内皮细胞一氧化氮合成酶基因多态性和股骨头缺血性坏死相关性的研究
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摘要
背景股骨头缺血性坏死(Avascular Necrosis of the Femoral Head, ANFH)是骨科常见疾病之一,可发生于所有年龄组,但在中青年中较为多见。其病因多由于环境危险因素和/或遗传易感因素共同作用而引起。人类血管内皮细胞一氧化氮合成酶(Endothelial nitric oxide synthase, eNOS)合成的一氧化氮(Nitric oxide, NO)作为具有多种功能的生物分子,参与了许多生理过程如血管再生、血栓形成、凝血和纤溶等功能。研究表明：由于eNOS的基因多态性影响血管内皮产生NO的功能,而与一些血管疾病如冠心病、心肌梗塞、高血压、中风和肾脏疾病等相关。其中关于eNOS基因中的内含子4(Intron4)的等位基因变异和外显子7(Exon7)的位点变异与多种疾病的关系已见报道,但罕见关于eNOS基因变异与ANFH关系的报告。
目的观察eNOS基因多态性和ANFH发病风险的关系,以及eNOS基因内含子4和外显子7不同的等位基因与已知的ANFH发病危险因素酗酒和使用激素的可能关系。进一步探索ANFH的遗传易感因素和相关发病机制,为ANFH易感人群的筛查、早期诊断和早期干预提供科学依据,有利于防止ANFH的发病和提高其诊断率及治疗成功率。
方法选择中南大学湘雅二医院骨科病房住院和门诊就医的2012年1月至2013年4月ANFH病人75例。排除明显的髋关节外伤史,按Ficat诊断与分期标准进行ANFH的临床诊断和分期,并按常见的临床病因分为特发性股骨头坏死、激素性股骨头坏死和酒精性股骨头坏死。另选健康体检门诊人群75例作为对照组,其年龄、性别、外伤史和血管病变史情况与病人组相匹配,两组人群均遵循了知情同意的原则。每例ANFH病人或健康对照者均从静脉采取5mlEDTA抗凝全血,24小时内Ficoll分离法分离外周血单个核细胞(Peripheral blood mononuclear cell, PBMC)。PBMC经细胞裂解液裂解后以常规异丙醇-乙醇法提取总DNA,并经0.8%琼脂糖凝胶电泳显示单个条带证实。以eNOS的内含子4特异性引物和外显子7特异性引物对每例标本进行多聚酶链式反应(polymerase chain reaction, PCR)特异性扩增。Intron4的PCR产物再经2%琼脂糖凝胶电泳显示出约420bp或393bp的Intron4目标条带,纯化后上机检测DNA序列图谱分析决定属于b/b等位基因,a/b等位基因或a/a等位基因。另外exon7的PCR产物经纯化后以限制性内切酶分析其DNA片段长度多态性(Retriction fragment length polymorphism, RLFP),以2%琼脂糖凝胶电泳后显示的248bp的1条、163bp+85bp的2条或163bp+85bp+248bp的3条带决定其属于G894T(即Glu298ASP)的野生型、纯和突变型或杂合型。实验结果采用spss18.0软件进行统计学分析。
结果共分析ANFH病人75例,其中男27例,女48例,年龄平均56.4±13.9岁；健康对照者75例,其中男30例,女45例,年龄平均58.9±11.6岁,两组均无髋关节外伤史和血管病变史,男女比例和年龄无明显区别(p>0.05)。ANFH人群根据临床病因可分为特发性、激素性和酒精性各41例、13例和21例。二组人群PBMC的DNA特异性扩增后,经基因检测分析显示eNOS内含子4等位基因的b/b型(野生型即无突变型)、b/a(杂合型即一条链变异)、a/a型(纯合突变型,即二条链均变异)的出现频率分别为：64例(85.3%)、10例(13.3%)、1例(1.3%)；正常对照组ANFH组71例(95.7%)、4例(5.3%)、0例(0)。ANFH组的b/a型出现频率(10/75,13.3%)明显高于正常对照组的b/a型出现频率(4/75,5.3%),二者比较有显著差异(p=0.0172,OR=3.903)。经PCR-RLFP分析二组的eNOS外显子7-G894T(对应于氨基酸序列的298位Glu->Asp变异)等位基因的G/G野生型(二个核苷酸位点均为鸟嘌呤)、G/T杂合型(一个位点变为胸腺嘧啶)、T/T纯合突变型(两个位点均变为胸腺嘧啶)的出现频率分别为：ANFH组51例(68%)、20例(26.7%)、4例(5.3%),正常对照组61例(81.3%)、12例(16%)、2例(2.7%)；ANFH组的G/T型出现频率(20/75,26.7%)明显高于正常对照组的G/T型出现频率(12/75,16.0%),二者比较有显著差异(p=0.0345,OR=2.876)。另外ANFH组的外显子7的T/T型出现频率(4/75,5.3%)也高于正常对照组的T/T型出现频率(2/75,2.7%)(p>0.05)。在ANFH组病人的内含子4序列中,特发性、激素性和酒精性病因的出现频率b/a型出现频率分别为7/41(17.1%)、1/13(7.7%)、2/21(9.5%),其中特发性ANFH病人b/a型出现频率明显高于正常对照组的b/a型出现频率(7/41(17.1%)vs.4/75(5.3%))；外显子7的G894T基因序列(Glu298Asp氨基酸)变异中,特发性、激素性和酒精性病因的T/T突变出现频率分别为3例(7.3%)、η例(0)、1例(4.8%),虽然因样本量太小,无显著统计学差异,但特发性ANFH组明显高于正常对照组3/41(7.3%)vs.2(2.7%))。
结论
1.首次发现中国人的eNOS基因和股骨头缺血性坏死的产生可能有一定关系,其基因多态性是影响股骨头坏死的病因之一。
2.发现eNOS基因的内含子4序列中b/a基因型使股骨头缺血性坏死的发生率增加,外显子7序列中894G/T基因型也是股骨头缺血坏死的危险因素之一。
3.在产生股骨头缺血性坏死的特发性、激素性、酒精性病因中,内皮细胞一氧化氮合成酶内含子4的b/a基因型和外显子7的894G/T基因型对特发性股骨头坏死的影响更明显。图8幅,表7个,参考文献76篇。
