Chinese Journal of Tissue Engineering Research ›› 2020, Vol. 24 ›› Issue (5): 747-752.doi: 10.3969/j.issn.2095-4344.1892
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Xu Qi1, Zhang Chao1, Ha Chengzhi2, Wang Dawei2
Received:
2019-05-17
Revised:
2019-05-25
Accepted:
2019-07-25
Online:
2020-02-18
Published:
2020-01-10
Contact:
Wang Dawei, Chief physician, Professor, Doctoral supervisor, Department of Bone and Joint, Liaocheng People’s Hospital, Liaocheng 252000, Shandong Province, China
About author:
Xu Qi, Master candidate, Shandong First Medical University & Shandong Academy of Medical Sciences, Taian 271000, Shandong Province, China
Supported by:
CLC Number:
Xu Qi, Zhang Chao, Ha Chengzhi, Wang Dawei. Susceptibility genes related to non-traumatic femoral head necrosis: improving detection accuracy and developing new treatment strategy[J]. Chinese Journal of Tissue Engineering Research, 2020, 24(5): 747-752.
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2.1 与血液循环相关的易感基因 2.1.1 凝血因子V(Factor V,F V) 非创伤性股骨头坏死是由于糖皮质激素、酒精等多种因素导致的血液供应减少,血液处于高凝状态,进而股骨头微血管内出现大量血栓,股骨头出现坏死。因此有研究表明非创伤性股骨头坏死的发病机制中存在高凝与低纤溶状态[11],即血栓形成或低纤维蛋白溶解,而凝血因子V Leiden突变被认为是血管血栓形成的危险遗传因素,与非创伤性股骨头坏死疾病之间具有密切的联系。凝血因子V Leiden突变是指凝血因子V中核苷酸1691位点上的特定鸟嘌呤被腺嘌呤所取代,使得肽链506位点精氨酸替代谷氨酰氨,导致凝血因子V对APC的抗凝反应较差,增加了血栓形成的风险。 BJORKMAN等[12]对63例非创伤性股骨头坏死患者与282名健康志愿者做病例-对照,非创伤性股骨头坏死患者出现了高频率的凝血因子V Leiden突变,并且36%基因突变患者的微血管中有血栓形成,提示凝血因子V Leiden突变与微血栓的形成有一定的联系。SHANG等[13]将481例患者与867名对照组进行了Meta分析,研究发现凝血因子V突变中,A等位基因患者患非创伤性股骨头坏死的风险比G等位基因携带者相比高4倍,因此不同的等位基因导致患非创伤性股骨头坏死的风险也不同。KIM 等[11]在韩国人群中进行了病例-对照研究,在423例非创伤性股骨头坏死患者和348名对照者中的单倍型进行了基因分析,发现凝血因子V Leiden突变在韩国人群中并不显著。