demonstrate an elevated risk of lung cancer (adjusted OR 4.6, 95% CI 1.19, 17.56). However, no statistically significant risk was observed in the AfricanAmerican study groups for both exon 3 and exon 4 polymorphisms. These findings suggest that the presence of the exon 4 and exon 3 polymorphisms of mEPHX may be associated with an increased risk of lung cancer particularly among younger MexicanAmericans in this study.
Abbreviations: CI, confidence interval; mEPHX, microsomal epoxide hydrolase; OR, odds ratio; PCR, polymerase chain reaction; RFLP, restriction fragment length polymorphism.
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Introduction
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Lung cancer is the leading cause of cancer death for both men and women in the United States with an estimated 169 500 new cases diagnosed in 2001 and 157 400 expected deaths (1). Approximately 80% of lung cancer deaths among men and 75% of lung cancer deaths among women can be attributed to smoking (2). Explaining why some cigarette smokers develop cancer while others do not has been difficult. Individuals may differ in their susceptibility to tobacco carcinogenesis, with some individuals being more susceptible while others being more resistant (3). Although factors such as gender, health and nutritional status contribute to these interindividual differences in susceptibility, an individual's genetic background is also thought to play a role (4). Genes encoding the xenobiotic-metabolizing enzymes that activate or inactivate potential carcinogens are of particular interest as genetically-encoded differences in the levels or activity of these enzymes could result in increased or decreased carcinogen activation (5,6). Genetic differences or polymorphisms in genes encoding these xenobiotic-metabolizing enzymes have been identified (4).
Microsomal epoxide hydrolase (mEPHX) is involved in the metabolism of highly reactive epoxide intermediates. Harmful polycyclic hydrocarbon oxides and epoxides are inactivated by this enzyme which works coordinately with P450 enzymes, such as CYP1A1 and CYP1A2. However, highly mutagenic and carcinogenic polycyclic hydrocarbon diol epoxides can result from further epoxidation of these inactive diols (4). The mEPHX gene is located on the long arm of chromosome 1 (7). The highest levels of mEPHX activity have been detected in the liver, kidney and testis with 10100-fold lower levels found in the lung and lymphocytes (810). The enzymes are localized in the endoplasmic reticulum, hence the name microsomal epoxide hydrolases.
Several polymorphisms of mEPHX have been reported and result from amino acid substitutions at specific sites. Four mEPHX alleles result from the presence or absence of two point mutations in the mEPHX gene (11). In one polymorphism in exon 3 of the mEPHX gene, tyrosine is replaced by histidine at residue 113 because a C has been substituted for a T in the codon coding for the amino acid in that position. This allelic variant of mEPHX has been referred to as the `slow allele' as this change results in a 4050% decrease in the enzyme's activity (11). In another polymorphism seen in exon 4 of the mEPHX gene, arginine replaces histidine at residue 139 because a G has been substituted for an A at that site. This change results in a 25% increase in activity and thus this allele has been called the `fast allele' (11). The third allele contains two mutations, one at residue 113 and the other at residue 139. The fourth allele is wild-type at both residues. The third and fourth alleles produce enzymes with normal levels of activity (11).
The hypothesis of this study was that inherent genetic susceptibility to lung cancer is associated with microsomal epoxide hydrolase (mEPHX) gene polymorphisms. To investigate this hypothesis, we jointly analyzed epidemiologic and molecular data from a casecontrol study of MexicanAmerican and AfricanAmerican individuals.
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Materials and methods
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Subjects
In this casecontrol study, the case group comprised 138 newly diagnosed (between 1990 and 1994), untreated patients with histologically confirmed lung cancer. There were no gender, age or stage restrictions. Cases were identified by collaborators at The University of Texas M.D.Anderson Cancer Center, as well as various county, community and Veterans Administration hospitals in the Houston, Galveston and San Antonio metropolitan areas. The control group consisted of 148 healthy volunteers. The MexicanAmerican and AfricanAmerican controls were obtained from community centers, churches, cancer-screening programs and employee groups, and were matched to the cases by gender, ethnicity and age (±5 years). The total study population included 60 MexicanAmerican lung cancer cases with 76 MexicanAmerican controls and 78 AfricanAmerican lung cancer cases with 72 AfricanAmerican controls.
mEPHX genotyping and interpretation
Two procedures for genotyping were used. The first method revealed the His/Arg 139 variant (11) while the second detected the Tyr/His 113 variant of the mEPHX gene (exon 4 and exon 3 polymorphisms, respectively) (12).
