Genome-Wide Association Study of Susceptibility Loci for Radiation-Induced Brain Injury.
Genome-Wide Association Study of Susceptibility Loci for Radiation-Induced Brain Injury.
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辐射引起的脑损伤易感位点的全基因组关联研究。
DOI：
10.1093/jnci/djy150
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发表时间：
2019-06-01
期刊：
影响因子：
--
通讯作者：
Jia WH
中科院分区：
文献类型：
--
作者：
Wang TM;Shen GP;Chen MY;Zhang JB;Sun Y;He J;Xue WQ;Li XZ;Huang SY;Zheng XH;Zhang SD;Hu YZ;Qin HD;Bei JX;Ma J;Mu J;Yao Shugart Y;Jia WH
在接受部分或全脑辐照治疗的癌症患者中，辐射引起的脑损伤是一个不可忽视的问题。尤其是颞叶损伤（TLI），作为鼻咽癌晚期的一种有害并发症，极大地影响了鼻咽癌患者的长期生活质量。尽管全基因组关联研究（GWASs）已经成功地确定了与辐射毒性相关的单核苷酸多态性（snp），但尚未对导致辐射诱导脑损伤的遗传变异进行评估。我们招募并随访了一个前瞻性观察队列，放疗毒性和预后的遗传结构，使用磁共振成像诊断TLI。我们对1082例患者进行了全基因组关联分析，并分别在1119例和741例患者的两个独立队列中验证了最重要的关联。所有统计检验均为双侧检验。我们在CEP128中发现一个启动子变异rs17111237 （a b> G，次要等位基因频率[MAF] = 0.14）与TLI风险相关（风险比= 1.45,95%置信区间= 1.26 ~ 1.66,Pcombined=3.18 × 10-7），该变异与CEP128中的顶级信号rs162171 （MAF = 0.18, R2 = 0.69）处于中度连锁不平衡（LD）状态（风险比= 1.46,95%置信区间= 1.29 ~ 1.66,Pcombined= 6.17 × 10-9）。结合临床变量和顶部SNP，我们将患者分为不同风险的不同亚组，5年无tli率从33.7%到95.5%不等。CEP128是母体中心粒的关键组成部分，与多个抗辐射基因紧密相互作用，在维持纤毛功能中发挥重要作用，否则将导致神经网络故障。我们发现，rs17111237的A > G改变会损害CEP128的启动子活性，而CEP128的敲低会降低辐射下U87细胞的克隆细胞存活率。值得注意的是，12.7%（27/212）的gwas相关基因在神经发生通路中富集（P < 0.001）。这项分为三个阶段的研究是辐射性脑损伤的第一个GWAS，它暗示了遗传易感基因CEP128参与TLI的发展，并为辐射性脑损伤的潜在机制提供了新的见解。
Radiation-induced brain injury is a nonnegligible issue in the management of cancer patients treated by partial or whole brain irradiation. In particular, temporal lobe injury (TLI), a deleterious late complication in nasopharyngeal carcinoma, greatly affects the long-term life quality of these patients. Although genome-wide association studies (GWASs) have successfully identified single nucleotide polymorphisms (SNPs) associated with radiation toxicity, genetic variants contributing to the radiation-induced brain injury have not yet been assessed. We recruited and performed follow-up for a prospective observational cohort, Genetic Architecture of Radiotherapy Toxicity and Prognosis, using magnetic resonance imaging for TLI diagnosis. We conducted genome-wide association analysis in 1082 patients and validated the top associations in two independent cohorts of 1119 and 741 patients, respectively. All statistical tests were two-sided. We identified a promoter variant rs17111237 (A > G, minor allele frequency [MAF] = 0.14) in CEP128 associated with TLI risk (hazard ratio = 1.45, 95% confidence interval = 1.26 to 1.66, Pcombined=3.18 × 10–7) which is in moderate linkage disequilibrium (LD) with rs162171 (MAF = 0.18, R2 = 0.69), the top signal in CEP128 (hazard ratio = 1.46, 95% confidence interval = 1.29–1.66, Pcombined= 6.17 × 10–9). Combining the clinical variables with the top SNP, we divided the patients into different subgroups with varying risk with 5-year TLI-free rates ranging from 33.7% to 95.5%. CEP128, a key component of mother centriole, tightly interacts with multiple radiation-resistant genes and plays an important role in maintaining the functional cilia, which otherwise will lead to a malfunction of the neural network. We found that A > G alteration at rs17111237 impaired the promoter activity of CEP128 and knockdown of CEP128 decreased the clonogenic cell survival of U87 cells under radiation. Noteworthy, 12.7% (27/212) of the GWAS-based associated genes (P < .001) were enriched in the neurogenesis pathway. This three-stage study is the first GWAS of radiation-induced brain injury that implicates the genetic susceptibility gene CEP128 involved in TLI development and provides the novel insight into the underlying mechanisms of radiation-induced brain injury.
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影响因子：
28.2
作者：
Kerns SL;Ostrer H;Rosenstein BS
通讯作者：
Rosenstein BS
DOI：
10.1198/106186006x133933
发表时间：
2006-09-01
影响因子：
2.4
作者：
Hothorn, Torsten;Hornik, Kurt;Zeileis, Achim
通讯作者：
Zeileis, Achim
DOI：
10.1016/j.ijrobp.2012.08.003
发表时间：
2013-01-01
影响因子：
7
作者：
Kerns, Sarah L.;Stock, Richard;Stone, Nelson;Buckstein, Michael;Shao, Yongzhao;Campbell, Christopher;Rath, Lynda;De Ruysscher, Dirk;Lammering, Guido;Hixson, Rosetta;Cesaretti, Jamie;Terk, Mitchell;Ostrer, Harry;Rosenstein, Barry S.
通讯作者：
Rosenstein, Barry S.
影响因子：
10.5
作者：
Hurov, Kristen E.;Cotta-Ramusino, Cecilia;Elledge, Stephen J.
通讯作者：
Elledge, Stephen J.
影响因子：
6.6
作者：
Kerns, Sarah L.;Stone, Nelson N.;Rosenstein, Barry S.
通讯作者：
Rosenstein, Barry S.