Lumbar disc degeneration is linked to a carbohydrate sulfotransferase 3 variant
Lumbar disc degeneration is linked to a carbohydrate sulfotransferase 3 variant
复制标题
DOI：
10.1172/jci69277
复制
发表时间：
2013-11-01
影响因子：
15.9
通讯作者：
Chan, Danny
中科院分区：
文献类型：
--
作者：
Song, You-Qiang;Karasugi, Tatsuki;Chan, Danny
腰椎间盘退变（LDD）与遗传和环境因素有关，影响着世界各地的许多人。LDD的标志是椎间盘髓核中蛋白聚糖和水含量的损失。虽然已经报道了一些遗传决定因素，但LDD的病因在很大程度上是未知的。在这里，我们报告了对32,642名受试者（包括4,043名LDD病例和28,599名对照受试者）进行的连锁和关联研究的结果。我们确定了碳水化合物磺基转移酶3（CHST 3），一种催化蛋白聚糖硫酸化的酶，作为LDD的易感基因。最强的全基因组连锁峰包括来自中国南方基于家族的数据集的CHST 3，而在使用多种族人群队列的荟萃分析中，在该基因的rs 4148941处观察到全基因组关联。rs 4148941位于潜在的microRNA-513 a-5 p（miR-513 a-5 p）结合位点内。与来自其他等位基因的转录物相比，miR-513 a-5 p与来自rs 4148941的易感性等位基因（A等位基因）转录的mRNA之间的相互作用在体外增强。此外，在携带rs 4148941的A等位基因的人类受试者的椎间盘细胞中，CHST 3 mRNA的表达显著降低。总之，我们的数据为LDD的病因学提供了新的见解，暗示了遗传风险因素和miRNA之间的相互作用。
Lumbar disc degeneration (LDD) is associated with both genetic and environmental factors and affects many people worldwide. A hallmark of LDD is loss of proteoglycan and water content in the nucleus pulposus of intervertebral discs. While some genetic determinants have been reported, the etiology of LDD is largely unknown. Here we report the findings from linkage and association studies on a total of 32,642 subjects consisting of 4,043 LDD cases and 28,599 control subjects. We identified carbohydrate sulfotran sferase 3 (CHST3), an enzyme that catalyzes proteoglycan sulfation, as a susceptibility gene for LDD. The strongest genome-wide linkage peak encompassed CHST3 from a Southern Chinese family-based data set, while a genome-wide association was observed at rs4148941 in the gene in a meta-analysis using multiethnic population cohorts. rs4148941 lies within a potential microRNA-513a-5p (miR-513a-5p) binding site. Interaction between miR-513a-5p and mRNA transcribed from the susceptibility allele (A allele) of rs4148941 was enhanced in vitro compared with transcripts from other alleles. Additionally, expression of CHST3 mRNA was significantly reduced in the intervertebral disc cells of human subjects carrying the A allele of rs4148941. Together, our data provide new insights into the etiology of LDD, implicating an interplay between genetic risk factors and miRNA.