Boccia Stefania, Sayed-Tabatabaei Fakhredin A, Persiani Roberto, Gianfagna Francesco, Rausei Stefano, Arzani Dario, La Greca Antonio, D'Ugo Domenico, La Torre Giuseppe, van Duijn Cornelia M, Ricciardi Gualtiero
Genetic Epidemiology and Molecular Biology Unit, Institute of Hygiene, Università Cattolica del Sacro Cuore, Rome, Italy.
BMC Cancer. 2007 Nov 8;7:206. doi: 10.1186/1471-2407-7-206.
The distribution and the potential gene-gene and gene-environment interaction of selected metabolic genetic polymorphisms was investigated in relation to gastric cancer risk in an Italian population.
One hundred and seven cases and 254 hospital controls, matched by age and gender, were genotyped for CYP1A1, CYP2E1, mEH, GSTM1, GSTT1, NAT2 and SULT1A1 polymorphisms. Haplotype analysis was performed for EPHX1 exons 3 and 4, as well as CYP2E1 RsaI (*5 alleles) and CYP2E1 DraI (*5A or *6 alleles). The effect modification by alcohol and cigarette smoking was tested with the heterogeneity test, while the attributable proportion (AP) was used to measure the biological interaction from the gene-gene interaction analysis.
Gastric cancer risk was found to be associated with the inheritance of GSTT1 null genotype (OR = 2.10, 95%CI: 1.27-3.44) and the SULT1A1 His/His genotype (OR = 2.46, 95%CI: 1.03-5.90). No differences were observed for the haplotype distributions among cases and controls. For the first time an increased risk was detected among individuals carrying the *6 variant allele of CYP2E1 if ever-drinkers (OR = 3.70; 95%CI: 1.45-9.37) with respect to never-drinkers (OR = 0.18; 95% CI: 0.22-1.46) (p value of heterogeneity among the two estimates = 0.001). Similarly, the effect of SULT1A1 variant genotype resulted restricted to ever-smokers, with an OR of 2.58 (95%CI: 1.27-5.25) for the carriers of His allele among smokers, and an OR of 0.86 (95%CI: 0.45-1.64) among never-smokers (p value of heterogeneity among the two estimates = 0.03). The gene-gene interaction analyses demonstrated that individuals with combined GSTT1 null and NAT2 slow acetylators had an additional increased risk of gastric cancer, with an OR of 3.00 (95%CI: 1.52-5.93) and an AP of 52%.
GSTT1, SULT1A1 and NAT2 polymorphisms appear to modulate individual's susceptibility to gastric cancer in this Italian population, particularly when more than one unfavourable genotype is present, or when combined with cigarette smoke. The increased risk for the carriers of CYP2E1*5A or *6 alleles among drinkers need to be confirmed by larger prospective studies.
在意大利人群中，研究了特定代谢基因多态性的分布以及潜在的基因-基因和基因-环境相互作用与胃癌风险的关系。
对107例病例和254例按年龄和性别匹配的医院对照进行CYP1A1、CYP2E1、mEH、GSTM1、GSTT1、NAT2和SULT1A1多态性的基因分型。对EPHX1外显子3和4以及CYP2E1 RsaI（*5等位基因）和CYP2E1 DraI（5A或6等位基因）进行单倍型分析。用异质性检验来检验酒精和吸烟的效应修饰，而归因比例（AP）用于衡量基因-基因相互作用分析中的生物学相互作用。
发现胃癌风险与GSTT1无效基因型的遗传（OR = 2.10，95%CI：1.27 - 3.44）和SULT1A1 His/His基因型（OR = 2.46，95%CI：1.03 - 5.90）相关。病例组和对照组之间的单倍型分布没有差异。首次发现，对于曾经饮酒者，携带CYP2E1 *6变异等位基因的个体相较于从不饮酒者风险增加（OR = 3.70；95%CI：1.45 - 9.37）（从不饮酒者OR = 0.18；95%CI：0.22 - 1.46）（两个估计值之间的异质性p值 = 0.001）。同样，SULT1A1变异基因型的效应仅限于曾经吸烟者，吸烟者中His等位基因携带者的OR为2.58（95%CI：1.27 - 5.25），从不吸烟者中OR为0.86（95%CI：0.45 - 1.64）（两个估计值之间的异质性p值 = 0.03）。基因-基因相互作用分析表明，GSTT1无效和NAT2慢乙酰化酶组合的个体患胃癌的风险进一步增加（OR = 3.00，95%CI：1.52 - 5.93），归因比例为52%。
在这个意大利人群中，GSTT1、SULT1A1和NAT2多态性似乎调节个体对胃癌的易感性，特别是当存在不止一种不利基因型时，或与香烟烟雾结合时。饮酒者中携带CYP2E1 5A或6等位基因者风险增加这一结果需要更大规模的前瞻性研究来证实。