Back ground:Avascular Necrosis of Femoral Head (ANFH) is a common osteoarticular disease, affecting all age groups, especially young adults between the ages of20and50. The pathological changes of the disease results from multiple environment/genetic risk factors. As a multifunctional biomolecule synthesized by eNOS, NO participate in many physiological process including angiogenesis, thrombosis, coagulation and fibrinolysis. Although some studies of eNOS gene polymorphisms were reported and most of them focus on the27-bp repeat polymorphism in intron4and G894T polymorphism in exon7, few of them is about eNOS gene polymorphisms and ANFH.
Objects:By observing association of eNOS polymorphisms and ANFH, we hope to find possible relationship between the ANFH incidence and27-bp repeat polymorphism in intron4and G894T polymorphism in exon7, and to provide scientific basis for further research about the pathogenic mechanism and early diagnosis of the disease.
Methods:A total of75atraumatic ANFH patients and75healthy controls without hip trauma history were enrolled. The ANFH gourp were divided into3subgroups:idiopathic, steroid-induced and alcohol-induced. The healthy controls were selected from healthy outpatients to match with ANFH group in age and gendar.
Gene polymorphisms in27-bp repeat polymorphism in intron4and G894T polymorphism in exon7were determined. Medical history were collected for etiology analysis.
Results:The ANFH group was composed of27male and48female subjects and the mean age was56.4±13.9, while25male and40female patients comprised the healthy control group and the mean age was58.9±11.6. No significant gender or age difference were found between the two groups(p>0.05). Of ANFH group, there are41,13and21samples in idiopathic, steroid-induced and alcohol-induced subgroups, respectively. In the group comparison, the frequency of b/a genotype of intron4in ANFH group is significantly higher than that of the healthy control group (10/75(13.3%) vs.4/75,(5.3%),P=0.0172,OR=3.903), and the result of G/T genotype of exon7also indicates statistical significance between ANFH group and healthy control group (20/75(26.7%) vs.12/75(16.0%), P=0.0345,OR=2.876). In addition, the frequencies of T/T genotype are also different between ANFH and healthy control group(4/75(5.3%),2/75(2.7%),P>0.05), although statistic analysis dose not show significance due to the low population frequency of T/T genotype and the relatively small sample. In subgroup analysis, compared with alcohol-induced group and steroid induced group, genotype b/a are especially higher in idiopathic group than that in healthy control group, while although T/T genotype frequency seems different in the three subgroups, they can't be analyzed owning to small number of samples.
