Hirata Hiroshi, Okayama Naoko, Naito Katsusuke, Inoue Ryo, Yoshihiro Satoru, Matsuyama Hideyasu, Suehiro Yutaka, Hamanaka Yuichiro, Hinoda Yuji
Department of Urology, Yamaguchi University School of Medicine, Yamaguchi, Japan.
Carcinogenesis. 2004 Dec;25(12):2379-84. doi: 10.1093/carcin/bgh254. Epub 2004 Aug 19.
It has been shown that the matrix metalloproteinase (MMP)-1 promoter polymorphism 1G/2G is associated with an increased risk of developing various cancers including renal cell carcinoma (RCC), and is in linkage disequilibrium (LD) with the MMP-3 promoter polymorphism 5A/6A. These two genes are localized in 11q22 adjacent to each other. However, the relationship between the MMP-3 5A/6A polymorphism and susceptibility to cancer remains ambiguous. In this study, we genotyped eight polymorphisms in the region containing the MMP-1 and MMP-3 genes in 177 healthy subjects, and explored the relationships between RCC and these polymorphisms or haplotypes in 156 RCC cases and 230 age- and gender-matched controls. All the subjects studied were of Japanese descent. There were three polymorphisms that showed stronger LD with the MMP-1 1G/2G promoter variant than with the MMP-3 5A/6A promoter variant. One of these three polymorphisms was present in exon 2 of the MMP-3 gene and caused an amino acid change, Glu45Lys (G/A). When the genotype distribution of Glu45Lys was compared between RCC patients and controls, the frequency of the G/G genotype was significantly higher in the patients [age- and gender-adjusted odds ratio (OR) = 1.81, 95% confidence interval (CI) = 1.20-2.74]. A significant increase in the frequency of the 2G/2G genotype of the MMP-1 1G/2G polymorphism was also observed in the patients (age- and gender-adjusted OR = 1.86, CI = 1.23-2.82), whereas there was no significant difference for the MMP-3 5A/6A polymorphism. As expected based on these genotype-level results, the frequency of the 2G-G haplotype of MMP-1 1G/2G and MMP-3 Glu45Lys (G/A) polymorphisms was significantly higher in the patients than in the controls (crude OR = 1.95, CI = 1.31-2.91). These findings suggest that this haplotype of MMP-1 and MMP-3 variants may be associated with the risk of developing RCC.
研究表明，基质金属蛋白酶（MMP）-1启动子多态性1G/2G与包括肾细胞癌（RCC）在内的多种癌症发生风险增加相关，且与MMP-3启动子多态性5A/6A处于连锁不平衡（LD）状态。这两个基因位于11q22且彼此相邻。然而，MMP-3 5A/6A多态性与癌症易感性之间的关系仍不明确。在本研究中，我们对177名健康受试者中包含MMP-1和MMP-3基因区域的8个多态性进行了基因分型，并在156例RCC病例和230例年龄及性别匹配的对照中探究了RCC与这些多态性或单倍型之间的关系。所有研究对象均为日本血统。有三个多态性与MMP-1 1G/2G启动子变异的LD比与MMP-3 5A/6A启动子变异的LD更强。这三个多态性之一存在于MMP-3基因的外显子2中，并导致了一个氨基酸变化，即Glu45Lys（G/A）。当比较RCC患者和对照之间Glu45Lys的基因型分布时，患者中G/G基因型的频率显著更高[年龄和性别调整后的优势比（OR）=1.81，95%置信区间（CI）=1.20 - 2.74]。在患者中还观察到MMP-1 1G/2G多态性的2G/2G基因型频率显著增加（年龄和性别调整后的OR = 1.86，CI = 1.23 - 2.82），而MMP-3 5A/6A多态性则无显著差异。基于这些基因型水平的结果，正如预期的那样，MMP-1 1G/2G和MMP-3 Glu45Lys（G/A）多态性的2G-G单倍型在患者中的频率显著高于对照（粗OR = 1.95，CI = 1.31 - 2.91）。这些发现表明，MMP-1和MMP-3变异的这种单倍型可能与RCC发生风险相关。
