发育性髋关节发育不良(Developmental dysplasia of the hip, DDH)是严重威胁我国出生人口素质的重大出生缺陷，其病因不清。前期，我们通过全基因组扫描，发现rs726252与DDH相关联。该位点位于PAPPA2基因内，提示PAPPA2基因可能是DDH的易感基因，推测PAPPA2基因可能是间接通过IGF途径导致DDH的。我们将在前期基础上，进一步对该基因的编码区及调控区进行突变筛查，并在RNA及蛋白水平证实PAPPA2基因与DDH的相关性及其表达调控机制；通过体外实验，明确PAPPA2在软骨细胞及成纤维细胞IGF信号通路中的作用；通过动物体内实验，采用跨胎盘RNA干扰，结合胎仔外科及激光捕获显微切割技术，观察PAPPA2基因沉默后对IGF信号通路的影响及胚胎髋臼软骨、髋周软组织发育与正常的差异，从而阐明PAPPA2基因导致DDH发生的分子生物学机制。

Developmental dysplasia of the hip (DDH) is a severe birth defect threatening the population health in China, and determined by genetic and environmental factors. The predisposing genes of DDH still remain unknown. In our previous study, A SNP of rs726252 within pregnancy-associated plasma protein A2 (PAPPA2) gene was confirmed associated with DDH by genome-wide scan and case-control analysis. The PAPPA2 gene was therefore a probable susceptibility gene of DDH. PAPPA2, a proteinase of insulin-like growth factor binding protein 5 (IGFBP-5), can regulate the bioavailability and activity of IGF by proteolyzing IGFBP-5. Meanwhile, the IGF signaling can modulate the synthesis of collagen in fibroblasts and the development of growth plate by interacting with the PTHrP and Ihh pathway in chondrocytes. However, the abnormal development in chondrocytes and fibroblasts are the main pathological features of DDH. Thus, we presumed that the PAPPA2 gene could play an important role in the development of DDH by IGF signaling pathway. Based on the previous study, we will sequentially endeavor to find the susceptive SNP genotype to DDH in the coded region of PAPPA2 gene by genotyping strategy, and investigate the expression of PAPPA2 in DDH at the level of RNA and protein. In vitro, we will further observe the effect of PAPPA2 to the development of cultured chondrocytes and fibroblasts. In addition, in vivo study, we will investigate the fetal development of the hip in mouse with the PAPPA2 gene silenced by RNAi technique. By this study, we expect to elucidate the effects of PAPPA2 gene in the pathogenesis of developmental dysplasia of the hip.