并且PENG等[14]研究表明凝血因子V Leiden突变在中国人群中非常罕见,因此,可以推测出凝血因子V Leiden突变与非创伤性股骨头坏死之间存在显著的关联性,但这种突变存在着地区、种族与人群的差异。 2.1.2 5,10-亚甲基四氢叶酸还原酶(5,10-methylenetetrahydrofolate reductase,MTHFR) MTHFR是给同型半胱氨酸提供甲基,将其转换为甲硫氨酸过程的酶。MTHFR的基因突变会显著降低酶的活性,导致血浆同型半胱氨酸水平升高,而同型半胱氨酸会导致血管内皮损伤,从而增殖血管内皮细胞,增强血管壁凝固活性,导致微血管内血栓的形成[15]。高同型半胱血症也被认为是造成血栓形成与股骨头坏死的重要危险因素[16]。其中MTHFR的677C/T(丙氨酸变为缬氨酸)基因发生突变与血浆同型半胱氨酸水平升高有密切的联系[17]。AZARPIRA等[16]研究表明发生非创伤性股骨头坏死疾病的发生率与C677T基因突变有显著的统计学差异,ZALAVRAS等[18]在66例患者的研究中也得出了相同的结果。但也有一些研究未支持此结果,KIM等[19]在443例非创伤性股骨头坏死韩国患者和273名对照受试者中进行15个单核苷酸多态性(single nucleotide polymorphism,SNP)基因分析,发现MTHFR的C677T基因突变与非创伤性股骨头坏死基因易感性之间并没有明显的联系,作者分析导致不同的原因可能与地区和种族的不同有关。通过进一步研究,SHANG等[20]通过对MTHFR C677T与非创伤性股骨头坏死的相关性研究进行了Meta分析,发现其与非创伤性股骨头坏死可以在非洲人中找到重要的联系,但在亚洲人中却找不到密切的相关性,由此表明MTHFR的C677T基因突变可能不是亚洲人群的主要危险因素,而是非洲人群非创伤性股骨头坏死的主要危险因素。 2.1.3 纤溶酶原激活物抑制剂1(plasminogen activator inhibitor-1, PAI-1) PAI-1基因是用来调控纤维蛋白溶解系统,位于人类7号染色体上,主要作用于组织纤溶酶原激活物和尿激酶纤溶酶原激活物,来维持凝血与纤维蛋白溶解系统的平衡。已有多项研究表明PAI-1启动子区4G/5G多态性与非创伤性股骨头坏死遗传易感性之间存在着明显相关性,且主要表现在3个SNP (rs1799889,rs2227631,rs11178)上[21-24]。SOBHAN等[25]通过对高加索后裔与东南亚后裔的比较进行Meta分析对比,发现4G/5G基因型可增加血浆中PAI-1的水平,而PAI-1水平的增加会促进非创伤性股骨头坏死的发生,可以推测由于PAI-1启动子区4G/5G多态性诱导PAI-1水平的增加,而高水平的PAI-1通过抑制纤溶酶原激活物来抑制纤维蛋白溶解,导致微血管血栓形成,从而阻塞血管[26]。LI等[27]则对106例非创伤性股骨头坏死患者与151名健康人直接利用聚合酶链式反应测序进行基因组分型,发现SNPs(rs6092,rs7242)的G-T单倍型可能是非创伤性股骨头坏死的保护因子。通过上述研究表明,PAI-1基因中既有非创伤性股骨头坏死的危险因子也有非创伤性股骨头坏死的保护因子。因此,PAI-1基因与非创伤性股骨头坏死之间联系密切,但具体机制尚不清楚,仍需要进一步的研究探讨,需更加深入研究PAI-1基因中危险因子与保护因子之间的联系,为以后治疗股骨头坏死提供新的依据。 2.2 与免疫相关的遗传基因 2.2.1 白细胞介素因子(interleukin,IL) 在免疫方面,各种免疫遗传因素与非创伤性股骨头坏死的发生越来越密切,免疫系统参与了骨代谢的形成过程,异常的免疫应答可能会影响骨骼形成而发生非创伤性股骨头坏死。白细胞介素1是一种主要的促炎细胞因子,它可以刺激与炎症、免疫相关基因的表达,AN等[28]利用质谱分析系统对中国人群进行了SNP基因型分析,结果表明白细胞介素1受体1(rs10490571、s3917225)与白细胞介素1受体2 (rs11674595)极大提高了患非创伤性股骨头坏死的风险。