Identification of the mEPHX gene His/Arg 139 variant (exon 4 polymorphism)
The primers for the PCR product used for the His/Arg 139 (exon 4) variant were 5'-GGG GTA CCA GAG CCT GAC CGT and 5'-AAC ACC GGG CCC ACC CTT GGC. PCR was performed in 25 µl final volume containing 0.3 µg DNA, 0.2 µM forward primer, 0.2 µM reverse primer, 2 mM MgCl2, 0.2 mM dNTP, 1.5 U Taq polymerase with the manufacturer's buffer (20 mM TrisHCl pH 8.4, 50 mM KCl). The reaction started with an initial denaturation at 94°C for 5 min, then 35 cycles of 30 s at 94°C, 30 s at 62°C and 45 s at 72°C followed by a final extension step of 5 min at 72°C. Following overnight (16 h) digestion of the 15 µl PCR product with 10 U RsaI, according to the manufacturer's instructions (New England Biolabs), the digested products were resolved on a 3% agarose gel (5 V/cm) containing ethidium bromide. Following digestion, homozygous wild-type (His139) was identified by two DNA bands (295 and 62 bp), whereas the homozygous mutant allele (Arg 139 alleles) produced three bands (174, 121 and 62 bp), and the heterozygotes displayed a combination of all four DNA fragments.
Identification of the mEPHX gene Tyr/His 113 variant (exon 3 polymorphism)
The primers for the PCR product used for the Tyr/His 113 (exon 3) variants were: 5'-GGG GTA CCA GAG CCT GAC CGT and (5') AAC ACC GGG CCC ACC CCT GGC. PCR was performed in 25 µl final volume containing 0.3 µg DNA, 0.2 µM forward primer, 0.2 µM reverse primer, 2 mM MgCl2, 0.2 mM dNTP, 1.5 U Taq polymerase with the manufacturer's buffer (20 mM TrisHCl pH 8.4, 50 mM KCl). The reaction started with an initial denaturation at 94°C for 5 min, then 35 cycles of 30 s at 94°C, 30 s at 54°C, and 45 s at 72°C followed by a final extension step of 5 min at 72°C. Following overnight (16 h) digestion of the 10 µl PCR product with 10 U TthIIII, according to the manufacturer's instructions (New England Biolabs), the digest product were resolved on a 3% agarose gel (5 V/cm) containing ethidium bromide. Homozygous wild-type (Tyr 113 alleles) were identified by one 231 bp band, while the homozygous mutant allele (His 113 alleles) produced 209 and 22 bp bands, and the heterozygotes displayed a combination of all four DNA fragments.
Data collection
After written informed consent was obtained from each subject, trained interviewers performed a structured interview lasting ~45 min to collect pertinent epidemiologic data for both case and control subjects. Bilingual interviewers were used for Spanish speaking subjects. Data collected related to socio-demographic characteristics, occupational exposures, recent and prior tobacco use, other life-style habits and family history of cancer. This study was carried out within each institution's guidelines for research conducted on human subjects. Upon completion of the interview, each study subject had 20 ml venous blood drawn by a trained phlebotomist. The blood sample was collected in sodium-heparinized tubes and then transported to the laboratory for cytogenetic and molecular genetic analyses. Laboratory personnel were blinded to case and control status of the samples.
