Genetics of pleiotropic effects of dexamethasone

Laura B. Ramsey, Stan Pounds, Cheng Cheng, Xueyuan Cao, Wenjian Yang, Colton Smith, Seth E. Karol, Chengcheng Liu, John C. Panetta, Hiroto Inaba, Jeffrey E. Rubnitz, Monika L. Metzger, Raul C. Ribeiro, John T. Sandlund, Sima Jeha, Ching-Hon Pui, William E. Evans, Mary V. Relling

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), and these variants were more likely to be in gene-regulatory regions (P=1.22×10) 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.