煙霧病遺傳學(xué)研究進展

湯 蕩 徐 蔚 龍 江

(昆明醫(yī)科大學(xué)第一附屬醫(yī)院神經(jīng)外一科，云南 昆明 650032)

煙霧病(MMD)因顱底異常血管網(wǎng)形似煙霧，在MMD高發(fā)的日本，流行病學(xué)顯示患病率為6.03/10萬，發(fā)病率為0.54/10萬〔1〕，我國最新的流行病學(xué)調(diào)查為南京地區(qū)MMD患者患病率為3.92/10萬，發(fā)病率0.43/10 萬〔2〕。日本和韓國最新的流行病學(xué)調(diào)查發(fā)現(xiàn)，發(fā)病率和患病率都呈上升趨勢〔1,3〕。

MMD病因復(fù)雜，與多種因素相關(guān)，但大多數(shù)報道顯示其中最重要的是遺傳因素。12.1%的MMD患者有家族史〔1〕,同卵雙生的兄弟姐妹中，一人患MMD，另一人的患病率為80%〔4〕。早在1999年，日本學(xué)者對16個家族性MMD進行研究發(fā)現(xiàn)3p24.2-26位點與該病有顯著聯(lián)系〔5〕。因為人類白細(xì)胞抗原(HLA)與眾多疾病相關(guān)，隨后研究者開始研究特定染色體如6號染色體上的HLA基因。日本研究者通過71例無血緣關(guān)系的MMD患者進行血清和HLA的DNA分型發(fā)現(xiàn)了MMD與HLA-B51顯著相關(guān)，也發(fā)現(xiàn)了與一些HLA等位基因顯著相關(guān)〔6〕。接著，日本研究者通過19個家庭發(fā)現(xiàn)了6號染色體上的D6S441(6q)可能與MMD相關(guān)〔7〕。1型多發(fā)性神經(jīng)纖維瘤患者偶爾見于煙霧綜合征，并且1型多發(fā)神經(jīng)纖維瘤(NF1)的致病基因定位于染色體17q11.2上，因此對24個家庭MMD的17號染色體進行相關(guān)性分析集中在了17q25上〔8〕。一項對12個家庭兄弟姐妹的基因組分析顯示MMD與8q23明顯相關(guān)〔最大奇數(shù)對數(shù)值(LOD)為3.6〕并且與12q12明顯相關(guān)(最大LOD為3.6)〔9〕。這些結(jié)果顯示了MMD致病基因的不同位點，但是遺傳學(xué)模式還沒有確定。例如，對家族性MMD的系譜分析未發(fā)現(xiàn)特殊遺傳基因型〔10〕。通過調(diào)查有3個或更多成員患MMD的15個日本家庭(52例MMD患者和14例MMD可疑者)〔11〕，12個家庭是3代都患MMD，2個家庭是4代，1個家庭是5代。135個后代中43.7%是MMD患者或是可疑者，并且推斷家族性MMD是不完全外顯常染色體顯性遺傳。對15個高度聚居的家庭的基因組參數(shù)相關(guān)性分析采用診斷學(xué)分類：狹義(明確的MMD)和廣義(頸內(nèi)動脈未閉塞性病變)。發(fā)現(xiàn)只和17q25.3顯著相關(guān)(狹義分類，最大LOD值為6.57；廣義分類，最大LOD值為8.07)。MMD基因被定位于D17S1806和17q的端粒之間的3.5 Mb區(qū)，鄰近于之前報道的17q25〔8〕，但這兩個基因位點沒有重疊。這個研究有3個獨特之處：只收集了三代以上高度聚居的家庭；參數(shù)相關(guān)性分析假設(shè)了常染色體顯性遺傳對象；MMD可疑者被認(rèn)為是受遺傳影響者〔12〕。Kamada等〔13〕和Liu等〔14〕分別證實了RNF213基因是MMD的易感基因。Wu等〔15〕對RNF213基因進一步定位于R4810K位點和A4399T位點，發(fā)現(xiàn)該位點突變與MMD顯著相關(guān)。Morito等〔16〕研究發(fā)現(xiàn)RNF213基因編碼的蛋白促進新生血管生成從而可能導(dǎo)致MMD。Miyawaki等〔17〕發(fā)現(xiàn)RNF213 c.14576G>A(rs112735-431)突變與MMD的動脈粥樣硬化有關(guān)，無動脈粥樣硬化的疑似MMD患者無RNF213 c.14576G>A突變。Guo等〔18〕研究發(fā)現(xiàn)ACTA2基因突變使血管平滑肌細(xì)胞增生從而產(chǎn)生血管阻塞性疾病包括MMD。Kang等〔19〕研究發(fā)現(xiàn)TIMP2基因啟動子-418位置上的G/C雜合子的出現(xiàn)是家族性MMD的遺傳易感因素。Li等〔20〕通過中國漢族人群進行了MMD易感基因基質(zhì)金屬蛋白酶(MMP)和金屬蛋白酶組織抑制劑(TIMP)基因多態(tài)性進行分析，分別是MMP-3-11715A/6A(rs3025058)位點,MMP-9C-1562T(rs3918242)位點,TIMP-2 G-418(rs8179090)位點,發(fā)現(xiàn)MMP-3在-1171位點的多態(tài)性與MMD和家族性MMD相關(guān)，TIMP-2 G-418C多態(tài)性與家族性MMD無關(guān)，MMP-9 C-1562T和TIMP-2 G-418C的基因型和等位基因與正常對照組差異無統(tǒng)計學(xué)意義。以下對MMD遺傳學(xué)的突出性研究做總結(jié)(表1)。

