title: Impact of immunogenetic polymorphisms in bone marrow failure syndromes.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  We studied a cohort of 77 patients with AA, 129 with MDS and 285 healthy controls for the frequencies of KIR-L 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Hematology Branch, School of Medicine, University of Salerno, Italy.
authors.forename: B
authors.initials: B
authors.lastname: Serio
authors.forename: C
authors.initials: C
authors.lastname: Selleri
authors.forename: J P
authors.initials: JP
authors.lastname: Maciejewski
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000741:Anemia, Aplastic / Q000235:genetics* / Q000276:immunology; D001855:Bone Marrow Diseases; D000080983:Bone Marrow Failure Disorders; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D016207:Cytokines / Q000235:genetics; D005787:Gene Frequency; D005838:Genotype; D006457:Hemoglobinuria, Paroxysmal / Q000235:genetics* / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics; D016753:Interleukin-10 / Q000235:genetics; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000235:genetics* / Q000276:immunology; D020641:Polymorphism, Single Nucleotide; D018121:Receptors, Cytokine / Q000235:genetics; D054340:Receptors, KIR / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000235:genetics
chemical_list: D016207:Cytokines; D018121:Receptors, Cytokine; D054340:Receptors, KIR; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D007371:Interferon-gamma