Wu X, Hudmon K S, Detry M A, Chamberlain R M, Spitz M R
Department of Epidemiology, University of Texas M. D. Anderson Cancer Center, Houston 77030, USA.
Cancer Epidemiol Biomarkers Prev. 2000 Oct;9(10):1021-6.
Recent research suggests that variant alleles (A1 and B1) of the DRD2 gene play a role in determining smoking status. However, no studies have evaluated these variant alleles in African-Americans and Mexican-Americans. The primary objective of this study, therefore, was to test the hypothesis that ever smokers in these ethnic groups are more likely than never smokers to have the DRD2 alleles associated with tobacco use (A1 and B1). Furthermore, because of a predicted higher prevalence of smokers in a family because of the patterns of inheritance of the genotypes associated with tobacco use, we also anticipated that individuals with these at-risk DRD2 alleles would be more likely to have a family history of smoking-related cancers. Because other inherited genetic variants may interact with smoking on cancer risk, we also hypothesized that this association might differ between cancer patients and control subjects. PCR was used to perform genotyping on peripheral WBC DNA from 140 lung cancer patients (43 Mexican-Americans and 97 African-Americans) and 222 age-, sex-, and ethnicity-matched controls (111 Mexican-Americans and 111 African-Americans). A personal family history was obtained from each participant. There were no statistically significant differences in the distribution of the DRD2 genotypes between cases and controls, although the frequency of the B1 genotype significantly differed by ethnicity (P = 0.002 for controls and P = 0.001 for cases). The DRD2 genotypes and smoking status showed a correlation among Mexican-American controls, although not among African-American controls. The cigarette pack-years in control subjects for the two ethnic groups combined were 30.8, 21.9, and 18.6 for the A1A1, A1A2, and A2A2 genotypes and 36.5, 20.8, and 18.5 for the B1B1, B1B2, and B2B2 genotypes, respectively. Similar trends were found for the number of cigarettes smoked per day among control subjects. From the standpoint of polymorphisms, however, there was a borderline significantly increased (3.6 times greater) frequency of smoking-related cancers among the first-degree relatives of case subjects with an A1 allele than among those without an A1 allele. There was also an elevated (1.8 times greater) frequency of smoking-related cancer among first-degree relatives of case subjects with a B1 allele compared with patients without a B1 allele, but this finding was not statistically significant. This phenomenon was not observed among control subjects. We noted a trend toward interaction of DRD2 A1 genotypes and case status for increased risk of smoking-related cancer among first-degree relatives. These findings suggest that the variant DRD2 genotypes are associated with a greater likelihood to smoke and a greater smoking intensity, as well as with a familial aggregation of smoking-related cancers. However, a large study is needed to confirm this finding.
近期研究表明，DRD2基因的变异等位基因（A1和B1）在决定吸烟状况方面发挥作用。然而，尚无研究对非裔美国人和墨西哥裔美国人中的这些变异等位基因进行评估。因此，本研究的主要目的是检验以下假设：这些种族群体中的曾经吸烟者比从不吸烟者更有可能携带与烟草使用相关的DRD2等位基因（A1和B1）。此外，由于与烟草使用相关的基因型的遗传模式预测家族中吸烟者的患病率更高，我们还预期携带这些有风险的DRD2等位基因的个体更有可能有吸烟相关癌症的家族史。由于其他遗传变异可能与吸烟在癌症风险方面相互作用，我们还假设这种关联在癌症患者和对照受试者之间可能存在差异。采用聚合酶链反应（PCR）对140例肺癌患者（43例墨西哥裔美国人，97例非裔美国人）和222例年龄、性别和种族匹配的对照者（111例墨西哥裔美国人，111例非裔美国人）的外周白细胞DNA进行基因分型。从每位参与者处获取个人家族史。病例组和对照组之间DRD2基因型的分布无统计学显著差异，尽管B1基因型的频率在种族上有显著差异（对照组P = 0.002，病例组P = 0.001）。DRD2基因型与吸烟状况在墨西哥裔美国对照者中呈相关性，而在非裔美国对照者中则不然。两个种族群体对照者的吸烟包年数，A1A1、A1A2和A2A2基因型分别为30.8、21.9和18.6，B1B1、B1B2和B2B2基因型分别为36.5、20.8和18.5。对照者中每天吸烟支数也发现了类似趋势。然而，从多态性角度来看，携带A1等位基因的病例受试者的一级亲属中吸烟相关癌症的频率有临界显著增加（高3.6倍），高于未携带A1等位基因的亲属。携带B1等位基因的病例受试者的一级亲属中吸烟相关癌症的频率也有所升高（高1.8倍），但这一发现无统计学意义。在对照受试者中未观察到这一现象。我们注意到DRD2 A1基因型与病例状态之间存在相互作用的趋势，即一级亲属中吸烟相关癌症风险增加。这些发现表明，DRD2变异基因型与更高的吸烟可能性、更大的吸烟强度以及吸烟相关癌症的家族聚集性相关。然而，需要大规模研究来证实这一发现。
