胃腺癌通常與癌前病變，如腸黏膜化生的發生有關聯性。最近許多證據都證實宿主基因多型性與細菌菌株基因型之間的交互作用會影響胃癌的形成。在台灣，幽門桿菌為幾乎100％同時帶有cagA+、 vacA s1+ 和 babA+的triple-positive菌株。因此，台灣最適合研究宿主基因多型性對於幽門桿菌感染所引起的癌前病變如腸黏膜化生之間所扮演的角色。在台灣，研究指出IL-10啟動子上基因多型性為胃癌發生之獨立風險因子，而非西方國家中所認定的IL-1β。本篇研究的第一部份探討是否IL-10啟動子上基因多型性同時也可成為幽門桿菌感染後增加腸黏膜化生的危險因子。而COX-2的過量表現明顯與幽門桿菌感染後之腸黏膜化生有正相關，本篇研究第二部份探討是否不同的COX-2基因型會得到不同幽門桿菌感染後的腸黏膜化生之風險。此外，MMP-9及抑制其作用的TIMP-1、TIMP-2一直被認為與胃癌的侵犯、轉移有關。因此第三部份探討是否宿主基因多型性影響MMP和TIMP之間不平衡的表現會與腸黏膜化生出現和發展有關聯。
本篇研究收入352名消化不良的病人，包含52位幽門桿菌感染陰性與300位幽門桿菌感染陽性，並連續施以上消化道內視鏡檢，紀錄腸黏膜化生出現的胃檢體。收集病人的血液檢體並萃取其DNA以用於宿主基因多型性的分析，以SSOP、RFLP等其他方法分析。
這一篇研究顯示幽門桿菌感染與年齡為明顯影響腸黏膜化生出現與否的風險因子(P < 0.001)。在年齡大於40歲的人有腸黏膜化生出現的風險為2倍，而年齡在50歲以上增加至約3倍的風險。在本篇文章所收集的300名病人中都具有於IL-10-819與IL-10-592連鎖不平衡的特性。帶有IL-10分泌較低的haplotype ATA (意指當-1082位置為A 對偶基因，-819位置為T 對偶基因，-592位置為A 對偶基因)比起其他的haplotype有較高的幽門桿菌盛行率(P < 0.05, OR＝6.8)。然而，IL-10 haplotype GCC與腸黏膜化生的出現並無關聯(P＞0.05)。另ㄧ方面本研究指出COX-2基因多型性與幽門桿菌感染後之腸黏膜化生有接近邊緣的相關性(P＝0.049)。此外，結合MMP-2, MMP-9, TIMP-2之間的基因多型性，並沒有發現和胃corpus部位的腸黏膜化生有關聯(p＞0.05)，但是若將年齡加入分析，竟發現小於40歲的病人身上MMP-2, MMP-9, TIMP-2之間的基因多型性(MMP-9-1562 C→T / TIMP-2-418 G→C /MMP-2-735 T→C)與胃corpus部位的腸黏膜化生出現有顯著的關係(p＜0.001)。另外，特別只在女性身上，TIMP-1 372 T-carrier比起基因型CC有明顯較高的腸黏膜化生比例(p<0.05)。
本篇研究顯示年齡與幽門桿菌感染為腸黏膜化生出現之重要因子。在台灣人身上，年齡小於40歲的人結合MMP-2, MMP-9, TIMP-2之間的基因多型性與女性帶有TIMP-1 372 T-carrier，而非IL-10基因多型性，有較高的風險得到腸黏膜化生。

Background and objectives: Gastric adenocarcinoma is usually linked with a precancerous lesion such as intestinal metaplasia (IM). Recent evidences demonstrated the host genetic polymorphisms and Helicobacter pylori (H. pylori) genotypes have been linked to the development of gastric cancer. The prevalence of the triple-positive (cagA, vacA s1 and babA-positive) H. pylori infection is nearly 100 % in Taiwan, therefore overwhere should be the most suitable site to determine whether there could be any host genetic predispositions to have gastric precancerous lesions as IM. In Taiwan, the IL-10 promoter single nucleotide polymorphism (SNP), instead of IL-1β SNP, is associated with an increased gastric cancer (GC) risk. The aim of first part in this study was to determine whether IL-10 polymorphism could be a risk factor simultaneously related with an increased risk to have IM after H. pylori infection. As cyclooxygenase-2 (COX-2) overexpression shall be also significantly correlated with the presence of IM after H. pylori infection, we also test whether COX-2 host genetic polymorphism could have different risk to get IM after H. pylori infection. Moreover, as matrix metallpproteinase-9 (MMP-9) and its inhibitors, known as tissue metalloproteinase inhibitor-1 (TIMP-1) and TIMP-2, can be important during the gastric cancer invasion. This study also deliberated if imbalance of MMPs and TIMPs contributed by the host genetic polymorphisms would be associated the presence or any progression of IM after H. pylroi infection.
Methods: A total of 352 dyspeptic patients, including 52 without and 300 with H. pylori infection, were sequentially included after panendoscopy. The gastric specimen about the presence of IM was recorded, and the host white blood cell DNA was collected for the analysis to the host genomic polymorphisms about the IL-10, COX-2, MMP-9, MMP-2, TIMP-1, and TIMP-2 using the SSOP, RFLP or other methods.
Results: This study revealed the presence of H. pylori infection and an old age were significant risk factor to correlate with the presence of IM (P < 0.001). People with age above 40 years old will have a 2-fold risk to have IM, whereas age above 50 years old become increased up to near 3 folds (P < 0.001). Our study included 352 patients, including 52 without and 300 with H. pylori infection, and all of them had complete linkage disequilibrium between IL-10-592 and IL-10-819. The carriage of a low IL-10 secreting haplotype (defined as A, T, and A allele over the -1082, -819, and -592 loci, respectively) had a higher prevalence of H. pylori than those with other IL-10 haplotypes (P < 0.05, relative risk: 6.8). However, there was no association between IL-10 haplotype GCC and the presence of IM (P＞0.05). Moreover, our data only observed a borderline significant correlation between COX-2 genetic polymorphism and the presence of IM in the H. pylori-infected patients (P＝0.049). The combination haplotype MMP-9-1562 C→T / TIMP-2-418 G→C /MMP-2-735 T→C had not an increased rate of IM in the gastric corpus in H. pylori-infected patients (p＞0.05). Nevertheless, when subjects were stratified by age as less than 40 years old, the combination haplotype of the MMP-9-1562 C→T / TIMP-2-418 G→C /MMP-2-735 T→C become significantly associated with the presence of IM over the gastric corpus (p＜0.001). Only in female, the genotype as TIMP-1 372 T-carrier has a significantly higher rate to have IM than the genotype as CC (p<0.05).
Conclusion: This study disclosed an increased age and H. pylori infection should be important factor to have the presence of IM in stomach. The host factors, as the combination haplotype of the TIMP-2, MMP-2, and MMP-9 in the patients’ age less than 40 years old and the genotype of TIMP1-372 as T-carrier in female, instead of the IL-10 polymorphyisms, should have increased the risk of getting IM after H. pylori infection in Taiwanese.

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