Departments of Orthopaedics and Rehabilitation (V.S., H.J.D., D.F., J.G., and J.S.R.), Pharmacology (K.E.V.), and Public Health Sciences (A.B.), Penn State Hershey College of Medicine, 500 University Drive, Hershey, PA 17033. E-mail address for J.S. Reid:
J Bone Joint Surg Am. 2014 Aug 6;96(15):1242-1248. doi: 10.2106/JBJS.M.00453.
UpdateThis article was updated on September 10, 2014, because of a previous error. On page 1242, in the byline, and on page 1247, in the author addresses, the academic degree for Henry J. Donahue had previously read "MD." The degree now reads "PhD."
We propose that fracture-healing potential is affected by the patient's genome. This genotype is then phenotypically expressed by the patient at the time of injury. We examined the hypothesis that patients who exhibit delayed or impaired fracture-healing may have one or more single nucleotide polymorphisms (SNPs) within a series of genes related to bone formation.
We performed a population-based, case-controlled study of delayed fracture-healing. Sixty-two adults with a long-bone fracture were identified from a surgical database. Thirty-three patients had an atrophic nonunion (delayed healing), and twenty-nine displayed normal fracture-healing. These patients underwent buccal mucosal cell harvesting. SNP genotyping was performed with use of bead array technology. One hundred and forty-four SNPs (selected from HapMap) within thirty genes associated with fracture-healing were investigated. Three SNPs did not segregate in the population and were excluded from the analysis. Eight of the remaining SNPs failed the test for Hardy-Weinberg equilibrium (p value smaller than the Bonferroni-corrected level of 0.05/141 = 0.000355) and were excluded.
Five SNPs on four genes were found to have a p value of <0.05 in the additive genetic model. Of these five significant SNPs, three had an odds ratio (OR) of >1, indicating that the presence of the allele increased the risk of nonunion. The rs2853550 SNP, which had the largest effect (OR = 5.9, p = 0.034), was on the IL1B gene, which codes for interleukin 1 beta. The rs2297514 SNP (OR = 3.98, p = 0.015) and the rs2248814 SNP (OR = 2.27, p = 0.038) were on the NOS2 gene coding for nitric oxide synthase. The remaining two SNPs had an OR of <1, indicating that the presence of the allele may be protective against nonunion. The rs3819089 SNP (OR = 0.26, p = 0.026) was on the MMP13 gene for matrix metallopeptidase 13, and the rs270393 SNP (OR = 0.30, p = 0.015) was on the BMP6 gene for bone morphogenetic protein 6.
Variations in the IL1B and NOS2 genes may contribute to delayed fracture-healing and warrant further investigation.
Impaired fracture union may have genetic contributions.
本文于 2014 年 9 月 10 日更新，原因是之前的错误。第 1242 页，在署名中，以及第 1247 页，在作者地址中，Henry J. Donahue 的学术学位之前显示为“MD”。现在的学位是“PhD”。
我们提出骨折愈合潜力受患者基因组的影响。该基因型随后在患者受伤时表现为表型。我们检验了这样一种假设，即表现出延迟或受损骨折愈合的患者可能在与骨形成相关的一系列基因中具有一个或多个单核苷酸多态性（SNP）。
我们进行了一项基于人群的延迟骨折愈合的病例对照研究。从手术数据库中确定了 62 名长骨骨折患者。33 名患者发生萎缩性骨不连（愈合延迟），29 名患者显示正常骨折愈合。这些患者接受颊黏膜细胞采集。使用珠阵列技术进行 SNP 基因分型。对 30 个与骨折愈合相关的基因中的 144 个 SNP（从 HapMap 中选择）进行了研究。三个 SNP 在人群中不分离，因此被排除在分析之外。其余 8 个 SNP 不符合 Hardy-Weinberg 平衡检验（p 值小于 Bonferroni 校正的 0.05/141=0.000355），因此被排除在外。
在加性遗传模型中，有五个 SNP 发现具有 <0.05 的 p 值。在这五个有意义的 SNP 中，有三个 SNP 的比值比（OR）>1，表明等位基因的存在增加了骨不连的风险。具有最大影响（OR=5.9，p=0.034）的 rs2853550 SNP 位于编码白细胞介素 1 β的 IL1B 基因上。rs2297514 SNP（OR=3.98，p=0.015）和 rs2248814 SNP（OR=2.27，p=0.038）位于编码一氧化氮合酶的 NOS2 基因上。其余两个 SNP 的 OR<1，表明等位基因的存在可能对骨不连具有保护作用。rs3819089 SNP（OR=0.26，p=0.026）位于编码基质金属蛋白酶 13 的 MMP13 基因上，rs270393 SNP（OR=0.30，p=0.015）位于编码骨形态发生蛋白 6 的 BMP6 基因上。
IL1B 和 NOS2 基因的变异可能导致骨折愈合延迟，需要进一步研究。
骨折愈合不良可能有遗传因素。