Conclusions:
1. eNOS gene polymorphisms is one of the risk factors of ANFH, there is underlying relevance of eNOS and the disease.
2. Both27-bp repeat polymorphism in intron4and G894T polymorphism in exon7associates with ANFH incidence.
3. Compared between subgroups of different etiology, the idiopathic group is most affected by the two gene polymorphisms.
目的观察eNOS基因多态性和ANFH发病风险的关系,以及eNOS基因内含子4和外显子7不同的等位基因与已知的ANFH发病危险因素酗酒和使用激素的可能关系。进一步探索ANFH的遗传易感因素和相关发病机制,为ANFH易感人群的筛查、早期诊断和早期干预提供科学依据,有利于防止ANFH的发病和提高其诊断率及治疗成功率。
方法选择中南大学湘雅二医院骨科病房住院和门诊就医的2012年1月至2013年4月ANFH病人75例。排除明显的髋关节外伤史,按Ficat诊断与分期标准进行ANFH的临床诊断和分期,并按常见的临床病因分为特发性股骨头坏死、激素性股骨头坏死和酒精性股骨头坏死。另选健康体检门诊人群75例作为对照组,其年龄、性别、外伤史和血管病变史情况与病人组相匹配,两组人群均遵循了知情同意的原则。每例ANFH病人或健康对照者均从静脉采取5mlEDTA抗凝全血,24小时内Ficoll分离法分离外周血单个核细胞(Peripheral blood mononuclear cell, PBMC)。PBMC经细胞裂解液裂解后以常规异丙醇-乙醇法提取总DNA,并经0.8%琼脂糖凝胶电泳显示单个条带证实。以eNOS的内含子4特异性引物和外显子7特异性引物对每例标本进行多聚酶链式反应(polymerase chain reaction, PCR)特异性扩增。Intron4的PCR产物再经2%琼脂糖凝胶电泳显示出约420bp或393bp的Intron4目标条带,纯化后上机检测DNA序列图谱分析决定属于b/b等位基因,a/b等位基因或a/a等位基因。另外exon7的PCR产物经纯化后以限制性内切酶分析其DNA片段长度多态性(Retriction fragment length polymorphism, RLFP),以2%琼脂糖凝胶电泳后显示的248bp的1条、163bp+85bp的2条或163bp+85bp+248bp的3条带决定其属于G894T(即Glu298ASP)的野生型、纯和突变型或杂合型。实验结果采用spss18.0软件进行统计学分析。
结果共分析ANFH病人75例,其中男27例,女48例,年龄平均56.4±13.9岁；健康对照者75例,其中男30例,女45例,年龄平均58.9±11.6岁,两组均无髋关节外伤史和血管病变史,男女比例和年龄无明显区别(p>0.05)。ANFH人群根据临床病因可分为特发性、激素性和酒精性各41例、13例和21例。二组人群PBMC的DNA特异性扩增后,经基因检测分析显示eNOS内含子4等位基因的b/b型(野生型即无突变型)、b/a(杂合型即一条链变异)、a/a型(纯合突变型,即二条链均变异)的出现频率分别为：64例(85.3%)、10例(13.3%)、1例(1.3%)；正常对照组ANFH组71例(95.7%)、4例(5.3%)、0例(0)。ANFH组的b/a型出现频率(10/75,13.3%)明显高于正常对照组的b/a型出现频率(4/75,5.3%),二者比较有显著差异(p=0.0172,OR=3.903)。经PCR-RLFP分析二组的eNOS外显子7-G894T(对应于氨基酸序列的298位Glu->Asp变异)等位基因的G/G野生型(二个核苷酸位点均为鸟嘌呤)、G/T杂合型(一个位点变为胸腺嘧啶)、T/T纯合突变型(两个位点均变为胸腺嘧啶)的出现频率分别为：ANFH组51例(68%)、20例(26.7%)、4例(5.3%),正常对照组61例(81.3%)、12例(16%)、2例(2.7%)；ANFH组的G/T型出现频率(20/75,26.7%)明显高于正常对照组的G/T型出现频率(12/75,16.0%),二者比较有显著差异(p=0.0345,OR=2.876)。另外ANFH组的外显子7的T/T型出现频率(4/75,5.3%)也高于正常对照组的T/T型出现频率(2/75,2.7%)(p>0.05)。在ANFH组病人的内含子4序列中,特发性、激素性和酒精性病因的出现频率b/a型出现频率分别为7/41(17.1%)、1/13(7.7%)、2/21(9.5%),其中特发性ANFH病人b/a型出现频率明显高于正常对照组的b/a型出现频率(7/41(17.1%)vs.4/75(5.3%))；外显子7的G894T基因序列(Glu298Asp氨基酸)变异中,特发性、激素性和酒精性病因的T/T突变出现频率分别为3例(7.3%)、η例(0)、1例(4.8%),虽然因样本量太小,无显著统计学差异,但特发性ANFH组明显高于正常对照组3/41(7.3%)vs.2(2.7%))。
结论
1.首次发现中国人的eNOS基因和股骨头缺血性坏死的产生可能有一定关系,其基因多态性是影响股骨头坏死的病因之一。
2.发现eNOS基因的内含子4序列中b/a基因型使股骨头缺血性坏死的发生率增加,外显子7序列中894G/T基因型也是股骨头缺血坏死的危险因素之一。
3.在产生股骨头缺血性坏死的特发性、激素性、酒精性病因中,内皮细胞一氧化氮合成酶内含子4的b/a基因型和外显子7的894G/T基因型对特发性股骨头坏死的影响更明显。图8幅,表7个,参考文献76篇。
Back ground:Avascular Necrosis of Femoral Head (ANFH) is a common osteoarticular disease, affecting all age groups, especially young adults between the ages of20and50. The pathological changes of the disease results from multiple environment/genetic risk factors. As a multifunctional biomolecule synthesized by eNOS, NO participate in many physiological process including angiogenesis, thrombosis, coagulation and fibrinolysis. Although some studies of eNOS gene polymorphisms were reported and most of them focus on the27-bp repeat polymorphism in intron4and G894T polymorphism in exon7, few of them is about eNOS gene polymorphisms and ANFH.
