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中华老年骨科与康复电子杂志 ›› 2019, Vol. 05 ›› Issue (02) : 68 -74. doi: 10.3877/cma.j.issn.2096-0263.2019.02.002

所属专题: 文献

基础研究

中国北方汉族人群中MMPs基因多态性与非创伤性股骨头坏死遗传易感性的关联分析
安非梦1, 曹玉举2, 王建忠3,()   
  1. 1. 010050 呼和浩特,内蒙古医科大学;010030 呼和浩特,内蒙古医科大学第二附属医院创伤一科
    2. 450000 郑州,郑州中医骨伤病医院科研科
    3. 010030 呼和浩特,内蒙古医科大学第二附属医院创伤一科
  • 收稿日期:2018-12-10 出版日期:2019-04-05
  • 通信作者: 王建忠
  • 基金资助:
    国家自然科学基金支持(81160228,81260284,81660378)

Association between genetic polymorphisms of MMPs and the risk of non-traumaticosteonecrosis of the femoral head in the Han population of northern China

Feimeng An1, Yuju Cao2, Jianzhong Wang3,()   

  1. 1. Inner Mongolia Medical University, Hohhot 010050, China; Department of Trauma Orthopedics, the Second Affiliated Hospital of Inner Mongolia Medical University, Hohhot 010030, China
    2. Department of Scientific Research, Zhengzhou TCM Traumatology Hospital, Zhengzhou 450000, China
    3. Department of Trauma Orthopedics, the Second Affiliated Hospital of Inner Mongolia Medical University, Hohhot 010030, China
  • Received:2018-12-10 Published:2019-04-05
  • Corresponding author: Jianzhong Wang
引用本文:

安非梦, 曹玉举, 王建忠. 中国北方汉族人群中MMPs基因多态性与非创伤性股骨头坏死遗传易感性的关联分析[J/OL]. 中华老年骨科与康复电子杂志, 2019, 05(02): 68-74.

Feimeng An, Yuju Cao, Jianzhong Wang. Association between genetic polymorphisms of MMPs and the risk of non-traumaticosteonecrosis of the femoral head in the Han population of northern China[J/OL]. Chinese Journal of Geriatric Orthopaedics and Rehabilitation(Electronic Edition), 2019, 05(02): 68-74.

目的

筛查MMPs系统中可能与非创伤性骨坏死发病相关的单核苷酸多态性(SNP)位点,为骨坏死的早期诊断和预防提供遗传学依据。

方法

在这项病例-对照研究中,设计非创伤性骨坏死病例组585例,对照组507例,分别提取外周血基因组DNA,应用MassARRAY分型技术对所选MMPs系统中9个基因上的42个SNP位点进行分型,并用卡方检验和SNPStats软件对SNP分型结果进行统计分析,评估所选位点与骨坏死发病的关联性。

结果

在中国北方汉族人群中,MMP8基因上的rs11225394、MMP3基因上rs522616可能与增加骨坏死的发病风险相关,MMP3基因上的rs650108、MMP9基因上的rs2274755可能与降低骨坏死的发病风险相关。另外,我们在单倍体分析中还发现MMP9基因中rs3918249,rs2274755,rs3918254三个位点的"TGC"、"CTC"单体型较野生单体型携带者降低骨坏死发病风险更显著。

结论

MMP3MMP8MMP9基因多态性与非创伤性骨坏死发病的遗传易感性相关。

Objective

The aim of this study was to identify the associations between genes selected from MMPs/TIMPs system and the risk of NONFH, which can provide the genetic basis for the early diagnosis and prevention.

Methods

In the case-control study, we recruited 585 patients who were diagnosed with NONFH and 507 controls. Peripheral blood DNA was extracted, respectively. We genotyped 42 SNPs chosen from 9 genes of MMPs by Sequenom Mass ARRAY. The chi-square test and SNPStats analysis software were used to make statistical analysis and evaluate the association between SNPs and NONFH.

Results

TheMMP8 rs11225394 SNP, the MMP3 rs522616 SNP were associated with an increased risk of NONFH. The MMP3 rs650108 SNP, the MMP9 rs2274755 SNP were associated with a decreased risk of NONFH. In addition, the haplotype "TGC" and the haplotype "CTC" of MMP9 were found to be more likely to decrease the risk of the NONFH than the wild haplotype.

Conclusion

The genetic polymorphisms of MMP3, MMP8, MMP9 are related to the risk of non-traumaticosteonecrosis of femoral head in the Han population of northern China.

