Melatonin receptor 1B (MTNR1B) gene polymorphism is associated with the occurrence of adolescent idiopathic scoliosis
Melatonin receptor 1B (MTNR1B) gene polymorphism is associated with the occurrence of adolescent idiopathic scoliosis
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DOI：
10.1097/brs.0b013e3180b9f0ff
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发表时间：
2007-07-15
期刊：
影响因子：
3
通讯作者：
Cheng, Jack C. Y.
中科院分区：
文献类型：
--
作者：
Qiu, Xu Sheng;Tang, Nelson L. S.;Cheng, Jack C. Y.
研究设计。目的利用国际HapMap项目衍生的一组标签单核苷酸多态(TagSNPs)对褪黑素受体1B基因多态性进行遗传关联研究。目的：探讨褪黑素受体1B(MTNR1B)基因多态性是否与青少年特发性脊柱侧凸(AIS)的易感性和(或)疾病严重程度相关。连锁研究表明AIS的遗传易感性。此外，有证据表明，AIS可能与褪黑激素缺乏和褪黑素信号通路功能障碍有关。MTNR1B基因位于与AIS连锁的染色体区域之一，是AIS的潜在候选基因。本研究采用两阶段病例对照分析：1)初始筛查(472例和304例对照)和2)单独复制试验(342例和347例对照)以确认筛查结果。在第一个筛选阶段，选择了5个Tag SNPs来覆盖MTNR1B基因的大部分遗传变异。在第二阶段，在单独的复制样本集中研究在筛选阶段显示关联的SNP以确认关联。用聚合酶链式反应-限制性片段长度多态性方法进行基因分型。第一阶段显示rs4753426与AIS之间可能存在关联，这在复制样本集中得到了证实。经Meta分析，病例组C等位基因位于启动子的频率显著高于对照组(Meta分析后P=0.006)。携带CC基因的受试者患AIS的优势比为1.29。启动子区域的另一个SNP rs741837与rs4753426存在中度连锁不平衡，与AIS也有一定的关联。MTNR1B基因启动子多态性与AIS相关，但与AIS患者的弯曲度无关。提示MTNR1B是AIS的易感基因。
Study Design. A genetic association study to comprehensively investigate variations of melatonin receptor 1B gene polymorphism by a set of tagging single nucleotide polymorphisms (tagSNPs) derived from the International Hapmap project.Objectives. To determine whether melatonin receptor 1B (MTNR1B) gene polymorphisms are associated with the predisposition and/ or disease severity of adolescent idiopathic scoliosis (AIS).Summary of Background Data. Linkage studies suggested a genetic predisposition for AIS. In addition, evidence showed that AIS might be related to melatonin deficiency and dysfunction of melatonin signaling pathway. Locating in one of the chromosomal regions linked to AIS, MTNR1B gene is a potential candidate gene for AIS.Methods. This study was carried out in 2-stage case-control analysis: 1) initial screening (472 cases and 304 controls) and 2) separate replication test (342 cases and 347 controls) to confirm results in the screening. In the first screening stage, 5 tagSNPs were selected to cover most of the genetic variation in the MTNR1B gene. In the second stage, SNPs showing association in the screening stage were studied in a separate replication sample set to confirm the association. Genotyping was performed by PCR-RFLP.Results. The first stage showed a putative association between rs4753426 and AIS, which was confirmed in the replication sample set. By meta-analysis, the frequency of C allele of this SNP locating in the promoter was significantly higher in the cases than controls (P = 0.006 after meta-analysis). Subjects with the CC genotype had an odds ratio of 1.29 for AIS. Another SNP rs741837 in promoter region, being moderate linkage disequilibrium with rs4753426, was also marginally associated with AIS.Conclusion. Polymorphisms of the promoter of MTNR1B gene were associated with AIS, but not with the curve severity in AIS patients. This suggested that MTNR1B was an AIS predisposition gene.