Ⅰ型胶原α1 Sp1多态性与骨密度和骨折关联性的Meta分析

doi:10.3969/j.issn.2095-4344.2015.33.027

摘要/Abstract

摘要：

背景：到目前为止，多项研究已经对Sp1多态性对骨质疏松和骨折的风险做出了评估。有报道称这种多态性与骨密度降低和骨折有密切联系，但也有研究称未发现类似联系，这些结果导致了很大的争议。

目的：通过仅纳入病例对照研究的Meta分析来评价Ⅰ型胶原α1 Sp1多态性对骨密度和骨折的影响。

方法：检索MEDLINE，EMBASE，PubMed数据库有关Ⅰ型胶原α1 Sp1对骨密度和骨折影响的病例对照研究，计算合并效应值比值比(ORs)及其95%可信区间(95%CI)。并对异质性和偏倚进行评估。

结果与结论：共32篇文献符合纳入标准。其中有22项研究评价了Sp1多态性对骨折的影响，在5个基因模型中均可发现Sp1多态性与骨折危险性有关联，但在亚组分析中，仅在欧洲人群有类似结果。有13项研究评价了Sp1多态性对骨密度降低的影响，结果发现Sp1与骨密度降低有密切关系，亚组分析在欧洲和美洲人群中有类似结果，但是在亚洲人群中并无类似发现。总体来说，Ⅰ型胶原α1 Sp1多态性是骨折和骨密度降低的危险因素，但也存在地区即地理性差异性。

中国组织工程研究杂志出版内容重点：组织构建；骨细胞；软骨细胞；细胞培养；成纤维细胞；血管内皮细胞；骨质疏松；组织工程

关键词: 组织构建, 骨组织工程, 骨密度, Ⅰ型胶原α1, Sp1, 多态性, 骨折, Meta分析

Abstract:

BACKGROUND: Currently, there are large numbers of studies related to the association between collagen type I alpha1 (COL1A1) Sp1 polymorphism and bone mineral density and fracture risk, but the results are inconsistent.

OBJECTIVE: To evaluate the impact of the COL1A1 Sp1 polymorphism on bone mineral density and fracture by using the Meta-analysis.

METHODS: We comprehensively searched the eligible studies for the present meta-analysis through MEDLINE, PubMed, EMBASE databases. Pooled odds ratios and 95% confidence intervals of Sp1 polymorphisms for bone mineral density and fracture risk were obtained, with attention to study quality and publication bias.

RESULTS AND CONCLUSION: A total of 32 studies met the inclusion criteria, among which, 22 studies evaluated the Sp1 polymorphism and fracture risk. Significant associations were found in five genetic models. In the stratified analysis by region, the same results were found in the Europeans but not Americans and Asians. Thirteen studies evaluated the Sp1 polymorphism and low bone mineral density risk. A similar result was obtained. However, the analysis of bone mineral density data showed an increased relation between Sp1 polymorphism and low bone mineral density in Europeans and Americans but not in Asians. Overall, the current meta-analysis concludes that the COL1A1 Sp1 polymorphism is associated with low bone mineral density and fracture risk, especially in Europeans. However, susceptibility to them varies markedly among populations from different regions.

中国组织工程研究杂志出版内容重点：组织构建；骨细胞；软骨细胞；细胞培养；成纤维细胞；血管内皮细胞；骨质疏松；组织工程

Key words: Fractures, Bone, Collagen Type I, Bone Density, Meta-Analysis

中图分类号:

R318

宗强，李立军，姜竹岩，时宇博，倪东馗. Ⅰ型胶原α1 Sp1多态性与骨密度和骨折关联性的Meta分析[J]. 中国组织工程研究, 2015, 19(33): 5395-5401.

Zong Qiang, Li Li-jun, Jiang Zhu-yan, Shi Yu-bo, Ni Dong-kui. Association of collagen type I alpha1 Sp1 polymorphism with bone mineral density and fracture: a Meta-analysis of case-control studies [J]. Chinese Journal of Tissue Engineering Research, 2015, 19(33): 5395-5401.

图/表（结果） 3

2.1 文献检索结果根据检索策略最终共检索得到108篇文献。根据纳入和排除标准，共筛选出32篇符合标准的文献^[1-2^，^6-8^，^12-13^，^17-19^，^24-27^，²⁹^，³¹^，³³^，³⁶^，^40-45^，^49-50^，⁵⁴^，⁵⁶^，^58-61]。其中有22篇文献是关于Sp1多态性与骨折的关系的研究^[1^，^6-8^，^12-13^，^18-19^，^25-26^，²⁹^，³¹^，³³^，³⁶^，^41-42^，^49-50^，^57-58^，^60-61]，其中病例组2 602例，对照组6 698例；13项研究关于Sp1多态性与骨密度的关系^[2^，¹³^，¹⁷^，²⁴^，²⁷^，³⁶^，⁴⁰^，^43-45^，⁵⁴^，^58-59]，病例组1 561例，对照组1 236例。所有纳入的文章均为病例对照研究(表1)。

