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The role of matrix metalloproteinases in atherosclerosis in the young: Genetic association studies and functional analyses of promoter polymorphisms.

机译：基质金属蛋白酶在年轻人的动脉粥样硬化中的作用：遗传关联研究和启动子多态性的功能分析。

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摘要

The role of extracellular matrix degrading enzymes and their inhibitors was investigated at early stages of atherosclerosis by genetic association studies since they have previously been shown to exhibit increased expression. Matrix metalloproteinases (MMPs), the major extracellular matrix degrading enzymes, are involved in transition from early to intermediate stages of disease which is accompanied by tissue remodeling.; The study material was the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) collection, which is a unique resource for studying early pathological changes in atherosclerosis. Genomic DNA was isolated from 995 livers and used for genotyping. Polymorphisms in the promoters of MMP1, MMP3, MMP9 and PAI-1 genes were tested for genetic association with the PDAY collection. In black females fibrous plaque lesions were significant associated with MMP1 genotypes by ordinary regression (p = 0.037) and MMP3 genotypes by chi-square test (p = 0.039). However, the analysis of other subgroups failed to reveal any significantly association, either because they were truly insignificant or because the association remained undetectable with the PDAY collection.; Three newly identified sequence variants among the twelve variants were regarded as polymorphisms. They were A to C at nt −955 in MMP2, and 11A/12A at nt −291 (MMP13v1) and A to G at nt −77 (MMP13v2) in MMP13. The A allele in MMP13v2 is located in the 5′ -end of the PEA-3 consensus sequence. The PDAY collection was used to test for association with these three polymorphisms. The MMP13v2 was highly significantly associated with fibrous plaque lesions in black males (ordinary regression; p = 0.0014).; Functional importance was investigated for the new MMP13 polymorphisms. Transfection assay showed a 2-fold higher expression for the A allele in MMP13v2 than the G allele (p = 0.030). Gel-shift assay also suggested that the binding capacity of transcription factors might be affected by the MMP13v2. The results provided evidence for a difference between the two alleles in MMP13v2 in the transcriptional activity through binding of transcription factors.
机译：通过遗传关联研究在动脉粥样硬化的早期研究了细胞外基质降解酶及其抑制剂的作用，因为以前已经证明它们表现出增加的表达。基质金属蛋白酶（MMPs）是主要的细胞外基质降解酶，参与疾病从早期到中期的过渡，并伴有组织重塑。研究材料是青年时期动脉粥样硬化的病理生物学决定因素（PDAY），这是研究动脉粥样硬化早期病理变化的独特资源。从995个肝脏中分离出基因组DNA，并用于基因分型。测试了MMP1，MMP3，MMP9和PAI-1基因启动子中的多态性与PDAY集合的遗传关联。在黑人女性中，通过常规回归分析（P = 0.037）与MMP1基因型显着相关的纤维斑病变和通过卡方检验（P = 0.039）与MMP3基因型显着相关。然而，对其他亚组的分析未能揭示任何显着的关联，可能是因为它们确实无关紧要，或者是因为在PDAY集合中仍然无法检测到该关联。在十二个变体中的三个新近鉴定的序列变体被认为是多态性。在MMP2中，它们在nt -955处为A到C，在nt -291（MMP13v1）处为11A / 12A，在MMP13中在nt -77处为A至G（MMP13v2）。 MMP13v2中的A等位基因位于PEA-3共有序列的5 '末端。 PDAY集合用于测试与这三个多态性的关联。 MMP13v2与黑人男性的纤维斑块病变高度相关（常规回归； p = 0.0014）。研究了新的MMP13多态性的功能重要性。转染分析显示，MMP13v2中A等位基因的表达比G等位基因高2倍（p = 0.030）。凝胶位移分析还表明，转录因子的结合能力可能受MMP13v2的影响。该结果提供了证据，表明通过转录因子的结合，MMP13v2中的两个等位基因在转录活性方面存在差异。

著录项

  • 作者

    Yoon, Sungpil.;

  • 作者单位

    Wayne State University.;

  • 授予单位 Wayne State University.;
  • 学科 Biology Genetics.; Biology Molecular.
  • 学位 Ph.D.
  • 年度 2001
  • 页码 110 p.
  • 总页数 110
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 遗传学;分子遗传学;
  • 关键词

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