Abstract:
Bone toxicities are common among paediatric patients treated for acute lymphoblastic leukaemia (ALL) with potentially major negative impact on patients\' quality of life. To identify the underlying genetic contributors, we conducted a genome-wide association study (GWAS) and a transcriptome-wide association study (TWAS) in 260 patients of European-descent from the DFCI 05-001 ALL trial, with validation in 101 patients of European-descent from the DFCI 11-001 ALL trial. We identified a significant association between rs844882 on chromosome 20 and bone toxicities in the DFCI 05-001 trial (p = 1.7 × 10-8). In DFCI 11-001 trial, we observed a consistent trend of this variant with fracture. The variant was an eQTL for two nearby genes, CD93 and THBD. In TWAS, genetically predicted ACAD9 expression was associated with an increased risk of bone toxicities, which was confirmed by meta-analysis of the two cohorts (meta-p = 2.4 × 10-6). In addition, a polygenic risk score of heel quantitative ultrasound speed of sound was associated with fracture risk in both cohorts (meta-p = 2.3 × 10-3). Our findings highlight the genetic influence on treatment-related bone toxicities in this patient population. The genes we identified in our study provide new biological insights into the development of bone adverse events related to ALL treatment.
摘要:
骨毒性在接受急性淋巴细胞白血病(ALL)治疗的儿科患者中很常见,可能对患者的生活质量产生重大负面影响。为了确定潜在的遗传因素,我们对来自DFCI05-001ALL试验的260名欧洲裔患者进行了全基因组关联研究(GWAS)和全转录组关联研究(TWAS),DFCI11-001ALL试验对101例欧洲裔患者进行了验证。在DFCI05-001试验中,我们确定了20号染色体上的rs844882与骨毒性之间的显着关联(p=1.7×10-8)。在DFCI11-001试验中,我们观察到这种变异与骨折的趋势一致。该变体是两个附近基因的eQTL,CD93和THBD。在TWAS中,遗传预测的ACAD9表达与骨毒性风险增加有关,这通过两个队列的荟萃分析得到证实(meta-p=2.4×10-6).此外,足跟定量超声声速的多基因风险评分与两个队列中的骨折风险相关(meta-p=2.3×10-3).我们的发现强调了遗传对该患者人群中治疗相关骨毒性的影响。我们在研究中确定的基因为与ALL治疗相关的骨不良事件的发展提供了新的生物学见解。