烟雾病遗传学研究进展

汤 荡 徐 蔚 龙 江

(昆明医科大学第一附属医院神经外一科，云南 昆明 650032)

烟雾病(MMD)因颅底异常血管网形似烟雾，在MMD高发的日本，流行病学显示患病率为6.03/10万，发病率为0.54/10万〔1〕，我国最新的流行病学调查为南京地区MMD患者患病率为3.92/10万，发病率0.43/10 万〔2〕。日本和韩国最新的流行病学调查发现，发病率和患病率都呈上升趋势〔1,3〕。

MMD病因复杂，与多种因素相关，但大多数报道显示其中最重要的是遗传因素。12.1%的MMD患者有家族史〔1〕,同卵双生的兄弟姐妹中，一人患MMD，另一人的患病率为80%〔4〕。早在1999年，日本学者对16个家族性MMD进行研究发现3p24.2-26位点与该病有显著联系〔5〕。因为人类白细胞抗原(HLA)与众多疾病相关，随后研究者开始研究特定染色体如6号染色体上的HLA基因。日本研究者通过71例无血缘关系的MMD患者进行血清和HLA的DNA分型发现了MMD与HLA-B51显著相关，也发现了与一些HLA等位基因显著相关〔6〕。接着，日本研究者通过19个家庭发现了6号染色体上的D6S441(6q)可能与MMD相关〔7〕。1型多发性神经纤维瘤患者偶尔见于烟雾综合征，并且1型多发神经纤维瘤(NF1)的致病基因定位于染色体17q11.2上，因此对24个家庭MMD的17号染色体进行相关性分析集中在了17q25上〔8〕。一项对12个家庭兄弟姐妹的基因组分析显示MMD与8q23明显相关〔最大奇数对数值(LOD)为3.6〕并且与12q12明显相关(最大LOD为3.6)〔9〕。这些结果显示了MMD致病基因的不同位点，但是遗传学模式还没有确定。例如，对家族性MMD的系谱分析未发现特殊遗传基因型〔10〕。通过调查有3个或更多成员患MMD的15个日本家庭(52例MMD患者和14例MMD可疑者)〔11〕，12个家庭是3代都患MMD，2个家庭是4代，1个家庭是5代。135个后代中43.7%是MMD患者或是可疑者，并且推断家族性MMD是不完全外显常染色体显性遗传。对15个高度聚居的家庭的基因组参数相关性分析采用诊断学分类：狭义(明确的MMD)和广义(颈内动脉未闭塞性病变)。发现只和17q25.3显著相关(狭义分类，最大LOD值为6.57；广义分类，最大LOD值为8.07)。MMD基因被定位于D17S1806和17q的端粒之间的3.5 Mb区，邻近于之前报道的17q25〔8〕，但这两个基因位点没有重叠。这个研究有3个独特之处：只收集了三代以上高度聚居的家庭；参数相关性分析假设了常染色体显性遗传对象；MMD可疑者被认为是受遗传影响者〔12〕。Kamada等〔13〕和Liu等〔14〕分别证实了RNF213基因是MMD的易感基因。Wu等〔15〕对RNF213基因进一步定位于R4810K位点和A4399T位点，发现该位点突变与MMD显著相关。Morito等〔16〕研究发现RNF213基因编码的蛋白促进新生血管生成从而可能导致MMD。Miyawaki等〔17〕发现RNF213 c.14576G>A(rs112735-431)突变与MMD的动脉粥样硬化有关，无动脉粥样硬化的疑似MMD患者无RNF213 c.14576G>A突变。Guo等〔18〕研究发现ACTA2基因突变使血管平滑肌细胞增生从而产生血管阻塞性疾病包括MMD。Kang等〔19〕研究发现TIMP2基因启动子-418位置上的G/C杂合子的出现是家族性MMD的遗传易感因素。Li等〔20〕通过中国汉族人群进行了MMD易感基因基质金属蛋白酶(MMP)和金属蛋白酶组织抑制剂(TIMP)基因多态性进行分析，分别是MMP-3-11715A/6A(rs3025058)位点,MMP-9C-1562T(rs3918242)位点,TIMP-2 G-418(rs8179090)位点,发现MMP-3在-1171位点的多态性与MMD和家族性MMD相关，TIMP-2 G-418C多态性与家族性MMD无关，MMP-9 C-1562T和TIMP-2 G-418C的基因型和等位基因与正常对照组差异无统计学意义。以下对MMD遗传学的突出性研究做总结(表1)。

MMD的临床干预手段和手术方法层出不穷，但其临床治疗效果和预后不佳，因此，找到MMD的病因显得尤为重要。随着分子遗传学的不断发展、研究人群的广泛性和前期相关研究成果的积累，将会对MMD的发病机制做出全面阐释，对其诊断和治疗做出巨大贡献。

表1 MMD遗传学主要研究进展

续表1 MMD遗传学主要研究进展

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25Hong SH,Wang KC,Kim SK,etal.Association of HLA-DR and-DQ genes with familial moyamoya disease in Koreans〔J〕.J Korean Neurosurg Soc,2009;46(6):558-63.

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34Miyatake S,Touho H,Miyake N,etal.Sibling cases of moyamoya disease having homozygous and heterozygous c.14576G.A variant in RNF213 showed varying clinical course and severity〔J〕.J Hum Genet,2012；57(12):804-6.

35Mineharu Y,Takagi Y,Takahashi JC,etal.Rapid progression of unilateral moyamoya disease in a patient with a family history and an RNF213 risk variant〔J〕.Cerebrovasc Dis,2013;36(2):155-7.

36Wang X,Zhang Z,Liu W,etal.Impacts and interactions of PDGFRB,MMP-3,TIMP-2 and RNF213 polymorphisms on the risk of Moyamoya disease in Han Chinese human subjects〔J〕.Gene,2013;526(2):437-42.

37Liu W,Senevirathna ST,Hitomi T,etal.Genomewide association study identifies no major founder variant in Caucasian moyamoya disease〔J〕.J Genet,2013;92(3):605-9.