A. Hahn, T. Fukuda, T. Mizuno, D. Hahn, R. W. Frenck, A. A. Vinks; Cincinnati Children's Hospital Medical Center, Cincinnati, OH

BACKGROUND: Up to 15% of children receiving beta-lactam therapy will develop neutropenia, but the molecular mechanisms are undefined. Bone marrow aspirates of patients with beta-lactam induced neutropenia and addition of beta-lactams to bone marrow cultures in vitro show dose-dependent inhibition of granulopoiesis. Multidrug resistance-associated protein 4 (MRP4) is responsible for transport of beta lactams out of renal proximal tubule cells and blood cells. MRP4 knockout mice have decreased elimination of beta-lactams and increased bone marrow toxicity. Single nucleotide polymorphisms (SNPs) can affect protein function and drug response. We hypothesized that SNPs may impair the function of MRP4, facilitating development of neutropenia.
METHODS: Subjects ≤ 25 years of age treated with ≥ 10 days of beta-lactam therapy were recruited. Cases had an absolute neutrophil count < 1,500/mm3, and controls were group matched for age, race, and gender. Human genomic DNA was isolated from whole blood (QIAamp DNA Mini Kit) and TaqMan SNP genotyping assays (Applied Biosystems) were performed for selected SNPs. Continuous and categorical variables were compared using Mann-Whitney or Fisher’s exact test, respectively. Odds ratios were also calculated.
RESULTS: 44 cases and 54 controls were analyzed for 7 SNPs. There was no statistical difference in age, gender, or race between cases and controls (p=0.449, 0.839, and 0.216). There was also no statistical difference in antibiotic use (28 versus 33 days, p=0.369). Subjects with a homozygous SNP at rs1751034 were 5.3 times more likely to develop neutropenia (95%CI 0.6-49.2, p=0.171).
CONCLUSION: We identified a homozygous SNP on MRP4 (rs1751034) that may contribute to beta-lactam induced neutropenia. Confirmatory testing of more subjects is needed.