Statistical analysis
The distribution of the mEPHX genotypes between cases and controls was evaluated using Pearson's
2 test or Fisher's exact test (when the expected number in any cell was less than five). All the analyses were stratified by ethnicity. The odds ratio (OR), determined by the Woolf method, was used to approximate relative risks for the casecontrol studies. To be considered a smoker, an individual must have smoked at least 100 cigarettes in their lifetime. A person who had smoked but quit at least one year before being diagnosed with cancer (or, for controls, one year before the interview) was termed a former smoker. Pack-years were determined by multiplying the number of cigarettes smoked per day by the number of years smoked and dividing that value by 20. Age was dichotomized at the median age of the study population. HardyWeinberg equilibrium was tested by a goodness-of-fit
2 test to compare the observed genotype frequencies within the casecontrol groups to the anticipated genotype frequencies calculated from the observed allele frequencies. Logistic regression was used to adjust for covariate effects.
The relationships between mEPHX exon 3 or exon 4 polymorphisms and median age (<65 years or
65 years for MexicanAmericans and <60 years or
60 years for AfricanAmericans) were also modeled using the logistic regression model by including an interaction term between the variables that tests a multiplicative model. The interaction terms were coded as 1, if the individuals had variant genotypes and are equal to or older than the median age. The interaction terms were coded as 0 for all other individuals.
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Results
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The study population consisted of 138 cases (60 MexicanAmerican and 78 AfricanAmerican) and 148 controls (76 MexicanAmerican and 72 AfricanAmerican). In Table I
selected characteristics of the lung cancer patients and the controls stratified by ethnicity are illustrated. In general, the cases and controls were well-matched on gender and age for each ethnic group.
The MexicanAmerican and AfricanAmerican cases were more likely to be current or former smokers and less likely to be non-smokers when compared with their respective controls (P = 0.002 for MexicanAmericans and P < 0.001 for AfricanAmericans). MexicanAmerican cases reported significantly higher pack-years (P < 0.001) and started smoking at an earlier age (P = 0.029) than their controls. Similarly, the AfricanAmerican cases who smoked had higher mean pack-year values (P < 0.001) than the controls. However, there was not a significant difference in the age at which AfricanAmerican cases and controls began smoking (P = 0.138).
In subsequent analyses, since the polymorphisms could not be clearly resolved for a few cases and controls, the number of cases and controls in Tables IIV


do not reflect those seen in Table I
. The distribution of mEPHX genotypes by ethnicity for the two control groups is shown in Table II
. For the exon 4 polymorphism of mEPHX, there was a statistically significant difference in the distribution of genotypes between the two ethnic groups (P < 0.001). The rare homozygous variant allele was 1.4% in both MexicanAmerican and AfricanAmerican controls. MexicanAmericans were also less likely to be heterozygous at mEPHX4 (9.6% compared with 50.7% of AfricanAmericans). A significant difference was not seen between the ethnic groups for genotype distribution of the exon 3 polymorphism.
Table III
summarizes the mEPHX genotype distributions in the cases and controls by ethnicity. Although the prevalence of both heterozygous and rare homozygous exon 4 variants were higher in cases than controls for the two ethnic groups, the difference was only statistically significant for the MexicanAmerican group (P = 0.021). Analysis by ethnic group did not show a significant difference between cases and controls for the exon 3 polymorphism.
As depicted in Table IV
, homozygous or heterozygous variants for the mEPHX exon 4 in MexicanAmericans were associated with a >3-fold elevated risk of lung cancer (adjusted OR 3.6, 95% CI 1.26, 10.42). The impact of this variant allele was even more pronounced among those cases under the age of 65 years (adjusted OR 7.4, 95% CI 1.36, 40.23). For those 65 years and older, the adjusted OR was 1.6, 95% CI 0.33, 7.80. Being homozygous or heterozygous for the exon 3 polymorphism was associated with a statistically significant elevated risk of lung cancer for younger MexicanAmericans (adjusted OR 4.6, 95% CI 1.19, 17.56). We also assessed the interaction between the dichotomized age variable and the variant genotypes for exon 3 and exon 4 using a logistic regression model (data not shown). After adjusting for age (<65 or
65 years), sex and pack-years, we found that EPHX exon 4 variant genotypes showed a significantly increased risk of lung cancer with an OR of 6.8 (95% CI 1.46, 31.80). The interaction term was negative and demonstrating an OR of 0.24 (95% CI 0.02, 2.11), but this term was not statistically significant (P = 0.199). In the case of exon 3, we found that the variant genotypes also demonstrated a significantly increased risk of lung cancer with an OR of 4.4 (95% CI 1.22, 16.17); however, unlike exon 4, the interaction term was statistically significant (P = 0.024) showing an OR of 0.12 (95% CI 0.02, 0.76). These results suggest that the association between the variant genotypes and lung cancer risk may be modified by age.
