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.