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The polymorphism of human leukocyte antigen (HLA), which is a genetic factor that influences the progression of hemorrhagic fever with renal syndrome (HFRS) after Hantaan virus (HTNV) infection, was incompletely understood. In this case-control study, 76 HFRS patients and 370 healthy controls of the Chinese Han population were typed for the HLA-A, -B, and -DRB1 loci. The general variation at the HLA-DRB1 locus was associated with the onset of HFRS (P<0.05). The increasing frequencies of HLA-DRB1*09 and HLA-B*46-DRB1*09 in HFRS patients were observed as reproducing a previous study. Moreover, the HLA-B*51-DRB1*09 was susceptible to HFRS (P=0.037; OR =3.62; 95% CI: 1.00–13.18). The increasing frequencies of HLA-B*46, HLA-B*46-DRB1*09, and HLA-B*51-DRB1*09 were observed almost in severe/critical HFRS patients. The mean level of maximum serum creatinine was higher in HLA-B*46-DRB1*09 (P=0.011), HLA-B*51-DRB1*09 (P=0.041), or HLA-B*46 (P=0.011) positive patients than that in the negative patients. These findings suggest that the allele HLA-B*46 and haplotypes HLA-B*46-DRB1*09 and HLA-B*51-DRB1*09 in patients could contribute to a more severe degree of HFRS and more serious kidney injury, which improve our understanding of the HLA polymorphism for a different outcome of HTNV infection.