表1 病例组与对照组样本基本信息
表2 候选基因位点的基本信息
SNP 基因 位置 等位基因 (A/B) MAF HWE Pa OR 95% CI Pb
病例组对照组 下限 上限
rs14983 MMP7 11q22.2 A/G 0.261 0.264 0.820 0.98 0.81 1.19 0.848
rs17352054 MMP7 11q22.2 C/A 0.121 0.122 0.679 0.99 0.77 1.28 0.948
rs10502001 MMP7 11q22.2 T/C 0.262 0.264 0.820 0.99 0.82 1.20 0.939
rs11568818 MMP7 11q22.2 C/T 0.096 0.090 0.584 1.07 0.80 1.44 0.631
rs17098318 MMP7 11q22.2 A/G 0.094 0.087 0.569 1.09 0.81 1.47 0.557
rs3740938 MMP8 11q22.2 A/G 0.243 0.235 0.621 1.04 0.86 1.27 0.680
rs2012390 MMP8 11q22.2 G/A 0.276 0.276 0.912 1.00 0.83 1.20 0.981
rs1940475 MMP8 11q22.2 T/C 0.387 0.369 0.775 1.08 0.91 1.29 0.378
rs11225394 MMP8 11q22.2 T/C 0.112 0.086 0.563 1.34 1.00 1.79 0.047*
rs11225395 MMP8 11q22.2 A/G 0.379 0.360 0.773 1.08 0.91 1.29 0.367
rs5854 MMP1 11q22.2 A/G 0.095 0.090 0.165 1.06 0.80 1.42 0.680
rs2071230 MMP1 11q22.2 G/A 0.186 0.190 0.042# 0.97 0.79 1.21 0.811
rs2239008 MMP1 11q22.2 G/A 0.491 0.480 0.929 1.05 0.88 1.24 0.602
rs470215 MMP1 11q22.2 C/T 0.095 0.090 0.165 1.06 0.80 1.42 0.680
rs2071232 MMP1 11q22.2 T/C 0.483 0.470 0.594 1.05 0.89 1.24 0.560
rs639752 MMP3 11q22.2 C/A 0.318 0.345 0.116 0.88 0.74 1.06 0.177
rs650108 MMP3 11q22.2 G/A 0.391 0.435 0.147 0.84 0.71 0.99 0.040*
rs520540 MMP3 11q22.2 A/G 0.318 0.345 0.116 0.88 0.74 1.06 0.177
rs646910 MMP3 11q22.2 A/T 0.072 0.086 1.000 0.82 0.60 1.13 0.224
rs602128 MMP3 11q22.2 A/G 0.320 0.344 0.235 0.90 0.75 1.07 0.234
rs679620 MMP3 11q22.2 T/C 0.318 0.347 0.202 0.88 0.74 1.05 0.156
rs678815 MMP3 11q22.2 G/C 0.319 0.347 0.141 0.88 0.74 1.05 0.165
rs522616 MMP3 11q22.2 C/T 0.396 0.354 0.923 1.20 1.01 1.42 0.044*
rs1053605 MMP2 16q12.2 T/C 0.112 0.129 0.843 0.85 0.66 1.10 0.217
rs243849 MMP2 16q12.2 T/C 0.191 0.167 1.000 1.18 0.95 1.47 0.146
rs243847 MMP2 16q12.2 C/T 0.415 0.405 0.117 1.04 0.88 1.24 0.634
rs243832 MMP2 16q12.2 C/G 0.362 0.382 0.347 0.92 0.77 1.10 0.353
rs7201 MMP2 16q12.2 C/A 0.245 0.255 0.349 0.95 0.78 1.15 0.603
rs2277698 TIMP2 17q25.3 T/C 0.202 0.203 1.000 0.99 0.81 1.22 0.942
rs2009196 TIMP2 17q25.3 C/G 0.394 0.384 0.452 1.04 0.88 1.24 0.646
rs7342880 TIMP2 17q25.3 A/C 0.166 0.148 0.725 1.14 0.91 1.44 0.253
rs11654470 TIMP2 17q25.3 C/T 0.228 0.238 1.000 0.95 0.78 1.16 0.601
rs2003241 TIMP2 17q25.3 C/T 0.161 0.163 0.414 0.99 0.78 1.24 0.897
rs4789936 TIMP2 17q25.3 T/C 0.250 0.281 0.913 0.85 0.71 1.04 0.111
rs3918249 MMP9 20q13.12 T/C 0.297 0.322 0.613 0.89 0.74 1.06 0.191
