Although the cause of MMD is unknown, genetic predisposition has been strongly suggested to play a role in the development of this disease. Loci for familial MMD have been found by linkage analyses and include chromosomes 3p24.2-p26, 6q25, 8q23, 12p12, and 17q25 [9– 13] . In a study with the hypothesis that the deregulation of TIMPs would disrupt the balance between matrix metalloproteinases (MMPs) and TIMPs and result in erroneous smooth muscle cell (SMC) dynamics that induce MMD, sequences of TIMP2 (in 17q25) and TIMP4 (in 3p25) genes were compared between familial patients with MMD, nonfamilial patients with MMD, and normal controls [2] . This study identified an SNP at the Sp1 binding site in the TIMP2 promoter region as a risk factor for familial MMD. Recently, increased expression of serum MMP-9 was demonstrated in patients with MMD, which might contribute to MMD pathogenesis in a similar way to TIMP2 polymorphisms [14] . Moreover, the importance of chromosome 17q25 for MMD has been emphasized again in a subsequent study [13] . We believe other genes pertinent to SMC dynamics need to be included in future genetic studies, including studies involving SNPs. Examples are the smooth muscle alpha-actin gene ( ACTA2 ) and a series of genes related to SMC differentiation [15] .
Conclusion
SNP studies are valuable in the research into MMD, which has a strong genetic background.
They can provide data supporting a hypothesis for the disease pathogenesis and produce valu- able information in accordance with other studies demonstrating protein expression. As effi- cient analysis methods and extensive databases for SNPs become available, more important and interesting data are anticipated to be revealed.
References
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53 Single Nucleotide Polymorphism
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Introduction
Although the pathogenesis of moyamoya disease (MMD) is still unclear [1] , several pieces of evidence suggest the involvement of genetic factors in this disease [2] . Over 10% of MMD patients have affected blood relatives, and concordance in the affection status has been proven in 80% of identical twins. Moreover, there is an ethnic predisposition to MMD, the incidence of the disease being the highest in East Asian populations, such as Japanese and Koreans. Data from an epidemiological study of familial MMD have suggested that MMD is probably inherited in a polygenic or autosomal dominant mode with a low pene- trance [3] . Microsatellite linkage analysis has identified genetic loci that are associated with MMD on chromosomes 3, 6, 8, and 17 [4– 8] . However, the relevant genes have not so far been identified [1, 8] .
In relation to genetic loci associated with MMD on chromosome 6, human leukocyte antigen (HLA) genes have been studied. There have been several studies investigating the associations of HLA genes with MMD. Associations of various HLA class I or class II alleles with the disease have been reported in several different studies of Japanese or Korean MMD patients with conflicting results [9– 13] . It is noteworthy that most of the associations were relatively weak, and none of the HLA class I or class II alleles has been corroborated by more than one report.
This chapter describes the genomic organization of HLA genes, underlying mechanisms of HLA and disease associations, statistical methods evaluating HLA and disease associations, and HLA studies thus far reported in MMD patients and their implications.
M.H. Park (!)
Department of Laboratory Medicine , Seoul National University College of Medicine , 101 Daehangno, Jongno-gu , Seoul 110–744 , Republic of Korea
e-mail: [email protected] S.H. Hong
Department of Neurosurgery , Asan Medical Center,
University of Ulsan College of Medicine , Seoul , Republic of Korea K.-C. Wang
Division of Pediatric Neurosurgery , Pediatric Clinical Neuroscience Center, Seoul National University Children’s Hospital, Seoul National University College of Medicine , Seoul , Republic of Korea
HLA Studies in Moyamoya Disease
Myoung Hee Park , Seok Ho Hong , and Kyu-Chang Wang
54 B.-K. Cho and T. Tominaga (eds.), Moyamoya Disease Update,
DOI 10.1007/978-4-431-99703-0_9, © Springer 2010
55 HLA Studies