The influence of exon 3 and exon 4 polymorphisms on lung cancer risk among AfricanAmericans is shown in Table V
. Overall neither the exon 4 nor the exon 3 polymorphism was associated with a significantly increased risk of lung cancer among AfricanAmericans, and there was no impact of age.
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Discussion
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Although cigarette smoking increases an individual's risk of developing lung cancer, as well as other smoking-related malignancies, not all individuals who smoke cigarettes develop lung cancer (3). It is thought that genetic differences or polymorphisms in those genes encoding xenobiotic-metabolizing enzymes may influence an individual's susceptibility to a potential carcinogen (4). Differences in the levels or activity of enzymes such as mEPHX may play a role in carcinogen activation. mEPHX, for example, can convert benzo[a]pyrene 7,8-oxide to benzo[a]pyrene trans-7,8-diol which undergoes further metabolism by cytochrome P450 enzymes to create a highly mutagenic 7,8-diol-9,10-epoxide compound (13).
Exon 3 and exon 4 polymorphisms of mEPHX have been studied for associations with smoking-related illnesses and malignancies. In 1997, Smith and Harrison in their casecontrol study of Caucasian individuals with a history of asthma, chronic obstructive pulmonary disease (COPD) or lung cancer reported a significantly higher proportion of individuals with the homozygous exon 3 variant allele with COPD or emphysema when compared with controls. Homozygotes for the exon 4 polymorphism were not found to be at increased risk in this study (14). The presence of at least one exon 3 variant allele was associated with a >3-fold increased risk of hepatocellular carcinoma (HCC) in a casecontrol study in China (15). The influence of this variant allele was greatly amplified if an individual was also positive for hepatitis B surface antigen (15). A casecontrol study of Caucasian women found a significant association between the wild-type genotype for the exon 4 polymorphism and ovarian cancer risk (12). In that study, 64% of ovarian cancer patients were homozygous for the wild-type of the exon 4 polymorphism while only 41% of the control population was homozygous. Harrison et al. (16) found an increased frequency of the exon 3 polymorphism but not the exon 4 polymorphism among individuals with colon cancer. Homozygosity for either the exon 3 or exon 4 polymorphisms was not found to be associated with an increased risk of bladder cancer among Caucasians in one casecontrol study (17). Few studies have examined the influence of polymorphisms of mEPHX on the risk of lung cancer. Benhamou et al. (18) did not find an association between lung cancer risk and the homozygous or heterozygous genotypes of the exon 3 and exon 4 variant alleles in a casecontrol study of Caucasian individuals with 152 lung cancer cases and 172 controls. However, they did find a statistically significant increased risk of lung cancer when the data were analyzed according to genotypes that predict for intermediate or high microsomal epoxide hydrolase activity. Jourenkova-Mironova et al. (19) similarly found an increased risk of oropharyngeal and laryngeal cancers among Caucasian smokers whose genotype predicted intermediate or high mEPHX activity.
In this study, the proportions of the exon 4 variant allele were found to be dissimilar between the controls of both ethnic groups. For example, MexicanAmericans were more likely to exhibit the wild-type allele (89.0%) while AfricanAmericans were almost as likely to be heterozygous (50.7%) as to have the wild-type allele (47.9%). Other groups have also noted differences in allelic distribution between ethnic groups. McGlynn et al. (15) reported a difference in allelic distribution of mEPHX between individuals from Ghana and those from China. In addition, ethnic differences in genotype polymorphisms have been observed for other carcinogen-metabolizing enzyme systems. In an earlier casecontrol study of lung cancer genetic susceptibility, we investigated the frequency of a restriction length polymorphism in codon 72 of the p53 gene (called Pro) among AfricanAmericans and MexicanAmericans (20). AfricanAmericans were found to have a higher prevalence of the susceptibility genotype (20.3% of control subjects) while MexicanAmericans were much less likely to have such a genotype (2.5%). It has also been noted that MexicanAmericans have a lower incidence of lung cancer as compared with AfricanAmericans (21). We observed MexicanAmericans to have a lower frequency of the rare fast allele which has been reported to have increased metabolic activity (11). This increase in metabolic activity may be responsible for a greater turnover of procarcinogens to carcinogenic metabolites. Therefore, the differences in the fast allele frequency may be associated with differences observed in lung cancer incidence between these two ethnic groups.