2.2 Meta分析结果根据上述统计学分析方法计算，在5个基因模型中Sp1多态性与骨折及其骨密度均存在密切关系，是骨折发生、骨密度降低的一项危险因素(①骨折：等位基因模型：OR=1.283， 95%CI=1.174-1.402，P=0.000；同质性模型：OR=1.764，95%CI=1.373-2.264，P=0.000；异质性模型：OR=1.234，95%CI=1.106-1.376，P=0.000；显性模型：OR=1.283，95%CI =1.174-1.402，P=0.000；隐性模型：OR=3.312，95%CI=1.706-6.430，P=0.000。②骨密度：等位基因模型：OR=1.980，95% CI=1.316-2.980，P=0.001；同质性模型：OR=4.321，95%CI=1.825-10.228，P=0.001；异质性模型：OR=1.806，95% CI= 1.197-2.723，P=0.005；显性模型：OR=2.129，95%CI=1.325-3.420，P=0.002；隐性模型：OR=3.312，95%CI=1.706-6.430，P=0.000)，见图1。为了探讨纳入研究的异质性，进行了亚组分析。亚组分析结果显示仅在欧洲人群中发现Sp1多态性增加了骨折的风险(等位基因模型：OR=1.283，95%CI=1.173-1.405；同质性模型：OR=1.783，95%CI=1.380-2.304；异质性模型：OR=1.228，95%CI=1.099-1.372；显性模型：OR=1.283， 95%CI=1.174-1.402；隐性模型：OR=1.732，95%CI=1.345-2.228)，而在欧洲人和美洲人群中发现Sp1多态性与骨密度降低有密切关系(①欧洲：等位基因模型：OR=2.010，95%CI=1.206-3.351；同质性模型：OR=4.343，95%CI=1.537-12.276；异质性模型：OR=1.820，95%CI=1.156-2.866；显性模型：OR=2.192， 95%CI=1.237-3.882；隐性模型：OR=3.309，95% CI=1.477-7.414。②美洲：等位基因模型：OR=4.357， 95%CI=2.565-7.400；同质性模型：OR=24.324，95%CI=1.309-451.933；异质性模型：OR=6.078， 95%CI=3.235-11.419；显性模型：OR=6.584，95% CI=3.518-12.322；隐性模型：OR=11.576，95%CI= 0.623-212.194)，见图2。

2.3 敏感性分析为了评估合并结果的稳定性，进一步做了敏感性分析。通过依次剔除某一研究，计算合并其他效应量，结果显示两组Meta分析的结果比较稳定(图3)。 2.4 发表偏倚通过漏斗图，Begg检验和Egger检验来评估纳入文章的潜在发表偏倚。漏斗图形状未发现明显的不对称，而且统计学数据也未发现明显的发表偏倚(Begg检验：骨折：P=0.074；骨密度：P=0.298；Egger检验：骨折：P=0.086；骨密度：P=0.620，见图4)。

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引言

材料方法

1.1 检索策略两名作者独立通过MEDLINE，PubMed和EMBASE数据库检索自建库以来至2014年10月有关COL1A1 Sp1基因多态性与骨密度和骨折风险相关性的文章。以“collagen”、“COL1A1”、“Sp1”、“polymorphism”、“genetics”、“fracture”、“BMD”、“osteoporosis”为关键词来进行检索。并且通过检索纳入文献的参考文献及综述文章来获取相关研究文章。

1.2 纳入及排除标准

纳入标准：①仅纳入病例-对照研究。②必须有完整的原始数据。③患者不能患有其他导致骨骼异常的疾病，如糖尿病、类风湿等。④可以获取病例组和对照组的国家、年龄等。⑤提供充分的数据来计算OR值及95%CI。⑥对文献发表的时间及语种不限。

排除标准：①不是关于Sp1多态性与骨密度和骨折关系的研究。②不包含Sp1基因型频率或基因频率数据的文章。③排除个案报道、队列研究、综述等。④重复发表的文章。⑤对照组不符合Hardy-Weinberg(H-w)遗传平衡定律的文章。

1.3 数据提取由2名作者根据纳入和排除标准独立评价检索到的文献并且提取数据。若出现争议，则2名作者或3名作者共同商议解决。采取统一的资料提取表进行提取，主要包括：第一作者姓名、发表年限、国家所在的地区、病例组和对照组Sp1基因型频率。

