HLA-DR4-Ala74β is associated with risk and poor outcome of severe aplastic anemia

Abstract

Severe aplastic anemia (SAA) is a heterogeneous hematological disorder with a high mortality. Genetic predisposition has been shown to play a role in a considerable proportion of SAA cases. For instance, the human lymphocyte antigen HLA-DR2 has been repeatedly demonstrated to be over-represented in SAA patients. In this paper, we expand on the evidence for the contribution of HLA polymorphism in the susceptibility to SAA, which was obtained using the "high-resolution" technique of HLA-DRB1 subtyping. The DRB1*1501 allele appeared to be responsible for the predominance of DR2 specificity in SAA patients and was the most significant risk factor for this disease. It was observed in 23/44 (52.3%) patients versus 22/100 (22.0%) donors [odds ratio (OR) = 3.9; 95% confidence interval (CI): 1.8-8.3; P = 0.0005, corrected P (Pc) < 0.05]. In addition, DRB1*04 alleles also displayed non-random distribution in the SAA group. In particular, DRB1*04 variants coding for alanine at position 74 of the DR beta 1 chain (HLA-DR4-Ala74 beta subtype) were detected in all 13 DR4-positive SAA patients but only in 15/24 (62.5%) controls (OR = 16.6; 95% CI: 0.9-312.0; P = 0.015). Multiple comparison analysis confirmed that the HLA-DR4-Ala74 beta subtype confers susceptibility to SAA independently from the DRB1*1501 allele. Finally, examination of the clinical records has shown that the HLA-DR4-Ala74 beta subtype is associated with poor outcome of SAA.

Association of human leukocyte antigen class II alleles with response to immunosuppressive therapy in Korean aplastic anemia patients

“…patients [7]. In our previous study, however, DR4 or DR4-Ala74␤ was not associated with disease susceptibility to AA [12].…”

“…HLA-DR2 and DR2 subtypes have been reported to be overrepresented among AA patients in several ethnic groups, including our recent study in Koreans [3][4][5][6][7][8][9][10][11][12]. DR2 or DR2 subtypes have also been shown to be associated with a good response to IST [3,5,6,8,10,11,13].…”

Increased frequency of HLA-DR2 in patients with paroxysmal nocturnal hemoglobinuria and the PNH/aplastic anemia syndrome

“…[7][8][9][10][11][12][13][14][15][16][17][18][19] An increased frequency of HLA-DR2 has been reported in some but not all studies. [9][10][11][12][13]16 An association with class I alleles (especially HLA-A2) has been inconsistently identified.…”

Correlations between HLA-A, HLA-B and HLA-DRB1 Allele Polymorphisms and Childhood Susceptibility to Acquired Aplastic Anemia

“…To our knowledge, reports on this aspect remain rare, and most reports have focused on the correlation between HLA and SAA [8,9,12,20]. In the current study, the susceptibility and protective genes among the nSAA, SAA and control groups were compared.…”

“…Researchers from Turkey, South Korea, Pakistan and China found that DRB1*15 is one of the susceptibility genes of childhood AA [8,9,10,11]. Further studies revealed that DRB1*1501 is a susceptibility gene of AA [11,12,13,14,15,16]. The expression of DRB1*1501 and DRB1*1502 among AA patients is notably higher than in the general population [13].…”