Single nucleotide polymorphisms of tissue inhibitor of metalloproteinase genes in familial Moyamoya disease
Single nucleotide polymorphisms of tissue inhibitor of metalloproteinase genes in familial Moyamoya disease
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DOI：
10.1227/01.neu.0000215854.66011.4f
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发表时间：
2006-06-01
期刊：
影响因子：
4.8
通讯作者：
Wang, Kyu-Chang
中科院分区：
文献类型：
--
作者：
Kang, Hyun-Seung;Kim, Seung-Ki;Wang, Kyu-Chang
目的：金属蛋白酶组织抑制因子（TIMP）4和TIMP2编码基因分别跨越家族性烟雾病（FMMD）基因所在的3p24.2-p26和17q25染色体。我们研究了FMMD患者中TIMP2和TIMP4基因的单核苷酸多态性，以确定遗传易感性。方法：收集11例FMMD患者的血液样本。对照组包括50份来自非家族性烟雾病患者的血液样本和另外50份来自非家族性烟雾病患者的血液样本。我们通过直接测序评估了TIMP2和TIMP4基因的启动子区域、外显子-内含子连接和外显子，并比较了研究组之间的单核苷酸多态性频率。结果：在FMMD的TIMP2启动子区域-418位置发现了高频率的杂合基因型；也就是说，在11例FMMD患者中有9例，50例非家族性MMD对照组中有16例，50例非MMD对照组中有14例（FMMD与非家族性MMD：优势比为9.56,95%可信区间为1.85-49.48,P = 0.005； FMMD与非MMD：优势比为10.50,95%可信区间为2.02-54.55,P = 0.001）， G/C杂合基因型位于-418位。这个位于-418位的碱基对应于GAGGCTGGG序列的第三个碱基，是Sp1的结合位点。因此，这个位置的变化可能影响Sp1结合和随后的基因转录。结论：TIMP2启动子-418位点存在G/C杂合基因型可能是FMMD的遗传易感因素。
OBJECTIVE: The genes encoding tissue inhibitor of metalloproteinase (TIMP)4 and TIMP2 span chromosomes 3p24.2-p26 and 17q25, respectively, which are the locations of familial moyamoya disease (FMMD) genes. We investigated single nucleotide polymorphisms of the TIMP2 and TIMP4 genes in FMMD patients to determine genetic predispositions.METHODS: Eleven blood samples from FMMD patients were recruited. Controls included 50 blood samples from patients with nonfamilial moyamoya disease (MMD) and another 50 blood samples from non-MMD persons. We evaluated the promoter regions, exon-intron junctions, and the exons of the TIMP2 and TIMP4 genes by direct sequencing, and compared single nucleotide polymorphisms frequencies among the study groups.RESULTS: A significantly higher frequency of a heterozygous genotype was found in the TIMP2 promoter region at position -418 in FMMD; that is, the G/C heterozygous genotype at position -418 was observed in nine of 11 patients with FMMD, in 16 out of 50 nonfamilial MMD control participants, and in 14 out of 50 non-MMD control participants (FMMD versus nonfamilial MMD: odds ratio, 9.56; 95% confidence interval, 1.85-49.48; P = 0.005; and FMMD versus non-MMD: odds ratio, 10.50; 95% confidence interval, 2.02-54.55; P = 0.001). This base at position -418 corresponds to the third base of the GAGGCTGGG sequence, an Sp1 binding site. Thus, changes in this position may influence Sp1 binding and subsequent transcription of the gene.CONCLUSION: Our findings suggest that the presence of a G/C heterozygous genotype at position -418 in TIMP2 promoter could be a genetic predisposing factor for FMMD.