基于高通量测序HOXD、DLX基因多态性在哈萨克族发育性髋关节脱位的相关性研究

Developmental dysplasia of the hip (DDH) also known as developmental dislocation of the hip or congenital dislocation of the hip, refers to the birth or shortly after the emergence of femoral head and acetabulum, accompanied by a certain degree of bone and soft tissue dysplasia is a common congenital malformation of the Department of orthopedics. Good effect of this disease to early diagnosis and treatment; if the delay in treatment, will lead to disease and ultimately the formation of irreversible painful osteoarthritis and different degree of disability, seriously affect the patient's quality of life, and bring a heavy burden to the patients and their families. Therefore, the early diagnosis and treatment of DDH is very important. However, the etiology and pathogenesis of this disease is not clear, which hinders the early diagnosis and treatment of the disease. Epidemiological investigation showed that the incidence of DDH was significantly correlated with race, region and gender. This project intends to HOXD through the second generation high-throughput sequencing technology on Xinjiang Kazak DDH patients peripheral blood DLX gene sequencing, the target of positive loci for SNP genotyping and verification, and to determine whether the Kazakh are related to the occurrence of DDH, whether the polymorphisms of two genes affect the occurrence of DDH, from the genetic point of theory the basis and new way for early diagnosis and treatment of DDH.

发育性髋关节发育不良（DDH）又称发育性髋关节脱位或先天性髋关节脱位，指出生时或出生后不久股骨头脱出髋臼，并伴有一定程度的骨和软组织发育不良，是骨科常见的先天畸形之一。本病若能早期诊断和治疗，效果较好；若治疗延误，将导致病患最终形成不可逆的痛性骨关节炎和不同程度残疾，严重影响病患的生活质量，并给患者及其家庭带来沉重的经济和精神负担。因此DDH 的早期诊断和治疗至关重要。然而，该病的病因和发病机制尚不明确，阻碍了该病的早期诊断和治疗。流行病学调查结果显示 DDH 发病率与种族、地区和性别等有显著相关性。本项目拟通过第二代高通量测序技术对新疆哈萨克族DDH患者外周静脉血中HOXD,DLX基因进行目标测序后对阳性位点进行SNP分型检测及验证，以明确是否与哈萨克族DDH发生有关，两组基因的多态性是否影响DDH发生，从遗传学角度为DDH早期诊断和治疗提供理论依据和新的途径。

采用人全基因组外显子芯片对20例哈萨克族DDH患者进行了全基因组外显子测序和分析，筛选了HOXD、DLX基因的单核苷酸多态性位点(single nucleotide variations, SNVs)。.全部20例哈萨克族DDH患者中共计测到208035个突变，其中单核苷酸多态性位点175897个、插入缺失多态性位点32138个。这些突变中112676个为玉内含子区，10453个位于基因间区，45189个位于外显子区，7138个位点3’端非翻译区，4535个位于5’端非翻译区，9982个位于剪切区，2741个位于基因上游区域，1277个位于基因下游区域。.我们通过全基因组外显子测序筛选了HOXD、DLX基因候选对75个SNVs，并通过生物信息学分析，选择了部分候选位点，在哈萨克族和汉族大样本群体中进行了关联分析，筛选了与新疆哈萨克族、汉族发育性髋关节脱位相关的SNVs。.通过对哈萨克族发育性髋关节脱位人群进行了全基因组外显测序，从测序数据中筛选到HOXD、DLX基因可能影响哈萨克族发育性髋关节脱位发病的阳性位点。.收集哈萨克族和汉族DDH患者和健康个体，利用LDR技术对候选SNVs位点进行了关联分析，探索HOXD、DLX 基因与发育性髋关节脱位的关联性和民族差异，更深层次的揭示发育性髋关节脱位发病的分子遗传学机制以及民族异质性的分子机理，为开展特异人群发育性髋关节脱位发病机制研究和药物研制提供新思路和新靶点。