rs2274755 MMP9 20q13.12 T/G 0.116 0.151 0.729 0.74 0.58 0.95 0.017*
rs3918254 MMP9 20q13.12 T/C 0.203 0.187 0.664 1.10 0.89 1.36 0.372
rs9619311 SYN3 22q12.3 C/T 0.083 0.068 0.720 1.24 0.90 1.71 0.188
rs715572 TIMP3 22q12.3 A/G 0.342 0.339 0.921 1.01 0.85 1.21 0.897
rs8136803 TIMP3 22q12.3 T/G 0.041 0.049 1.000 0.82 0.55 1.24 0.351
rs9609643 TIMP3 22q12.3 A/G 0.138 0.131 0.696 1.06 0.83 1.35 0.660
rs11547635 TIMP3 22q12.3 T/C 0.344 0.349 1.000 0.98 0.82 1.17 0.819
表3 SNPs与NONFH发病风险关系的基因型模型分析
SNP 模型 基因型 对照组 病例组 调整后 AIC BIC
OR(95% CI Pa
rs11225394 共显性 C/C 405(83.2%) 456(78.1%) 1 0.073 1437.9 1462.8
    T/C 80(16.4%) 125(21.4%) 1.44(1.05-1.98)      
    T/T 2(0.4%) 3(0.5%) 1.14(0.18-7.08)      
  显性 C/C 405(83.2%) 456(78.1%) 1 0.023* 1435.9 1455.9
    T/C-T/T 82(16.8%) 128(21.9%) 1.44(1.05-1.96)      
  隐性 C/C-T/C 485(99.6%) 581(99.5%) 1 0.950 1441.1 1461
    T/T 2(0.4%) 3(0.5%) 1.07(0.17-6.61)      
  加性 --- --- --- 1.40(1.04-1.90) 0.027* 1436.3 1456.2
rs650108 共显性 A/A 153(30.3%) 216(37%) 1 0.058 1461.8 1486.8
    A/G 265(52.5%) 279(47.8%) 0.73(0.55-0.96)      
    G/G 87(17.2%) 89(15.2%) 0.74(0.51-1.07)      
  显性 A/A 153(30.3%) 216(37%) 1 0.017* 1459.8 1479.8
    A/G-G/G 352(69.7%) 368(63%) 0.73(0.56-0.95)      
  隐性 A/A-A/G 418(82.8%) 495(84.8%) 1 0.500 1465 1485
    G/G 87(17.2%) 89(15.2%) 0.89(0.64-1.24)      
  加性 --- --- --- 0.83(0.70-1.00) 0.044* 1461.5 1481.4
rs522616 共显性 T/T 212(41.9%) 224(38.3%) 1 0.052 1464.3 1489.2
    T/C 230(45.5%) 259(44.3%) 1.08(0.83-1.40)      
    C/C 64(12.7%) 102(17.4%) 1.57(1.08-2.29)      
  显性 T/T 212(41.9%) 224(38.3%) 1 0.190 1466.4 1486.4
    T/C-C/C 294(58.1%) 361(61.7%) 1.18(0.92-1.52)      
  隐性 T/T-T/C 442(87.3%) 483(82.6%) 1 0.018* 1462.6 1482.5
    C/C 64(12.7%) 102(17.4%) 1.52(1.07-2.14)      
  加性 --- --- --- 1.21(1.02-1.44) 0.033* 1463.6 1483.6
rs2274755 共显性 G/G 364(71.8%) 457(78.1%) 1 0.040* 1508.4 1523.4
    G/T 133(26.2%) 120(20.5%) 0.70(0.52-0.93)      
    T/T 10(2%) 8(1.4%) 0.65(0.25-1.68)      
  显性 G/G 364(71.8%) 457(78.1%) 1 0.011* 1506.4 1516.4
    G/T-T/T 143(28.2%) 128(21.9%) 0.70(0.52-0.92)      
  隐性 G/G-G/T 497(98%) 577(98.6%) 1 0.470 1511.6 1521.6
    T/T 10(2%) 8(1.4%) 0.70(0.27-1.83)      
  加性 --- --- --- 0.72(0.56-0.94) 0.013* 1506.5 1516.5
图2 MMP3基因SNP连锁不平衡图
表4 MMP9多态性单体型频率及其与NONFH的关联性
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