Survivors of childhood cancer treated with radiation therapy (RT) and osteotoxic chemotherapies are at increased risk for fractures. However, research focusing on how genetic and clinical susceptibility factors jointly contribute to fracture risk among long-term (≥5 years) survivors of childhood cancer has been limited. To address this gap, we conducted genome-wide association studies of fracture risk in 2,453 participants from the Childhood Cancer Survivor Study (CCSS) using Cox regression models and prioritized sex- and treatment-stratified genetic associations. Replication analyses were conducted in an independent survivor sample from the St. Jude Lifetime Cohort Study (SJLIFE). We identified a genome-wide significant (P<5x10^-8) fracture risk locus, 16p13.3 (HAGHL), among female CCSS survivors (N=1,289) with strong evidence of sex-specific effects (P_{sex-heterogeneity}<7x10^-6). We found rs1406815 showed the strongest association with fracture risk after replication (HR_{meta-analysis per risk allele}=1.43, P=8.2x10^-9; N=1,935 women). While the association between rs1406815 and fracture risk was weak among female survivors who did not receive radiation therapy (RT) (HR_CCSS=1.22, P=0.11), the association strength increased with greater RT doses to the head or neck (HR_CCSS=1.88, P=2.4x10^-10 in those with any head/neck RT; HR_CCSS=3.79, P=9.1x10^-7 in those treated with >36 Gray). In silico bioinformatics analyses suggest these fracture risk alleles regulate HAGHL gene expression and related bone resorption pathways, and are plausibly moderated by head/neck RT. Genetic risk profiles integrating this locus may help identify young female survivors who would benefit from targeted interventions to reduce fracture risk.

中文翻译：

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全基因组关联研究揭示了在儿童癌症幸存者中具有特定性别/治疗特异性骨折风险作用的新型基因座

接受放射治疗（RT）和骨毒性化学疗法治疗的儿童期癌症的幸存者骨折风险增加。但是，有关遗传和临床易感因素如何共同导致儿童癌症的长期（≥5岁）骨折风险的研究有限。为了弥补这一差距，我们使用Cox回归模型以及按性别和治疗分层的遗传关联对儿童癌症幸存者研究（CCSS）的2453名参与者进行了骨折风险的全基因组关联研究。复制分析是在来自圣裘德终身队列研究（SJLIFE）的独立幸存者样本中进行的。我们确定了全基因组范围内显着的（P <5x10 ^-8）骨折风险位点16p13.3（HAGHL），在女性CCSS幸存者（N = 1,289）中，有强烈的性别特异性效应（P_{性别异质性}<7x10 ^-6）。我们发现rs1406815在复制后显示出与骨折风险的最强关联（_{每个风险等位基因的}HR_荟萃分析= 1.43，P = 8.2x10 ^-9； N = 1,935妇女）。尽管未接受放射治疗（RT）的女性幸存者中rs1406815与骨折风险之间的关联性较弱（HR _CCSS = 1.22，P = 0.11），但随着头或颈部的RT剂量增加，关联强度增加（HR _CCSS = 1.88，P = 2.4x10 ^-10在任何头/颈RT患者中； HR _CCSS = 3.79，P = 9.1x10 ^-7在那些使用> 36灰色治疗的患者中）。计算机生物信息学分析表明，这些骨折风险等位基因可调节HAGHL基因表达和相关的骨吸收途径，并且可能通过头颈RT调节。整合该基因座的遗传风险概况可能有助于确定年轻女性幸存者，这些女性幸存者将受益于针对性干预措施以降低骨折风险。