Single nucleotide polymorphisms of tissue inhibitor of metalloproteinase genes in familial Moyamoya disease

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.