HLA-DRB1 Allele Frequency and TNF Polymorphism in Patients with Myelodysplastic Syndromes (MDS).

Abstract

MDS, a heterogeneous group of hematopoietic stem cell disorders, are associated with dysregulated cytokine profiles in marrow and blood plasma, including upregulation of tumor necrosis factor alpha (TNF-alpha). Other data suggest that patients with MDS who carry the human leukocyte antigen (HLA)-DRB1*1501 allele are more likely to respond to immunosuppressive therapy. The genes for HLA-DR and TNF are in close linkage on human chromosome 6. Preliminary data had shown a higher than expected frequency of single nucleotide polymorphism (SNP) at position -238 of the TNF gene. We wanted to determine, therefore, the strength of linkage disequilibrium between a given TNF polymorphism and HLA-DR alleles. We analyzed HLA-DR allele frequencies in 1,040 patients with MDS, in comparison to 2,474 patients with chronic myeloid leukemia (CML); 1,422 and 160 of these patients, respectively, had TNF polymorphism data (AA vs. AC vs. CC alleles) for SNP 308 and 863 available. Significant differences in frequency were observed for HLA-DRB1*0401 (9.1% vs. 6.9%; p=0.03), *0701 (3.8% vs. 1.3%; p<0.0001), *1302 (2.7% vs. 4.3%; p=0.03), and *1501 (13.6% vs. 9.9%; p=0.0009). When determining the association of a given TNF SNP with the presence of two, one, or no copy of a given HLA-DR allele, TNF SNP 863 showed a significant association with HLA-DRB1*0101 (p=0.003), *0301 (p<0.0001), *0401 (p=0.0002), and *1101 (p=0.02); HLA-DRB1*0301 was also associated with TNF SNP 308 (p<0.0001). There was no significant correlation of either one of these two TNF SNPs with diagnosis. However, when only MDS patients were considered, there was a suggestion of a correlation of SNP 308 and HLA-DR*1501 (p=0.11); among patients with the TNF genotype AA or AC only 3 of 24 (12%) carried at least one DRB1*1501 allele, compared to 20 of 56 (36%) among those with the CC genotype. While TNF SNPs remain to be typed in a large proportion of MDS patients, results suggest a higher frequency of some HLA-DR alleles, in particular *0701 and *1501, in patients with MDS than seen in CML, and a correlation of TNF SNPs, in particular, TNF 308 CC with HLA-DRB1*1501. Thus, these data are consistent with an association of DRB1 *1501 and TNF alleles, and it will be of interest to identify the pattern of TNF polymorphism in HLA-DRB1*1501 negative patients, Additional studies are needed to further determine potential haplotypes that are associated with MDS and possible correlations with disease course and treatment responses.