Department of Environmental Health, Harvard School of Public Health, Boston, MA 02115, USA.
Carcinogenesis. 2010 Jul;31(7):1259-63. doi: 10.1093/carcin/bgq092. Epub 2010 May 7.
The incidence of esophageal adenocarcinoma (EA) has been increasing rapidly, particularly among white males, over the past few decades in the USA. However, the etiology of EA and the striking male predominance is not fully explained by known risk factors. To identify susceptible genes for EA risk, we conducted a pathway-based candidate gene association study on 335 Caucasian EA cases and 319 Caucasian controls. A total of 1330 single-nucleotide polymorphisms (SNPs) selected from 354 genes were analyzed using an Illumina GoldenGate assay. The genotyped common SNPs include missense and exonic SNPs, SNPs within untranslated regions and 2 kb 5' of the gene, and tagSNPs for genes with little functional information available. Logistic regression adjusted for potential confounders was used to assess the genetic effect of each SNP on EA risk. We also tested gene-gender interactions using the likelihood ratio tests. We found that the genetic variants in the apoptosis pathway were significantly associated with EA risk after correcting for multiple comparisons. SNPs of rs3127075 in Caspase-7 (CASP7) and rs4661636 in Caspase-9 (CASP9) genes that play a critical role in apoptosis were found to be associated with an increased risk of EA. A protective effect of SNP rs572483 in the progesterone receptor (PGR) gene was observed among women carrying the variant G allele [adjusted odds ratio (OR) = 0.19; 95% confidence interval (CI) = 0.08-0.46] but was not observed among men (adjusted OR = 1.38; 95% CI = 0.95-2.00). In conclusion, this study suggests that the genetic variants of CASP7 and CASP9 in the apoptosis pathway may be important predictive markers for EA susceptibility and that PGR in the sex hormone signaling pathway may be associated with the gender differences in EA risk.
食管腺癌（EA）的发病率在过去几十年中在美国白人男性中迅速上升。然而，EA 的病因和明显的男性优势不能完全用已知的危险因素来解释。为了确定 EA 风险的易感基因，我们对 335 例白种人 EA 病例和 319 例白种人对照进行了基于途径的候选基因关联研究。使用 Illumina GoldenGate 测定法分析了从 354 个基因中选择的 1330 个单核苷酸多态性（SNP）。所鉴定的常见 SNP 包括错义 SNP 和外显子 SNP、非翻译区 SNP 和基因 5'端的 2kb 区 SNP 以及功能信息较少的基因的标签 SNP。使用逻辑回归调整潜在混杂因素来评估每个 SNP 对 EA 风险的遗传效应。我们还使用似然比检验测试了基因-性别相互作用。我们发现，在调整了多种比较后，凋亡途径中的遗传变异与 EA 风险显著相关。在凋亡中起关键作用的 Caspase-7（CASP7）基因中的 rs3127075 多态性和 Caspase-9（CASP9）基因中的 rs4661636 多态性与 EA 风险增加相关。PGR 基因中的 SNP rs572483 变异在携带变异 G 等位基因的女性中观察到保护作用[调整后的优势比（OR）=0.19；95%置信区间（CI）=0.08-0.46]，但在男性中未观察到[调整后的 OR=1.38；95%置信区间（CI）=0.95-2.00]。总之，这项研究表明，凋亡途径中的 CASP7 和 CASP9 基因的遗传变异可能是 EA 易感性的重要预测标志物，而性激素信号通路中的 PGR 可能与 EA 风险的性别差异有关。
