Vol. 6, 1075-1080, December 1997 Cancer Epidemiology,Biomarkers & Prevention 1075 3 The abbreviations used are: ARE, aryl hydrocarbon hydroxylase; CI, confi- dence interval. Susceptibility to Lung Cancer in Light Smokers Associated with CYPJA1 Polymorphisms in Mexican- and African-Americans1 Naoko Ishibe, John K. Wiencke, Zheng-fa Zuo, Alex McMillan, Margaret Spitz, and Karl T. Kelsef Departments of Epidemiology and Environmental Health, Harvard School of Public Health, Boston, Massachusetts 021 15 [N. 1.1; Laboratory for Molecular Epidemiology, Departments of Epidemiology and Biostatistics, University of California-San Francisco, San Francisco, CA 94143-0560 EJ. K. W.]; Department of Cancer Biology Harvard School of Public Health, Boston, Massachusetts 021 15 [Z-f. Z., K. T. K.]; Department of Biostatistics, University of California-San Francisco, San Francisco, California 94143 [A. M.]; Department of Epidemiology, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030 EM. S.]; and Occupational Health Program, Harvard School of Public Health, Boston, Massachusetts 02115 [K. T. K.] Abstract The gene-environment associations between potential carcinogenic agents modified by polymorphisms in the cytochrome P450 1A1 (CYPJAJ) gene and lung cancer risk were assessed in a hospital-based case-control study composed of African- and Mexican-Americans. The study involved 171 cases and 295 controls identified from the greater Houston and San Antonio metropolitan areas. Both the exon 7 and MspI polymorphisms were analyzed by RFLP of PCR-ampllfied DNA, and in addition, the African-American-specific polymorphism was assayed for subjects who reported that they were African-American. Lo slic regression analysis was performed to assess the association between each of the CYPJA1 polymorphisms and lung cancer, adjusting for the matching variables (age, sex, ethnicity) and other potential risk factors. Interactions between pack-years smoked, CYPJAJ genotypes, and case status were also evaluated. The variant allele frequendes did not differ by case status, but the distributions of genotypes were strikingly different by ethnicity. In addition, both the exon 7 and MspI polymorphisms, but not the African-American- specific polymorphism, were modified by the amount of cigarette consumption measured In pack-years. An approximate 2-fold increase in lung cancer risk among individuals with one or more of the variant alleles was observed among light smokers (defined as having smoked 3O pack-years). The respective risk ratios for the exon 7 and MspI polymorphisms were 2.26 (95% confidence interval, 0.82-6.26) and 2.03 (95% confidence interval, Received 6/3/97; revised 8/25/97; accepted 8/27/97. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. I This study was made possible by Grants ES00002, ES06717, ES08357, ES04705 and T32ES07069 from the National Institute of Environmental Health Sciences. 2 To whom requests for reprints should be addressed, at Department of Cancer Biology, 665 Huntington Avenue, Boston, MA 02115. Phone: (617) 432-3313; Fax: (617) 432-0107; E-mail: kelsey@hohp.harvard.edu. 1.03-4.01) at low smoking dose. No such increase in risk was found among heavy smokers (>30 pack-years). This phenomenon at low smoking dose was also observed when the two common polymorphisms were combined, which resulted in was a progressive increase in risk with an increasing number of variant alleles. These results indicate that at low smoking levels, the MspI and exon 7 CYPJAJ genetic polymorphisms confer susceptibility to lung cancer. Introduction Lung cancer is the leading cause of all cancer deaths in the United States. Approximately 150,000 individuals will suc- cumb to this disease this year (1). Although environmental exposures such as cigarette smoke have consistently been found to be associated with the development of lung cancer, only a fraction of exposed individuals actually develop the disease, suggesting that there may be genetically determined factors that modify environmental exposures and result in variations in host susceptibility. The AHH3 enzyme is responsible for activating the car- cinogenic pobyaromatic hydrocarbons found in tobacco (2, 3). Inherited variations in AHH have been observed, and conse- quently, there has been great interest in the CYPJAJ gene that contributes to AHH activity. Phenotypically, CYP1A1 induc- ibility has been reported to be associated with lung cancer development (4). In the human CYPJA] gene, three pobymor- phisms have been reported: a MspI RFLP in the 3’-noncoding region (5); an adenine-to-guamne transition at nucleotide 4889 in exon 7 (6); a cytosine-to-adenine transversion at nucbeotide 4887 (7), and another MspI RFLP, also in the 3’-noncoding region, that has only been observed among individuals of Af- rican descent (8). Each locus has been investigated epidemiobogicalby for any relationship with lung cancer development, with varying results. In the Japanese, where the MspI variant allele frequency is 0.31, the homozygous variant individuals have been observed to be overrepresented among lung cancer patients (5, 9). A similar association between the exon 7 polymorphism and lung cancer risk has also been reported for this ethnic group (6). More interestingly, studies conducted among Japanese have consistently reported a stronger association between the variant genotypes and lung cancer risk among light smokers (10-12). To address this observation, several researchers have analyzed and presented their findings in various ways. Among individuals who develop lung cancer, cumulative smoking dose has been found to be bower among persons carrying the MspI variant alleles than for wild-type individuals (10). This phe- nomenon was observed to be stronger when the analysis was on December 4, 2021. © 1997 American Association for Cancer Research. cebp.aacrjournals.org Downloaded from