白细胞介素4是巨噬细胞功能调节的关键因子,可下调CD14水平并抑制干扰素与肿瘤坏死因子的分泌,JIN等[29]研究表明白细胞介素4基因的易感性是导致非创伤性股骨头坏死发生的重要因素,其中白细胞介素4(rs2243283)是危险的单核苷酸基因。WEI等[30]通过对147例非创伤性股骨头坏死患者与135名健康个体的mRNA与蛋白表达量作对比,发现白细胞介素10中的SNP是非创伤性股骨头坏死的遗传易感因子。WANG等[31]研究发现白细胞介素23受体基因染色体位于1p31.3上,并且rs6693831的基因型T/C会降低患非创伤性股骨头坏死的风险。通过上述发现,白细胞介素1、白细胞介素4、白细胞介素10、白细胞介素23中的某些易感基因都导致非创伤性股骨头坏死的发生,因此对白介素因子中易感基因的早期检测,会对早期预防与治疗股骨头坏死提供帮助。 2.2.2 肿瘤坏死因子α(tumor necrosis factor-α,TNF-α) 肿瘤坏死因子α主要是由巨噬细胞分泌的炎性细胞因子,其基因位于人类染色体6p21.4上的组织相容性复合体Ⅲ区域内,内含4个外显子和3个内含子,在免疫系统内起重要的作用。肿瘤坏死因子α的基因于1975年被发现以来,经过40多年的研究,发现该基因与非创伤性股骨头坏死也有一定的联系。张佳音等[32]研究发现肿瘤坏死因子α基因可以导致股骨头局部发生炎症及血栓形成,进而引起炎症反应与股骨头营养不足,发生坏死。FANG等[33]研究表明DNA甲基化和组蛋白修饰在遗传调控肿瘤坏死因子α基因对成骨分化的影响中起重要作用,DNA甲基化可以阻断转录因子与DNA调节位点结合,而组蛋白修饰可以干扰转录因子与染色体相互作用。在肿瘤坏死因子α基因的启动子内,有2种常见的SNP影响着肿瘤坏死因子α的表达水平,PENG等[34]通过Meta分析,发现TNF-α-308(G/A) and -238(G/A)的多态性就与非创伤性股骨头坏死易感性相关。与免疫相关的遗传基因是近几年发现的新遗传易感因素,多发生在红斑狼疮斑伴股骨头坏死患者当中,但两者是否具有相关性,还需进一步研究。 2.3 与代谢相关的遗传基因 2.3.1 药物代谢 腺苷三磷酸结合盒转运体B1 (ATP-binding cassette subfamily B member 1, ABCB1)又称多药耐药基因,位于人类染色体7q21.12上,长 4.5 kb,编码了1 280个氨基酸肽,参与了多种药物的转运过程,是细胞内药物吸收与转运的关键蛋白。WANG等[31]利用质谱分析系统分析了ABCB1基因的8个SNP,发现其中的SNP(rs743506)会诱导非创伤性股骨头坏死的发生。ZHANG等[35]利用聚合酶链反应-限制性长度多态性技术对113例非创伤性股骨头坏死患者的ABCB1多态性进行了基因分型,发现了与正常人的基因型相比,C3435T TT基因型出现的频率较低,因此可以推测出TT基因型通过增加P-gp活性来降低患非创伤性股骨头坏死的风险,TT基因型可能为非创伤性股骨头坏死的保护因子。ZHANG等[36]通过Meta分析发现与C3435T中CC基因型携带者相比,TT型基因携带者患非创伤性股骨头坏死的人群少1/3,由此又验证了TT基因型较CC基因型患非创伤性股骨头坏死的风险性较低。因此,早期对高危人群进行筛查,结合ABCB1的基因型进行合理精确用药,可以有效降低非创伤性股骨头坏死的发病率。 细胞色素P450(cytochromeP450,CYP450)主要分布在内质网和线粒体内膜上,是参与脂溶性药物代谢的主要酶,其中CYP3A4基因是糖皮质代谢的关键酶基因,在激素性股骨头坏死中起主要作用的[37]。WANG等[38]通过150例激素性股骨头坏死患者与250名健康者作对照研究,在基因分型中发现CYP3A4基因中的SNP(rs2242480)会导致激素性股骨头坏的发生,继而类固醇代谢异常,造成脂肪栓塞,发生股骨头缺血坏死,但具体机制有望逐步阐明。 