1.4 统计学分析通过合并OR和95%CI评估Sp1多态性与骨密度和骨折的关系。根据z检验评价合并OR值。通过Pearson卡方检验来对对照组进行Hardy-Weinberg平衡检验，P < 0.05具有统计学意义。根据同质性模型(ss vs. SS)、异质性模型(Ss vs. SS)、显性模型[(Ss+ss) vs. SS]、隐性模型[ss vs. (SS+Ss)]和等位基因模型(s vs.S)评估风险。纳入研究的异质性根据Cochrane Q检验和I²来评估^[5，34]。I²值25%，50%，75%通常被认为是低、中、高异质性^[22]。当研究间异质性较大时，采用随机效应模型来合并OR 值^[39]，否则用固定效应模型^[11]。同时，根据地区(亚洲、美洲、欧洲)进行亚组分析来探讨异质性来源。最后通过依次剔除某一研究计算其他研究的合并效应量来判断研究结果的稳定性，并且根据漏斗图、Begg检验和Egger检验来评估潜在的发表偏倚^[4，14]。数据统计软件为STATA 12.0。

讨论

骨质疏松是常见的代谢性疾病，以骨密度减少，骨结构破坏为特征。其常导致骨折，目前其发病率和引发的死亡率不断增高，据统计全世界有2亿人患有骨质疏松^[9-10]。除此之外，它还给社会带来的巨大的经济压力^[53]。因此，在过去的几十年里，见证了骨质疏松基因学研究的巨大进步。在这些基因中，COL1A1基因是导致骨质疏松和骨折的重要的易感基因，并且其在多种疾病中都在发挥着作用^[15-16^，²¹^，^62]。而在COL1A1基因多态性中，Sp1多态性备受关注。 Sp1多态性即COL1A1基因中第1内含子中Sp1转录因子结合部位G→T的突变。其突变已经被证实可以影响DNA和蛋白之间的结合，胶原转录及胶原mRNA和蛋白形成，从而导致Ⅰ型胶原a1链增加^[37]。而Ⅰ型胶原a1链正常比例增加可以破坏骨质结构从而导致骨密度降低并且发生骨质疏松性骨折。据多项研究报道，Sp1多态性与骨密度和骨折存在密切联系^[19^，³⁷^，⁴⁷^，^55]，而且在其他方面比如股骨颈形态、骨矿物质减少、骨长度降低等均有关系^[37^，^51]。然而也有一些研究者在他们的实验中并没有发现明显的联系^[1^，^8]。因此，Sp1多态性与骨折及骨密度降低是否存在联系一直是争论的焦点。同时，大量的研究又不能得出确切的结论^[28^，^38]。因此，本文通过Meta分析这个工具来对多项研究结果进行合并，从而获取更加确切的结论。虽然之前有Meta分析对此项研究进行过分析，但是由于其纳入文献研究类型不统一并没有对地理因素做出分析且文章数量有限，因此为了控制研究质量，获得更加可靠的结论，本文仅纳入了病例对照研究，进一步分析Sp1多态性与不同地区(欧洲、亚洲、美洲)相关性的影响。在研究中结果显示，对骨折及骨密度降低的研究结果与之前大部分的报道相似^{[6，31，33，38]}。相比其他Meta分析，本文得出的结果具有更明显的统计学意义^[28，38]。除此之外，作者发现Sp1多态性存在不同地区人群的差异性^[3]。仅在欧洲人群中发现Sp1多态性与骨折有密切关系，在欧洲、美洲人群中发现与骨密度降低有关系。然而必须承认在本篇Meta分析中依然存在某些缺陷：①所纳入的研究的样本量并不足够大。②本文结果是基于未校正的结果，应该通过校正其他因素包括年龄、体质量指数、身高、体质量等来获取更精确的结果。③在根据地理区域进行的亚组分中，本文结果说明在某些地区人群中COL1A1 Sp1多态性与骨折、骨密度降低存在明显的联系，但是确是有差异的。这种差异的原因可能是因为本文所纳入的研究数量不够并且纳入不同地区的人群数量不同所致(大部分为欧洲人群)。这就导致了可能出现假阴性的结果。例如在某些研究报道的亚洲人群中并没有发现此种多态性^[3^，²⁰^，^32]。而且，本文所纳入的原始研究中缺少某些地区的人群，如非洲等。因此，针对其他地区人群的研究依然有待于开展。④虽然纳入标准中不限定语言标准，但是本文所纳入的文章都以英文为主，某些高质量的非英语文章并没有纳入。因此，并不能够确定Sp1多态性是否在所有地区人群中都存在与骨折及骨密度降低的相关性。综上所述，本Meta分析结果显示COL1A1 Sp1多态性与骨折易感性和骨密度降低存在密切联系，但是存在地区性差异。因此，不能仅通过单方面的研究来预测其风险，而需综合考虑多种因素如环境、种族、不同基因等对骨折及骨密度的影响，并且未来通过更大规模的、设计更完善的研究来再次进行评价。中国组织工程研究杂志出版内容重点：组织构建；骨细胞；软骨细胞；细胞培养；成纤维细胞；血管内皮细胞；骨质疏松；组织工程