Significant Association Between Promoter Polymorphism of the Erythropoietin Gene and Myelodysplastic Syndrome.

Abstract 3825

Poster Board III-761

The risk of developing myelodysplastic syndrome (MDS) increases in the presence of a combination of genetic susceptibility factors and environmental carcinogenic factors. While numerous toxic agents have been described, genetic susceptibility factors for MDS are not well defined. A recent study showed that the TT genotype of the SNP rs1617640, located in the promoter of the eosinophile peroxidase (EPO) gene, is significantly associated with diabetic retinopathy and end-stage renal disease in patients with diabetes. Experimental models showed that the GG genotype is associated with several-fold lower erythropoietin expression than is the TT genotype. Since EPO plays a major role in the growth and differentiation of hematopoietic cells, we explored the association of the rs1617640 SNP genotype with MDS. We compared the EPO promoter SNP genotype in 187 MDS patients, 256 AML patients, and 95 normal control individuals. The GG genotype was significantly more common in patients with MDS (25.1%) than in normal control subjects (6.3%) and AML patients (12.5%) (P=0.0003); the GT genotype was present in 38.4% of MDS patients, 43.2% of AML patients, and 46.2% of normal control subjects. Combined analysis of data from MDS and control subjects indicated an elevated risk of MDS in individuals with the GG genotype relative to those with a non-GG genotype (odd ratio [OR] =4.98; 95% confidence interval [CI]=2.04-12.13). The GG (vs non-GG) genotype was also associated with elevated MDS risk when analysis was limited to the MDS and AML groups (OR =2.35; 95% CI=1.43-3.86). In contrast, analysis of AML and control group data showed a statistically insignificant elevated risk for AML in individuals with the GG genotype (OR=2.12; 95% CI=0.86-5.24). The odds of MDS and AML did not differ significantly with respect to GT (vs non-GT) or TT (vs non-TT) genotypes when compared with control subjects. Clinical and follow up data were available for 112 MDS patients and 186 AML patients. There was no correlation between EPO promoter genotype and response to therapy or overall survival in MDS or AML. In the MDS group, the GG genotype was significantly associated with shorter complete remission duration, as compared with the TT genotype (P=0.03). We found no correlation between EPO genotype and cytogenetic abnormalities, performance status, or other laboratory variables. In conclusion, the EPO promoter GG genotype shows strong association with MDS. Since MDS is well documented to develop after exposure to toxic agents, the clinical value of screening for the EPO promoter GG genotype in individuals at high risk due to exposure to toxic agents, then storing hematopoietic stem cells from those with the GG genotype for possible future use, should be investigated.