2.3.2 脂类代谢 脂类代谢的异常是发生股骨头坏死的主要发病因素。长期服用糖皮质激素和大量饮酒会导致脂类代谢异常,促进皮下的脂肪动员,产生高脂血症。高脂血症会增加血液的黏稠性,造成脂质在血管内皮沉积,形成脂肪栓塞,使骨组织血运发生障碍,骨细胞变性死亡,最终发生股骨头的坏死。 载脂蛋白(apolipoprotein,Apo)是一种血浆蛋白,通过与细胞受体相互作用介导脂质的转运,是脂类代谢发生异常的敏感标志物。载脂蛋白B反映的是低密度脂蛋白的情况,而载脂蛋白A1反映的是高密度脂蛋白的情况,研究表明低密度脂蛋白与高密度脂蛋白的比值可增加脂肪栓塞的发生率,在非创伤性股骨头坏死发生中起关键作用[39]。YIN等[40]利用聚合酶链反应-限制性长度多态性技术对4种SNP进行基因分型,发现载脂蛋白A1基因型启动区-75 G > A的AA基因型频率高于对照组,推测载脂蛋白A1基因的AA基因型可能为非创伤性股骨头坏死发生的易感基因。韦向东等[41]采用SNaPshot单碱基延伸技术及直接测序法检测载脂蛋白B,结果在载脂蛋白B的SNP(rs1042031)位点发现了GG、AG共2个基因型,且与AG基因型相比,GG基因型患非创伤性股骨头坏死的患者少,因此载脂蛋白B的SNP(rs1042031)位点的AG基因型可能为非创伤性股骨头坏死的易感基因。对载脂蛋白的进一步研究中,YUAN等[42]发现载脂蛋白E也可以通过影响体内的胆固醇的代谢来造成股骨头坏死的发生,并且rs7412的T等位基因与rs429358的C等位基因会诱导非创伤性股骨头坏死的发生。载脂蛋白通过脂类代谢来调控骨代谢,其基因易感性是影响非创伤性股骨头坏死发生的新机制,目前主要调节脂类代谢的药物是他汀类药物,很多研究已证实他汀类药物与载脂蛋白有关[43],但能否用他汀类药物治疗股骨头坏死有待进一步研究。 2.3.3 骨基质胶原代谢 COL2A1基因是第1个被发现与非创伤性股骨头坏死相关的遗传性基因。COL2A1基因是造成骨骼发育不良的关键基因,多项研究表明COL2A1基因突变会导致软骨发育不良与生长停滞,严重者导致脊柱畸形与股骨头发育不良[44-45]。CHEN等[8]发现具有股骨头坏死的2个台湾家族,呈现出显著的常染色体显性遗传方式,将连锁分析应用于4代谱系,结果显示股骨头坏死的易感基因定位于染色体12q13上D12S1663 和D12S1632之间的15-cM区域中。LIU等[46]在染色体12q13易感基因的基础上,利用单倍型分析,并对COL2A1的启动子与外显子区域进行了测序,发现COL2A1基因在33外显子处有个G-A突变,导致丝氨酸取代了甘氨酸;50外显子处有G-A的突变,导致甘氨酸取代了丝氨酸,而在散发非创伤性股骨头坏死患者中,并未发现此编码区有所突变,由此可见COL2A1基因突变可能为非创伤性股骨头坏死的一个遗传因素。MIYAMOTO等[47]通过qRT-PCR及直接测序的方式在一个日本家庭的6名成员中发现了与LIU等[46]相同的COL2A1基因突变(p.Gly1170Ser突变),但其表型表现为Legg-Calvé-Perthes病,后SU等[48]对5名中国成员的2条DNA链上所有外显子与剪接位点的PCR反应产物进行测序,也证实了该基因(p.Gly1170Se)的突变,并且表现出显著的年龄变化。LI等[49]研究发现同时患有Legg-Calvé-Perthes病与非创伤性股骨头坏死病的家族中发现了新的COL2A1基因突变(c.1888 G.A, p. Gly630Ser), 因此推测出COL2A1基因突变有显著的年龄变化,并早期会影响股骨头骨骺的闭合,导致儿童时期发生股骨头坏死。因此,早期对COL2A1基因突变进行筛查,并对年轻股骨头坏死患者进行预防性治疗,有利于早期治愈股骨头坏死,降低股骨头坏死的严重程度。"
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