Cis- and trans-acting gene regulation is associated with osteoarthritis
Cis- and trans-acting gene regulation is associated with osteoarthritis
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DOI：
10.1086/503849
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发表时间：
2006-05-01
影响因子：
9.8
通讯作者：
Müller, B
中科院分区：
文献类型：
--
作者：
Mahr, S;Burmester, GR;Müller, B
骨关节炎（OA）是一种复杂的骨骼疾病，与衰老有关。环境因素和遗传因素共同参与了其发病机制。我们着手鉴定与OA相关的新基因，集中于允许差异表达的调控多态性。我们的策略，以确定差异表达的基因，包括初步转录组分析的外周血单核细胞的6例OA患者和6个年龄匹配的健康对照。这些被筛选的等位基因表达不平衡和潜在的调控单核苷酸多态性（SNP）的5'区域的基因。为了建立疾病关联，在较大的群组中测试与差异表达相关的不同启动子SNP分布。我们的方法产生了26个候选基因在患者和对照之间差异表达。而BLP 2和CIAS 1似乎是反式调节的，因为不存在等位基因表达失衡表明，等位基因失衡的存在证实了RHOB和TXNDC 3的顺式调节机制。有趣的是，开/关开关提示TXNDC 3的额外反式调节。此外，我们证明了RHOB和TXNDC 3在5'SNP和暗示调节功能的疾病之间的统计学显著关联。研究各自的基因功能不仅会揭示疾病的关联，但也将增加对OA的致病过程的理解，并可能指出新的治疗方法。
Osteoarthritis (OA) is a complex disease of the skeleton and is associated with aging. Both environmental and genetic factors contribute to its pathogenesis. We set out to identify novel genes associated with OA, concentrating on regulatory polymorphisms allowing for differential expression. Our strategy to identify differentially expressed genes included an initial transcriptome analysis of the peripheral blood mononuclear cells of six patients with OA and six age-matched healthy controls. These were screened for allelic expression imbalances and potentially regulatory single-nucleotide polymorphisms (SNPs) in the 5' regions of the genes. To establish disease association, disparate promoter SNP distributions correlating with the differential expression were tested on larger cohorts. Our approach yielded 26 candidate genes differentially expressed between patients and controls. Whereas BLP2 and CIAS1 seem to be trans-regulated, as the absence of allelic expression imbalances suggests, the presence of allelic imbalances confirms cis-regulatory mechanisms for RHOB and TXNDC3. Interestingly, on/off-switching suggests additional trans-regulation for TXNDC3. Moreover, we demonstrate for RHOB and TXNDC3 statistically significant associations between 5' SNPs and the disease that hint at regulatory functions. Investigating the respective genes functionally will not only shed light on the disease association but will also add to the understanding of the pathogenic processes involved in OA and may point out novel therapeutic approaches.