Objects:By observing association of eNOS polymorphisms and ANFH, we hope to find possible relationship between the ANFH incidence and27-bp repeat polymorphism in intron4and G894T polymorphism in exon7, and to provide scientific basis for further research about the pathogenic mechanism and early diagnosis of the disease.
Methods:A total of75atraumatic ANFH patients and75healthy controls without hip trauma history were enrolled. The ANFH gourp were divided into3subgroups:idiopathic, steroid-induced and alcohol-induced. The healthy controls were selected from healthy outpatients to match with ANFH group in age and gendar.
Gene polymorphisms in27-bp repeat polymorphism in intron4and G894T polymorphism in exon7were determined. Medical history were collected for etiology analysis.
Results:The ANFH group was composed of27male and48female subjects and the mean age was56.4±13.9, while25male and40female patients comprised the healthy control group and the mean age was58.9±11.6. No significant gender or age difference were found between the two groups(p>0.05). Of ANFH group, there are41,13and21samples in idiopathic, steroid-induced and alcohol-induced subgroups, respectively. In the group comparison, the frequency of b/a genotype of intron4in ANFH group is significantly higher than that of the healthy control group (10/75(13.3%) vs.4/75,(5.3%),P=0.0172,OR=3.903), and the result of G/T genotype of exon7also indicates statistical significance between ANFH group and healthy control group (20/75(26.7%) vs.12/75(16.0%), P=0.0345,OR=2.876). In addition, the frequencies of T/T genotype are also different between ANFH and healthy control group(4/75(5.3%),2/75(2.7%),P>0.05), although statistic analysis dose not show significance due to the low population frequency of T/T genotype and the relatively small sample. In subgroup analysis, compared with alcohol-induced group and steroid induced group, genotype b/a are especially higher in idiopathic group than that in healthy control group, while although T/T genotype frequency seems different in the three subgroups, they can't be analyzed owning to small number of samples.
Conclusions:
1. eNOS gene polymorphisms is one of the risk factors of ANFH, there is underlying relevance of eNOS and the disease.
2. Both27-bp repeat polymorphism in intron4and G894T polymorphism in exon7associates with ANFH incidence.
3. Compared between subgroups of different etiology, the idiopathic group is most affected by the two gene polymorphisms.
引文
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