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CRHR1 Polymorphisms Predict Bone Density in Survivors of Acute Lymphoblastic Leukemia

Terreia S. Jones, Sue C. Kaste, Wei Liu, Cheng Cheng, Wenjian Yang, Kelan G. Tantisira, Ching-Hon Pui, Mary V. Relling

From the Colleges of Pharmacy and Medicine and the Department of Radiology, University of Tennessee; and the Departments of Pharmaceutical Sciences, Radiological Sciences, and Biostatistics and Oncology, St Jude Children's Research Hospital, Memphis TN; and the Channing Laboratory and Pulmonary Division, Brigham and Women's Hospital and Harvard Medical School, Boston, MA

Corresponding author: Mary V. Relling, PharmD, Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, 332 North Lauderdale, Memphis, TN 38105-2794; e-mail: mary.relling{at}stjude.org

Purpose: Corticosteroids are a critical component of therapy for acute lymphoblastic leukemia (ALL) but are associated with late effects, such as osteoporosis. Risk factors remain poorly defined. Because CRHR1 polymorphisms have been associated with other corticosteroid effects, our goal was to define whether CRHR1 polymorphisms predict which patients with ALL are likely to develop bone mineral deficits.

Patients and Methods: The mean bone mineral density z scores of 309 long-term survivors of ALL were determined by quantitative computed tomography of the trabecular lumbar spine. We analyzed whether CRHR1 genotypes, adjusted for sex, ALL treatment regimen, and weight, could predict bone density.

Results: We found that three single nucleotide polymorphisms (SNPs), all in linkage disequilibrium, were associated with bone density in a sex-specific manner. Bone density was lower in males (P = .001), in nonblack patients (P < .08), in those who were not overweight (P < .001), and in those who received intensive antimetabolites and glucocorticoids (P < .001). After adjustment for these features, the G allele at the rs1876828 SNP was associated with lower z scores (P = .02) in males but tended to have the opposite association in females (P = .09).

Conclusion: CRHR1 polymorphisms may impact the risk of bone density deficits in patients treated with corticosteroids and antimetabolites in a sex-specific manner.

Supported by Grants No. NCI CA 51001, CA 78224, CA21765 from the National Institutes of Health; by the NIH/NIGMS Pharmacogenetics Research Network and Database Grants No. U01 GM61393, U01 HL65899, U01GM61374 (http://pharmgkb.org), and PS207386 from the National Institutes of Health; by the American Cancer Society; by the Center of Excellence grant from the state of Tennessee; and by American Lebanese Syrian Associated Charities.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.