Musculoskeletal Research Group, Institute of Cellular Medicine, Newcastle University, Newcastle, UK.
BMC Med Genet. 2012 Mar 2;13:12. doi: 10.1186/1471-2350-13-12.
A genome-wide association scan with subsequent replication study that involved over 67,000 individuals of European ancestry has produced evidence of association of single nucleotide polymorphism rs2277831 to primary osteoarthritis (OA) with a P-value of 2.9 × 10(-5). rs2277831, an A/G transition, is located in an intron of MICAL3. This gene is located on chromosome 22q11.21 and the association signal encompasses two additional genes, BCL2L13 and BID. It is becoming increasingly apparent that many common complex traits are mediated by cis-acting regulatory polymorphisms that influence, in a tissue-specific manner, gene expression or transcript stability.
We used total and allelic expression analysis to assess whether the OA association to rs2277831 is mediated by an influence on MICAL3, BCL2L13 or BID expression. Using RNA extracted from joint tissues of 60 patients who had undergone elective joint replacement surgery, we assessed whether rs2277831 correlated with allelic expression of either of the three genes by: 1) measuring the expression of each gene by quantitative PCR and then stratifying the data by genotype at rs2277831 and 2) accurately discriminating and quantifying the mRNA synthesised from the alleles of OA patients using allelic-quantitative PCR.
We found no evidence for a correlation between gene expression and genotype at rs2277831, with P-values of 0.09 for BCL2L13, 0.07 for BID and 0.33 for MICAL3. In the allelic expression analysis we observed several examples of significant (p < 0.05) allelic imbalances, with an allelic expression ratio of 2.82 observed in BCL2L13 (P = 0.004), 2.09 at BID (P = 0.001) and the most extreme case being at MICAL3, with an allelic expression ratio of 5.47 (P = 0.001). However, there was no correlation observed between the pattern of allelic expression and the genotype at rs2277831.
In the tissues that we have studied, our data do not support our hypothesis that the association between rs2277831 and OA is due to the effect this SNP has on MICAL3, BCL2L13 or BID gene expression. Instead, our data point towards other functional effects accounting for the OA associated signal.
一项全基因组关联扫描和随后的复制研究涉及超过 67000 名欧洲血统的个体，产生了单核苷酸多态性 rs2277831 与原发性骨关节炎（OA）关联的证据，P 值为 2.9×10(-5)。rs2277831 是一种 A/G 转换，位于 MICAL3 的内含子中。该基因位于 22q11.21 染色体上，关联信号包含另外两个基因 BCL2L13 和 BID。越来越明显的是，许多常见的复杂特征是由顺式作用调节多态性介导的，这些多态性以组织特异性的方式影响基因表达或转录稳定性。
我们使用总表达和等位基因表达分析来评估 rs2277831 与 OA 的关联是否是由对 MICAL3、BCL2L13 或 BID 表达的影响介导的。我们使用从 60 名接受择期关节置换手术的患者的关节组织中提取的 RNA，通过以下两种方法评估 rs2277831 是否与三个基因中的任意一个的等位基因表达相关：1）通过定量 PCR 测量每个基因的表达，然后根据 rs2277831 的基因型对数据进行分层；2）使用等位基因定量 PCR 准确区分和定量 OA 患者等位基因合成的 mRNA。
我们没有发现基因表达与 rs2277831 基因型之间存在相关性的证据，BCL2L13 的 P 值为 0.09，BID 的 P 值为 0.07，MICAL3 的 P 值为 0.33。在等位基因表达分析中，我们观察到了几个具有统计学意义（p<0.05）的等位基因失衡的例子，在 BCL2L13 中观察到 2.82 的等位基因表达比（P=0.004），在 BID 中观察到 2.09 的等位基因表达比（P=0.001），最极端的情况是在 MICAL3 中，观察到 5.47 的等位基因表达比（P=0.001）。然而，我们没有观察到等位基因表达模式与 rs2277831 基因型之间存在相关性。
在我们研究的组织中，我们的数据不支持我们的假设，即 rs2277831 与 OA 之间的关联是由于该 SNP 对 MICAL3、BCL2L13 或 BID 基因表达的影响。相反，我们的数据表明，其他功能效应解释了与 OA 相关的信号。
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