Aim: To explore whether predisposition to bone marrow failure syndromes (BMF), such aplastic anemia (AA), paroxysmal nocturnal hemoglobinuria (PNH) and myelosysplastic syndromes (MDS), is found in killer cell immunoglobulin-like receptor (KIR) and human leukocyte antigen (HLA) ligand (KIR-L) gene variations or cytokine polymorphisms.
Patients: We studied a cohort of 77 patients with AA, 129 with MDS and 285 healthy controls for the frequencies of KIRL and KIR genotypes and 22 selected single nucleotide polymorphisms (SNPs) located within 10 cytokine (IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-10, IL12, IFN-γ, TNF-α, TGF-β) and 3 cytokine receptor (IL-1R, IL-1RA, IL-4Rα) genes.
Results: In AA we found a decreased frequency of inhibitory KIR-2DL3 genes. In MDS, no difference in the frequency of KIR genotype was identified; however, a decreased frequency of 2DL3 was found in hypocellular MDS. Analysis of the KIR genotype in correlation with the corresponding KIR-L profile, revealed a decreased frequency of stimulatory 2DS1/C2 mismatch both in AA and MDS. In AA and MDS cohorts, compared to controls, we found a higher frequency of TT codon 10 variant and of GG codon 25 variant of TGF-β gene, consistent with a high secretory phenotype. This relationship was even more pronounced in PNH and hypocellular MDS. We confirm that the hypersecretory genotype T/T at position -874 of INF-γ gene was overrepresented only in AA and correlates with presence of a PNH clone. Instead in MDS patients, the frequency of G/A polymorphism at position – 308 on the TNF-α gene promoter, which correlates with higher TNF-α production, was found significantly higher. Moreover, hypocellular MDS was characterized by a higher prevalence of IL-10 GCC/GCC haplotype, which is functionally associated with a low secretor phenotype.
Conclusion: Our findings suggest that alterations in KIR/KIR-L matching, such as increased 3DL2 and decreased 2DS1 mismatch, and in the polymorphisms of TGFβ1, IFN-γ, TNF-α and IL-10 may account for the propensity to immunemediated killing of hematopoietic stem cells and/or ineffective hematopoiesis characteristic of AA and MDS. Further studies are needed to elucidate whether these immunogenetic traits may be involved in increased risk of developing immune-mediated BMF.
Keywords: Aplastic anemia, myelodysplastic syndromes, cytokine polymorphisms, KIR-KIR-L, predisposition, bone marrow failure syndromes, BMF, paroxysmal nocturnal hemoglobinuria, PNH, MDS, killer cell, KIR, HLA, polymorphisms