Comparative Orthopaedic Research Laboratory, School of Veterinary Medicine, University of Wisconsin-Madison, 2015 Linden Drive, Madison, Wisconsin, USA.
Department of Animal Sciences, College of Agricultural and Life Sciences, University of Wisconsin-Madison, 1675 Observatory Drive, Madison, Wisconsin, USA.
BMC Genet. 2018 Jun 26;19(1):39. doi: 10.1186/s12863-018-0626-7.
Anterior cruciate ligament rupture (ACLR) is a debilitating and potentially life-changing condition in humans, as there is a high prevalence of early-onset osteoarthritis after injury. Identification of high-risk individuals before they become patients is important, as post-treatment lifetime burden of ACLR in the USA ranges from $7.6 to $17.7 billion annually. ACLR is a complex disease with multiple risk factors including genetic predisposition. Naturally occurring ACLR in the dog is an excellent model for human ACLR, as risk factors and disease characteristics in humans and dogs are similar. In a univariate genome-wide association study (GWAS) of 237 Labrador Retrievers, we identified 99 ACLR candidate loci. It is likely that additional variants remain to be identified. Joint analysis of multiple correlated phenotypes is an underutilized technique that increases statistical power, even when only one phenotype is associated with the trait. Proximal tibial morphology has been shown to affect ACLR risk in both humans and dogs. In the present study, tibial plateau angle (TPA) and relative tibial tuberosity width (rTTW) were measured on bilateral radiographs from purebred Labrador Retrievers that were recruited to our initial GWAS. We performed a multivariate genome wide association analysis of ACLR status, TPA, and rTTW.
Our analysis identified 3 loci with moderate evidence of association that were not previously associated with ACLR. A locus on Chr1 associated with both ACLR and rTTW is located within ROR2, a gene important for cartilage and bone development. A locus on Chr4 associated with both ACLR and TPA resides within DOCK2, a gene that has been shown to promote immune cell migration and invasion in synovitis, an important predictor of ACLR. A third locus on Chr23 associated with only ACLR is located near a long non-coding RNA (lncRNA). LncRNA's are important for regulation of gene transcription and translation.
These results did not overlap with our previous GWAS, which is reflective of the different methods used, and supports the need for further work. The results of the present study are highly relevant to ACLR pathogenesis, and identify potential drug targets for medical treatment.
前交叉韧带撕裂（ACL）是人衰弱且潜在改变生活的疾病，因为受伤后早期发生骨关节炎的发病率很高。在他们成为患者之前识别高风险个体很重要，因为在美国，ACL 治疗后的终生负担每年在 76 亿至 177 亿美元之间。ACL 是一种复杂的疾病，有多种风险因素，包括遗传易感性。狗的自然 ACL 是人类 ACL 的理想模型，因为人类和狗的风险因素和疾病特征相似。在对 237 只拉布拉多猎犬的单变量全基因组关联研究（GWAS）中，我们确定了 99 个 ACL 候选基因座。很可能还有其他变体有待发现。多个相关表型的联合分析是一种利用不足的技术，即使只有一个表型与性状相关，也能增加统计效力。胫骨近端形态已被证明会影响人和狗的 ACL 风险。在本研究中，我们测量了从我们最初的 GWAS 招募的纯种拉布拉多猎犬双侧 X 光片的胫骨平台角（TPA）和相对胫骨结节宽度（rTTW）。我们对 ACLR 状态、TPA 和 rTTW 进行了多变量全基因组关联分析。
我们的分析确定了 3 个具有中度关联证据的位点，这些位点以前与 ACL 无关。与 ACLR 和 rTTW 都相关的 Chr1 上的一个位点位于 ROR2 内，该基因对软骨和骨骼发育很重要。与 ACLR 和 TPA 都相关的 Chr4 上的一个位点位于 DOCK2 内，该基因已被证明可促进滑膜中的免疫细胞迁移和浸润，而滑膜是 ACLR 的重要预测因素。仅与 ACLR 相关的 Chr23 上的第三个位点位于长非编码 RNA（lncRNA）附近。lncRNA 对基因转录和翻译的调控很重要。
这些结果与我们之前的 GWAS 没有重叠，这反映了所使用的不同方法，并支持进一步的工作。本研究的结果与 ACLR 发病机制高度相关，并确定了潜在的药物治疗靶点。
