Helicobacter pylori-related host gene polymorphisms associated with susceptibility of gastric carcinogenesis: a two-stage case-control study in Chinese
Helicobacter pylori-related host gene polymorphisms associated with susceptibility of gastric carcinogenesis: a two-stage case-control study in Chinese
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DOI：
10.1093/carcin/bgt079
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发表时间：
2013-07-01
期刊：
影响因子：
4.7
通讯作者：
Yuan, Yuan
中科院分区：
文献类型：
--
作者：
He, Caiyun;Tu, Huakang;Yuan, Yuan
胃癌的发生从正常粘膜/浅表性胃炎、萎缩性胃炎（GA）到胃癌（GC）逐步进展。独立于幽门螺杆菌感染或与幽门螺杆菌感染相结合的宿主因素可能调节癌发生过程。在这项两阶段的研究中，我们选择了6个H.pylori相关宿主基因MUC1、Toll样受体4（TLR4）、蛋白酪氨酸磷酸酶、非受体11型（PTPN11）、IL-1B、PGC和PGA35的24个推定功能标签单核苷酸多态性（tagSNP），并分析了它们与H.pylori对GA和GC风险的影响和相互作用。使用高通量基因分型，在 552 名对照、254 名 GA 和 236 名 GC 受试者的筛查人群中初步评估了 24 个 tagSNP；随后，在 1276 名对照者、907 名 GA 和 714 名 GC 受试者中重新评估了 TLR4、PGC 和 PTPN11 基因中胃部疾病风险的 5 个候选 tagSNP。我们观察到 PGC rs6458238、PGC rs4711690 和 PTPN11 rs12229892 与 GA 和/或 GC 的易感性相关。此外，rs4711690 和 rs12229892 与幽门螺杆菌对 GA 风险存在显着的相互作用。在胃癌标本中，我们观察到携带PGC rs6458238 GA基因型的受试者的信使RNA水平显着高于具有常见GG基因型的受试者。这些发现表明，两个关键的幽门螺杆菌相关宿主基因（幽门螺杆菌粘膜效应子PGC基因和幽门螺杆菌细胞信使PTPN11基因）的遗传变异，无论是依赖于还是独立于与幽门螺杆菌的相互作用，都与癌前GC和/或GA的风险相关。仍需要功能研究和进一步独立的大规模研究，特别是在其他种族人群中，以证实我们的结果。
Stomach carcinogenesis progresses stepwise from normal mucosa/superficial gastritis, atrophic gastritis (GA) to gastric cancer (GC). Host factors independent of or combined with Helicobacter pylori infection may modulate the carcinogenesis process. In this two-stage study, we selected 24 putative functional tag single-nucleotide polymorphisms (tagSNPs) for six H.pylori-related host genes, MUC1, toll-like receptor 4 (TLR4), protein tyrosine phosphatase, non-receptor type 11 (PTPN11), IL-1B, PGC and PGA35, and analyzed their influence and interaction with H.pylori on the GA and GC risks. Using high-throughput genotyping, the 24 tagSNPs were preliminarily assessed in a screening population of 552 controls, 254 GA and 236 GC subjects; subsequently, five candidate tagSNPs for gastric diseases risk in the TLR4, PGC and PTPN11 genes were re-evaluated in a larger population of 1276 controls, 907GA and 714 GC subjects. We observed that PGC rs6458238, PGC rs4711690 and PTPN11 rs12229892 were associated with susceptibilities to GA and/or GC. Moreover, rs4711690 and rs12229892 and H.pylori demonstrated significant interaction effects on GA risk. In gastric cancerous specimens, we observed significantly higher messenger RNA level in the subjects carrying the PGC rs6458238 GA genotype than that in subjects with the common GG genotype. These findings indicated that genetic variations of two crucial H.pylori-related host genes, H.pyloris mucosal effecter PGC gene and H.pyloris cellular messenger PTPN11 gene, either dependent or independent of interaction with H.pylori, were associated with the risks of GC and/or GA that precede carcinoma. Functional studies and further independent large-scale studies especially in other ethnic populations are still needed to confirm our results.