Genetics of glucocorticoid-associated osteonecrosis in children with acute lymphoblastic leukemia
Genetics of glucocorticoid-associated osteonecrosis in children with acute lymphoblastic leukemia
复制标题
DOI：
10.1182/blood-2015-05-643601
复制
发表时间：
2015-10-08
期刊：
影响因子：
20.3
通讯作者：
Relling, Mary V.
中科院分区：
文献类型：
--
作者：
Karol, Seth E.;Yang, Wenjian;Relling, Mary V.
糖皮质激素是治疗急性淋巴细胞白血病（ALL）的重要疗法，其主要不良反应是骨坏死。我们的目标是确定骨坏死的遗传和非遗传危险因素。我们在一个由 2285 名 ALL 儿童组成的发现队列中进行了单核苷酸多态性 (SNP) 的全基因组关联研究，这些儿童接受儿童肿瘤组 AALL0232 方案 (NCT00075725) 治疗，并调整协变量。 SNP rs10989692（靠近谷氨酸受体GRIN3A位点）的次要等位基因与骨坏死相关（风险比= 2.03；P = 3.59 x 10(-7)）。该关联得到了 2 个复制队列的支持，其中包括 361 名接受 St. Jude's Total XV 方案 (NCT00137111) 的 ALL 儿童和来自范德比尔特大学 BioVU 存储库的 309 名接受糖皮质激素治疗的非 ALL 患者（比值比 [OR] 51.87 和 2.26；P 分别为 0.063 和 0.0074）。在荟萃分析中，rs10989692 也排名最高 (P = 2.68 x 10(-8))，谷氨酸途径是排名最高的途径 (P = 9.8 x 10(-4))。骨坏死相关的谷氨酸受体变异还与其他血管表型相关，包括脑缺血（OR=1.64；P=2.5×10(-3)）、动脉栓塞和血栓形成（OR=1.88；P=4.2x10(-3)）。总之，骨坏死与谷氨酸受体基因附近的遗传变异有关。进一步了解这种关联可能有助于采取干预措施来减少骨坏死。这些试验在 www.clinicaltrials.gov 上注册为#NCT00075725 和#NCT00137111。
Glucocorticoids are important therapy for acute lymphoblastic leukemia (ALL) and their major adverse effect is osteonecrosis. Our goal was to identify genetic and nongenetic risk factors for osteonecrosis. We performed a genome-wide association study of single nucleotide polymorphisms (SNPs) in a discovery cohort comprising 2285 children with ALL, treated on the Children's Oncology Group AALL0232 protocol (NCT00075725), adjusting for covariates. The minor allele at SNP rs10989692 (near the glutamate receptor GRIN3A locus) was associated with osteonecrosis (hazard ratio = 2.03; P = 3.59 x 10(-7)). The association was supported by 2 replication cohorts, including 361 children with ALL on St. Jude's Total XV protocol (NCT00137111) and 309 non-ALL patients from Vanderbilt University's BioVU repository treated with glucocorticoids (odds ratio [OR] 51.87 and 2.26; P=.063 and .0074, respectively). In a meta-analysis, rs10989692 was also highest ranked (P = 2.68 x 10(-8)), and the glutamate pathway was the top ranked pathway (P = 9.8 x 10(-4)). Osteonecrosis-associated glutamate receptor variants were also associated with other vascular phenotypes including cerebral ischemia (OR = 1.64; P = 2.5 x 10(-3)), and arterial embolism and thrombosis (OR=1.88; P=4.2x10(-3)). In conclusion, osteonecrosis was associated with inherited variations near glutamate receptor genes. Further understanding this association may allow interventions to decrease osteonecrosis. These trials are registered at www.clinicaltrials.gov as #NCT00075725 and #NCT00137111.