Ramsey Laura B, Pounds Stan, Cheng Cheng, Cao Xueyuan, Yang Wenjian, Smith Colton, Karol Seth E, Liu Chengcheng, Panetta John C, Inaba Hiroto, Rubnitz Jeffrey E, Metzger Monika L, Ribeiro Raul C, Sandlund John T, Jeha Sima, Pui Ching-Hon, Evans William E, Relling Mary V
Departments of aPharmaceutical Sciences bBiostatistics cOncology dComprehensive Cancer Center, St Jude Children's Research Hospital, Memphis, Tennessee, USA.
Pharmacogenet Genomics. 2017 Aug;27(8):294-302. doi: 10.1097/FPC.0000000000000293.
Glucocorticoids such as dexamethasone have pleiotropic effects, including desired antileukemic, anti-inflammatory, or immunosuppressive effects, and undesired metabolic or toxic effects. The most serious adverse effects of dexamethasone among patients with acute lymphoblastic leukemia are osteonecrosis and thrombosis. To identify inherited genomic variation involved in these severe adverse effects, we carried out genome-wide association studies (GWAS) by analyzing 14 pleiotropic glucocorticoid phenotypes in 391 patients with acute lymphoblastic leukemia.
We used the Projection Onto the Most Interesting Statistical Evidence integrative analysis technique to identify genetic variants associated with pleiotropic dexamethasone phenotypes, stratifying for age, sex, race, and treatment, and compared the results with conventional single-phenotype GWAS. The phenotypes were osteonecrosis, central nervous system toxicity, hyperglycemia, hypokalemia, thrombosis, dexamethasone exposure, BMI, growth trajectory, and levels of cortisol, albumin, and asparaginase antibodies, and changes in cholesterol, triglycerides, and low-density lipoproteins after dexamethasone.
The integrative analysis identified more pleiotropic single nucleotide polymorphism variants (P=1.46×10(-215), and these variants were more likely to be in gene-regulatory regions (P=1.22×10(-6)) than traditional single-phenotype GWAS. The integrative analysis yielded genomic variants (rs2243057 and rs6453253) in F2RL1, a receptor that functions in hemostasis, thrombosis, and inflammation, which were associated with pleiotropic effects, including osteonecrosis and thrombosis, and were in regulatory gene regions.
The integrative pleiotropic analysis identified risk variants for osteonecrosis and thrombosis not identified by single-phenotype analysis that may have importance for patients with underlying sensitivity to multiple dexamethasone adverse effects.
地塞米松等糖皮质激素具有多种效应，包括预期的抗白血病、抗炎或免疫抑制作用，以及非预期的代谢或毒性作用。地塞米松在急性淋巴细胞白血病患者中最严重的不良反应是骨坏死和血栓形成。为了确定与这些严重不良反应相关的遗传基因组变异，我们通过分析391例急性淋巴细胞白血病患者的14种多效性糖皮质激素表型进行了全基因组关联研究（GWAS）。
我们使用“投影到最有趣的统计证据”整合分析技术来识别与多效性地塞米松表型相关的遗传变异，按年龄、性别、种族和治疗进行分层，并将结果与传统的单表型GWAS进行比较。这些表型包括骨坏死、中枢神经系统毒性、高血糖、低钾血症、血栓形成、地塞米松暴露、体重指数、生长轨迹、皮质醇、白蛋白和天冬酰胺酶抗体水平，以及地塞米松治疗后胆固醇、甘油三酯和低密度脂蛋白的变化。
整合分析识别出更多的多效性单核苷酸多态性变异（P=1.46×10⁻²¹⁵），与传统的单表型GWAS相比，这些变异更可能位于基因调控区域（P=1.22×10⁻⁶）。整合分析在F2RL1中产生了基因组变异（rs2243057和rs6453253），F2RL1是一种在止血、血栓形成和炎症中起作用的受体，这些变异与包括骨坏死和血栓形成在内的多效性效应相关，且位于调控基因区域。
整合多效性分析识别出单表型分析未发现的骨坏死和血栓形成的风险变异，这可能对那些对地塞米松多种不良反应具有潜在敏感性的患者具有重要意义。
