双膦酸盐诱导的颌骨坏死(BRONJ)在接受双膦酸盐(BP)和其他抗血管生成药物治疗骨质疏松症或骨相关癌症并发症的患者中表现出典型的颌骨坏死模式。
这项研究根据处方病因将38例BRONJ患者分为两组:癌症(n=13)和骨质疏松症(n=25)。并进行了全外显子组测序,并将其与正常对照组(n=90)进行了比较。为了确定候选基因和变异,我们进行了三项分析:传统的遗传模型,逐基因变异评分负担,和稀有变量分析方法。
在加性趋势模型分析中,BRONJ癌症组中PZP基因的停止增益突变(rs117889746)得到了显着鉴定。在癌症组中,ARIDS,HEBP1、LTBP1和PLVAP被鉴定为候选基因。在骨质疏松症组中,VEGFA,DFFA,和FAM193A基因显示出显著的关联。在稀有变体分析流程中没有鉴定出显著的基因。与BRONJ发生-血管生成相关信号(VEGFA和PLVAP基因)相关的生物学负责功能,TGF-β信号(LTBP1和PZP基因),血红素毒性(HEBP1)和成骨细胞成熟(ARIDS)-显示在候选基因中。
这项研究表明,有助于BRONJ发育的候选致病基因因BP剂量和背景疾病而异。
Bisphosphonate-induced osteonecrosis of the jaw (BRONJ) presents with a typical pattern of jaw necrosis in patients who have been prescribed bisphosphonates (BPs) and other antiangiogenetic drugs to treat osteoporosis or bone-related complications of cancer.
This study divided 38 patients with BRONJ into two groups according to the prescribing causes: cancer (n = 13) and osteoporosis (n = 25), and underwent whole exome sequencing and compared them with normal controls (n = 90). To identify candidate genes and variants, we conducted three analyses: a traditional genetic model, gene-wise variant score burden, and rare-variant analysis methods.
The stop-gain mutation (rs117889746) of the PZP gene in the BRONJ cancer group was significantly identified in the additive trend model analysis. In the cancer group, ARIDS, HEBP1, LTBP1, and PLVAP were identified as candidate genes. In the osteoporosis group, VEGFA, DFFA, and FAM193A genes showed a significant association. No significant genes were identified in the rare-variant analysis pipeline. Biologically accountable functions related to BRONJ occurrence-angiogenesis-related signaling (VEGFA and PLVAP genes), TGF-β signaling (LTBP1 and PZP genes), heme toxicity (HEBP1) and osteoblast maturation (ARIDS)-were shown in candidate genes.
This study showed that the candidate causative genes contributing to the development of BRONJ differ according to the BP dose and background disease.