中国是慢性乙型肝炎患病大国，阿德福韦酯（ADV）是抗乙型肝炎病毒的长期治疗常用药物，但愈来愈多证据显示小剂量口服5年以上发生低磷性骨软化症等肾小管障碍不良反应达10-27%。我们前期利用较大样本ADV导致低磷性骨软化症，在国际上率先报告ADV转运关键基因SLC22A6和ABCC2存在风险基因型，本项目拟在前期工作基础上，使用病例-对照研究方法，ADV引起低磷性骨软化症和没发生该不良反应病例各300例，利用全外显子组测序和基因分型技术，检测ADV在肾小管转运相关的共29个药物转运体编码基因，以发现该药物导致低磷性骨软化症的高风险基因型或突变，并通过细胞实验证实不同基因型在摄取或排泌[3H]标记-ADV中的功能差异。本研究有望鉴定到ADV引起低磷性骨软化症之风险基因型或突变，以指导临床对高风险基因型者避免长期使用ADV，以达到个体化用药之目的，将显著减少ADV引起肾小管障碍之严重不良反应。

Chronic hepatitis B is highly prevalent in China, and adefovir dipivoxil (ADV) is one of the most widely used antiviral drugs for long-term anti-hepatitis B virus treatment. However, more and more findings have demonstrated that the incidence rate of renal tubular dysfunction such as hypophosphatemic osteomalacia caused by low-dose of oral ADV for more than 5 years is up to 10-27%. We firstly reported that there were risk genotypes and mutations of ADV transporter genes SLC22A6 and ABCC2 previously, by analyzing a large sample of ADV induced hypophosphatemic osteomalacia. In this study,we intended to adopt case-control study based on previous work, including 300 cases with ADV induced hypophosphatemic osteomalacia and 300 cases without the adverse reaction. Whole exome sequencing and genotyping technology are carried out to detect the 29 drug transporter-coding genes related to ADV transport in renal tubular, and try to find out the high risk genotypes or mutations of ADV induced hypophosphatemic osteomalacia. Functional differences in uptake or excretion of [3H] marked-ADV of different genotypes will be verified through cell experiments. This study will help to identify the risk genotypes or mutations of ADV-induced hypophosphatemic osteomalacia. On this basis, individualized medication could be carried out by establishing clinical instructions of avoiding long-term treatment with ADV for patients with high-risk genotypes, and the incidence of ADV-induced hypophosphatemic osteomalacia will be significantly reduced.