知識分享

2022.08.24

第二型金屬蛋白酶組織抑制劑(TIMP2)的 rs2277698位點發生單核苷酸基因多型性(SNP)會影響女性試管嬰兒的臨床結果

研究問題

女性的試管嬰兒臨床結果與基質金屬蛋白酶或金屬蛋白酶組織抑制劑的基因多型性是否有關聯?
Is there any association between clinical outcomes of women undergoing in vitro fertilization (IVF) and the polymorphic variants of matrix metalloproteinases (MMPs) or tissue inhibitors of metalloproteinases (TIMPs)?

答案總結

研究數據指出女性的試管嬰兒臨床結果與TIMP2上rs2277698位點的基因多型性(SNP)的有關聯。
Our findings suggested that clinical outcomes of women undergoing IVF were associated with rs2277698 SNPs in TIMP2.

已知

細胞外基質的蛋白水解過程是調節胚胎滋養層細胞穿透子宮內膜表皮層的其中一個主要機制。基質金屬蛋白酶(MMPs)和金屬蛋白酶組織抑制劑(TIMPs)會參與細胞外基質蛋白水解的過程,具有調節細胞外基質降解的能力,並且在胚胎滋養層細胞穿透子宮內膜表皮層的過程中起到關鍵作用。
The extracellular matrix proteolytic machinery is one of the most important mechanisms for regulating trophoblast invasion. Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs), which are involved in the extracellular matrix proteolysis process, have the ability to regulate the degradation of the extracellular matrix and play a critical role in trophoblast invasion.

研究設計

這個前瞻性研究收集在2014年1月至2015年12月期間進行首次非供卵試管嬰兒週期的1,014位女性患者。
A prospective study was composed of 1014 women undergoing their first fresh IVF cycle with non-donor from January 2014 to December 2015.

研究方法

此研究在台灣茂盛醫院進行。從所有參與者的周邊血液中提取DNA,並透過即時聚合酶連鎖反應(Real-time PCR)對 SNP 進行基因型鑑定。針對以下3種SNP基因型對試管嬰兒結果的影響進行探討:
  1. TIMP1 (rs4898 C/T)
  2. TIMP2 (rs2277698 C/T)
  3. MMP2 (rs243865 C/T)
此研究分析了SNP的基因型與臨床懷孕、胚胎著床、流產及試管嬰兒活產率的關聯性。
The present study was carried out in Lee Women’s Hospital, Taiwan. DNA was extracted from the peripheral blood of all participants, and the SNPs were genotyped by real-time polymerase chain reaction. The effects of the following three single nucleotide polymorphisms (SNPs) on IVF outcomes were explored: TIMP1 (rs4898 C/T), TIMP2 (rs2277698 C/T) and MMP2 (rs243865 C/T). The SNP genotype, correlation with clinical pregnancy, embryo implantation, abortion and live birth rates of IVF were analyzed.

研究結果

針對1,014位患者的第一個試管嬰兒週期分析,發現TIMP2 (rs2277698 C/T) 基因多型性與臨床結果之間有顯著關聯。對於TIMP2基因多型性,具有原生基因型(CC)的女性相較於CT/TT 基因型女性擁有較高的臨床妊娠率(34.8% v.s 28.0%;p= 0.032)、胚胎著床率(19.4% v.s 15.4%; p = 0.009)、活產率(29.8% v.s 22.1%; p ¼ 0.006)以及較低的流產率(7.0% vs 17.1%;p = 0.005)。此外,TIMP1及MMP2的基因多型性與臨床結果並沒有顯著關聯性。
In the analysis of 1014 patients attempting their first cycle of IVF, the genotypes frequencies of the study population showed a statistically significant association between TIMP2 (rs2277698 C/T) and clinical outcome. For TIMP2 polymorphisms, women with wild genotype (CC) hadhigher clinical pregnancy rate (34.8% v.s 28.0%; p = 0.032), embryo implantation rate (19.4% v.s 15.4%; p = 0.009), live birth rate (29.8% v.s 22.1%; p = 0.006), and lower abortion rate (7.0% v.s 17.1%; p = 0.005) compared women with CT/TT genotype. On the other hand, the clinical outcomes in different TIMP1 or MMP2 gene polymorphisms groups were no statistically significant difference.

研究限制

研究樣本數的大小。
The size number of the study samples.

研究結果的更廣泛意義

此研究觀察到TIMP2基因多型性中帶有 CT或TT基因者有較差的臨床結果。TIMP2的T等位基因對於試管嬰兒結果的影響仍有待考證,在未來需要更多大型研究來佐證此發現。
This study showed that the TIMP2 SNP polymorphisms CT/TT was associated with low trend of clinical outcomes. The mechanism of TIMP2 gene T allele affected the outcomes of IVF remains to be determined. Further studies should focus on the mechanism of these associations in a larger, more heterogeneous cohort.

李侑蓁 博士簡介

原文內容

C.I Lee, Y.J Lee, E.H Cheng, H.M Tsao, C.C Huang, T.H Lee, P.Y Lin, C.I Chen, S.F Yang, M.S Lee, P-523 rs2277698 Single nucleotides polymorphisms in tissue inhibitors of metalloproteinases 2 (TIMP2) affected clinical outcomes of women undergoing in vitro fertilization, Human Reproduction, Volume 37, Issue Supplement_1, July 2022, deac107.484, https://doi.org/10.1093/humrep/deac107.484