MMD的臨床干預(yù)手段和手術(shù)方法層出不窮，但其臨床治療效果和預(yù)后不佳，因此，找到MMD的病因顯得尤為重要。隨著分子遺傳學(xué)的不斷發(fā)展、研究人群的廣泛性和前期相關(guān)研究成果的積累，將會對MMD的發(fā)病機制做出全面闡釋，對其診斷和治療做出巨大貢獻。

表1 MMD遺傳學(xué)主要研究進展

續(xù)表1 MMD遺傳學(xué)主要研究進展

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9Sakurai K,Horiuchi Y,Ikeda H,etal.A novel susceptibility locus for moyamoya disease on chromosome 8q23〔J〕.J Hum Genet,2004;49(5):278-81.

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13Kamada F,Aoki Y,Narisawa A,etal.A genome-wide association study identifies RNF213 as the first Moyamoya disease gene〔J〕.J Hum Genet,2011;56(1):34-40.

14Liu W,Morito D,Takashima S,etal.Identification of RNF213 as a susceptibility gene for moyamoya disease and its possible role in vascular development〔J〕.PLoS One,2011;6(7):e22542.

15Wu Z,Jiang H,Zhang L,etal.Molecular analysis of RNF213 gene for moyamoya disease in the Chinese Han population〔J〕.PLoS One,2012;7(10):e48179.

16Morito D,Nishikawa K,Hoseki J,etal.Moyamoya disease-associated protein mysterin/RNF213 is a novel AAA+ ATPase,which dynamically changes its oligomeric state〔J〕.Sci Rep,2014;24(4):4442.

17Miyawaki S,Imai H,Shimizu M,etal.Genetic analysis of RNF213 c.14576G>A variant in nonatherosclerotic quasi-moyamoya disease〔J〕.J Stroke Cerebrovasc Dis,2015;24(5):1075-9.

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19Kang HS,Kim SK,Cho BK,etal.Single nucleotide polymorphisms of tissue inhibitor of metalloproteinase genes in familial moyamoya disease〔J〕.Neurosurgery,2006;58(6):1074-80.

20Li H,Zhang ZS,Liu W,etal.Association of a functional polymorphism in the MMP-3 gene with moyamoya disease in the Chinese han population〔J〕.Cerebrovasc Dis,2010;30(6):618-25.

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24Mineharu Y,Liu W,Inoue K,etal.Autosomal dominant moyamoya disease maps to chromosome 17q25.3〔J〕.Neurology,2008;70(24 Pt 2):2357-63.

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.

26Liu W,Hashikata H,Inoue K,etal.A rare Asian founder polymorphism of Raptor may explain the high prevalence of Moyamoya disease among east Asians and its low prevalence among Caucasians〔J〕.Environ Health Prev Med,2010;15(2):94-104.

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28Park YS,Min KT,Kim TG,etal.Age-specific eNOS polymorphisms in moyamoya disease〔J〕.Childs Nerv Syst,2011;27(11):1919-26.

29Roder C,Peters V,Kasuya H,etal.Common genetic polymorphisms in moyamoya and atherosclerotic disease in Europeans〔J〕.Childs Nerv Syst,2011;27(2):245-52.

30Kraemer M,Horn PA,Roder C,etal.Analysis of human leucocyte antigen genes in Caucasian patients with idiopathic moyamoya angiopathy〔J〕.Acta Neurochir(Wien),2012;154(3):445-54.

31Liu C,Roder C,Schulte C,etal.Analysis of TGFB1 in European and Japanese Moyamoya disease patients〔J〕.Eur J Med Genet,2012;55(10):531-4.

32Miyatake S,Miyake N,Touho H,etal.Homozygous c.14576G.A variant of RNF213 predicts early-onset and severe form of moyamoya disease〔J〕.Neurology,2012;78(11):803-10.

33Miyawaki S,Imai H,Takayanagi S,etal.Identification of a genetic variant common to moyamoya disease and intracranial major artery stenosis/occlusion〔J〕.Stroke,2012;43(12):3371-4.

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.