The majority of studies examining the influence of mEPHX polymorphisms on cancer risk have been performed on Caucasian populations. We compared our exon 3 and exon 4 allele frequencies from the minority participants in our study with those of several other studies. Overall, the frequencies were quite similar for exon 3. Among the published studies, the frequency of the rare allele ranged from 0.31 to 0.37 in the Caucasian control groups (11,12,14). We found a frequency of 0.34 for MexicanAmerican controls and 0.23 for AfricanAmerican controls. The frequencies were more diverse for exon 4. For Caucasians, Hassett et al. (11) reported a rare allele frequency for exon 4 of 0.23 and Smith and Harrison (14) reported a frequency of 0.15. We found that the rare allele frequency was higher in AfricanAmerican controls (0.27) and lower in MexicanAmerican controls (0.06).
In our casecontrol study, the association between lung cancer risk and the mEPHX genotype appeared to be influenced by ethnicity. The exon 4 variant allele (either homozygous or heterozygous) was associated with an increased risk of lung cancer among MexicanAmericans, particularly those under the age of 65 years (adjusted OR 7.4, 95% CI 1.36, 40.23). There is a potential for effect modification by age in exon 4 due to the difference in ORs between the two age groups (adjusted OR 7.4 in <65 years, adjusted OR 1.6 in
65 years). A possible reason for this result is that genetic susceptibility factors may play a more important role in younger patients than in older ones. The presence of this variant allele did not influence lung cancer risk among the AfricanAmericans. The presence of the exon 3 variant allele did not appear to influence lung cancer risk among any of the study groups analyzed except for MexicanAmericans younger than 65 years (adjusted OR 4.6, 95% CI 1.19, 17.56). In previous work we reported no significant difference in genotype distribution of cytochrome P4502E1 polymorphisms (c1 and c2) between AfricanAmerican cases and controls (22). MexicanAmerican lung cancer cases were significantly more likely to have the wild-type genotype for CYP2E1 (c1/c1) when compared with controls. In that analysis, the wild-type genotype for CYP2E1 was associated with an increased risk of lung cancer among MexicanAmericans but not AfricanAmericans. We now report that the association between lung cancer risk and the mEPHX genotype also appears to be influenced by ethnicity. It is plausible that the differences between the ethnic groups may be explained by linkage disequilibrium with one or more allelic variants that influence overall metabolic activity. These additional allelic variants may be present in different frequencies between the two ethnic subgroups. Additionally, the differences between the ethnic subgroups could be explained by linkage disequilibrium with another gene that is causally related to lung cancer (23). Lin et al. (24) reported that individuals with a combination of homozygous CYP1A1*2A and high/normal mEPHX (consisting of wild-type and heterozygous exon 3 and at least one exon 4 allele) genotypes demonstrated high risk (OR = 6.76, 95% CI 2.29, 19.10) of developing lung cancer, especially squamous cell carcinoma. However, further investigations would have to be conducted to substantiate these theories.
In summary, the results of this work support the hypothesis that genetic susceptibility to lung cancer may be associated with mEPHX gene polymorphisms. The effect(s) of these polymorphisms on lung cancer risk may be further influenced by ethnicity and possibly age.
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Notes
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4 To whom correspondence should be addressed: Department of Epidemiology, Box 189, The University of Texas M.D.Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA 
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Acknowledgments
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This work was supported by grants CA 55769 (to M.R.S.) and CA 68437 (to W.K.H.) from the National Cancer Institute.
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Received May 22, 2000;
revised January 25, 2001;
accepted January 31, 2001.