Oxidant Pathway Functional Polymorphisms Influence the Risk of Myeloid Leukemia/Transient Myeloproliferative Disorder In Children with Down Syndrome.

Abstract 1680

Individuals with Down syndrome have a 2% cumulative risk for the development of leukemia by the time they reach 30 years of age. In addition, as many as 5–10% of infants with Down syndrome may develop a transient myeloproliferative disorder (TMD). The molecular basis for the increased risk for hematologic disorders and other congenital developmental abnormalities with DS remains unknown. Additional genetic material from the critical Down syndrome locus at 21q22 includes the Cu/Zn superoxide dismutase gene and other genes contributing to high oxidative stress and increased endogenous DNA damage observed in cells from patients with Down syndrome. We hypothesized that functional polymorphic variants in enzymes associated with detoxification of oxidants and repair of oxidant associated DNA damage would be associated with an increased risk for the development of myeloid leukemia (ML) and TMD in children with Down syndrome. We studied the role of functional polymorphisms in the oxidant metabolizing genes, Paraoxonase 1 (PON1) and NADH/NADPH oxidase p22 phox (P22_PHOX) in the potential genetic etiology of ML/TMD in children with Down syndrome. Genotyping was conducted in 192 patients with Down Syndrome ML or TMD, and 251 healthy blood donor controls. All genotype frequencies in patients and control populations were consistent with those expected from Hardy-Weinberg equilibrium. We found that the variant PON1 Gln192Arg allele, associated with reduced free radical metabolism, occurred at a higher frequency in the Down syndrome ML/TMD population compared to healthy controls (OR, 2.71; 95% CI, 1.50–4.97; p=0.0003). Consistent with our hypothesis of increased oxidant sensitivity in these patients, we also observed decreased frequency of the protective variant P22_PHOX His72Tyr allele, purportedly associated with reduced generation of reactive oxygen species, in the Down syndrome ML/TMD population compared to healthy controls (OR, 0.48; 95% CI, 0.23–0.95; p=0.025). Notably, the variant PON1 Gln192Arg allele has also been associated with increased risk for non-Hodgkin's lymphoma in adults (Kerridge et al. Br J Haematol, 2002). Conclusion: These preliminary studies suggest that functional polymorphic variants in the oxidant metabolizing enzymes PON1 and P22_PHOX may influence risk for development of ML/TMD in children with Down syndrome. Studies to confirm these observations in a separate cohort of patients are in progress.