HLA Class I Alleles Associated with MMD
Reported associations of HLA class I alleles with MMD are presented in Table 1 . Kitahara et al. reported weak associations of HLA-A24, B46, and B54 ( P < 0.05 or < 0.025) in Japanese MMD patients in the early 1980s [9] . When they reanalyzed a total of 49 cases including their
57 HLA Studies
own cases and 31 reviewed cases from two different reports, weak associations of B54 and B61 were observed ( P < 0.005, each). Another study of Japanese MMD patients by Aoyagi et al. showed associations of B51 (RR 3.7, corrected P < 0.05) and B67 ( P < 0.01) [10] . They found Cw1 was weakly protective against the disease ( P < 0.05). Inoue et al. analyzed HLA class I alleles by molecular typing in Japanese MMD patients and reported a weak association of A*2602 allele with early-onset MMD (onset at £ 10 years of age, P < 0.05) [11] . Han et al.
reported an association of B35 in Korean MMD patients, and the association was somewhat stronger in late-onset (onset at >10 years of age, RR 6.2, corrected P < 0.05) and in female patients (RR 7.9, corrected P < 0.05) [13] .
HLA Class II Alleles Associated with MMD
Reported associations of HLA class II alleles with MMD are presented in Table 2 . Aoyagi et al. reported a weak association of HLA-DR1 with MMD ( P < 0.05) in Japanese patients by serological typing [10] . Inoue et al. reported weak associations of HLA-DR and DQ alleles in Japanese MMD patients by molecular typing [11, 12] . When they analyzed early-onset and late-onset patients separately, different HLA associations were observed. In early-onset patients, DRB1*0405 was a protective and DRB1*1501 and DQB1*0602 were susceptible alleles, whereas in late-onset patients, DQB1*0502 was a susceptible allele for the development of MMD [11] .
Most of the studies on the HLA and MMD associations have been performed with relatively small numbers of patients, and familial and nonfamilial (sporadic) MMD patients have not been analyzed separately. Recently, we have found that HLA-DRB1*1302 [odds ratio (OR) 12.76, corrected P 0.008] and a closely linked DQB1*0609 allele (OR 14.67, corrected P 0.02) were very strongly associated with familial MMD, but not with nonfamilial cases in Koreans (unpublished data). These associations of HLA-DRB1*1302 and DQB1*0609 alleles with familial MMD are much stronger than any other association thus far reported for MMD.
Table 1 Reported associations of HLA class I alleles with moyamoya disease Ethnic MMD patients HLA alleles
MMD associations
References Risks P P corr
Japanese Unrelated ( n = 18) A24 RR 3.83 <0.05 Kitahara et al. [9]
B46 RR 6.50 <0.05 B54 RR 3.58 <0.025 Unrelated ( n = 49) a B54 RR 3.80 <0.005 B61 RR 3.80 <0.005
Japanese Unrelated ( n = 32) B51 RR 3.7 <0.002 <0.05 Aoyagi et al. [10]
B67 RR 12.6 <0.01 Cw1 RR 0.3 <0.05
Japanese Total ( n = 68) A*2602 RR 2.33 NS Inoue et al. [11]
Early-onset ( n = 48) A*2602 RR 3.42 <0.05
Korean Total ( n = 28) B35 RR 4.2 <0.008 Han et al. [13]
Late-onset ( n = 22) B35 RR 6.2 <0.002 <0.05 b Female ( n = 17) B35 RR 7.9 <0.0007 <0.05 b
MMD moyamoya disease; P corr corrected P value; RR relative risk; NS not significant
a Including 18 cases of the authors’ study and 31 reviewed cases
b P corr values were calculated from the data presented in the paper
58 M.H. Park et al.
We suggest that other MHC gene(s) closely linked with HLA-DRB1*1302 and DQB1*0609 alleles in Koreans might be associated with the susceptibility to familial MMD. As a candi- date genetic factor, TNF- a , high producer allele closely linked with DRB1*1302-DQB1*0609 haplotype in this population, might be involved in the pathogenesis of the disease.
Implications of HLA Associations with MMD
Most of the HLA associations reported in MMD patients are rather weak in the strength of association and the results do not correlate with each other. Although Japanese and Koreans are very close in the distribution of HLA alleles [17] , HLA studies in MMD patients failed to reveal common HLA alleles associated with the disease between Japanese and Koreans.
Moreover, different studies in Japanese MMD patients also failed to reveal common HLA alleles associated with the disease. HLA class I or class II alleles may be simply disease-associated markers and are not directly associated with disease susceptibility or disease protection in MMD. It is more probable that other gene(s) closely linked with those HLA alleles showing associations with MMD are responsible for the pathogenesis of the disease.
Although we have no definite explanation for the pathogenesis of MMD, the final common pathway seems to involve proliferation of smooth muscle cells and their migration from the media to the intima in the carotid terminations of cerebral arteries in MMD patients [18] . This process is regulated by various growth factors, and the results from previous studies have shown that concentrations of certain growth factors or cytokines are increased in the cerebrospinal fluid and/or their expression is increased in the intracranial and extracranial arteries of patients with MMD: basic fibroblast growth factor, soluble adhesion molecules, cellular retinoic acid-binding protein I (CRABP-I), and hepatocyte growth factor [1] . In vascular injury and repair, a balance between the activities of connective tissue-degrading enzymes, matrix metalloproteinases (MMPs) and their endogenous inhibitors, and tissue inhibitors of metal- loproteinases (TIMPs) is important [19] , which might be deranged in MMD. It is of interest that a recent study of TIMP2 gene in Korean MMD patients suggested a difference in the Table 2 Reported associations of HLA class II alleles with moyamoya disease
Ethnic MMD patients HLA alleles
MMD associations
References Risks P P corr
Japanese Unrelated ( n = 32) DR1 RR 9.1 <0.05 Aoyagi et al. [10]
Japanese Total ( n = 71) DRB1*0405 RR 0.35 <0.01 Inoue et al. [11]
DQB1*0401 RR 0.40 <0.025 DQB1*0502 RR 3.27 <0.025 Early-onset ( n = 49) DRB1*0405 RR 0.38 <0.05
DRB1*1501 RR 2.3 <0.05 DQB1*0602 RR 2.42 <0.025 Late-onset ( n = 22) DQB1*0502 RR 4.72 <0.05
Korean Total ( n = 64) DRB1*1302 OR 1.67 0.14 Hong et al. a Familial ( n = 10) DRB1*1302 OR 12.76 0.0003 0.008
DQB1*0609 OR 14.67 0.001 0.02
OR odds ratio
a Unpublished data (submitted for publication)
59 HLA Studies
genetic predisposition of familial and nonfamilial MMD [20] , as we have found in the study of HLA-DR and -DQ genes in Korean patients.
Different subsets of MMD patients might differ in the genetic predisposition to develop the disease. Different subsets of MMD may be associated with different susceptibility genes and their products leading to the final common pathway involving proliferation of smooth muscle cells and their migration in the affected cerebral arteries in MMD patients. As one of the genetic factors, whether TNF- a high producer allele is associated with familial form of the disease has to be further studied.
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