Case-control study of the association between select HLA genes and anti-erythropoietin antibody-positive pure red-cell aplasia.
OBJECTIVE
Antibody (Ab)-positive pure red-cell aplasia (PRCA) is a very rare but serious adverse event associated with recombinant human erythropoietin treatment (4.1 reports per 100,000 patient-years) in which patients produce antibodies to recombinant and endogenous erythropoietin, halting red blood cell production. In a previous case series, four Thai subjects with chronic kidney disease and Ab-positive PRCA were reported to have the HLA-DRB1*9 allele. To confirm a possible association of HLA-DRB1*9 and Ab-positive PRCA, we performed a pharmacogenomic analysis using subjects from an earlier case-control study of risk factors associated with Ab-positive PRCA, which had been performed using subjects from Europe or Canada. The primary goal of the analysis was to test the association between HLA-DRB1*9 and Ab-positive PRCA. A secondary goal was to perform an exploratory analysis in order to identify additional HLA alleles potentially associated with Ab-positive PRCA.


METHODS
Subjects were taken from a case-control study of Ab-positive PRCA in chronic kidney disease patients treated in Europe or Canada. Ab-positive PRCA cases (n=24) were matched to controls (n=81) by timing of treatment exposure and, when possible, by location.


RESULTS
The allele frequency of HLA-DRB1*9 was 12.5% in cases vs 1.2% in controls (p=0.002). The frequency of the HLA-DRB1*9/other genotype was 25.0% in cases vs 2.5% in controls (p=0.004; OR: 10.8 [95% CI: 2.2-53.7]). Within the exploratory analysis, six additional HLA alleles (HLA-A*25, HLA-B*53, HLA-C*12, HLA-DQB1*3, HLA-DQB1*6 and HLA-DRB1*4) were also found to be associated with Ab-positive PRCA.


CONCLUSIONS
This study confirmed that HLA-DRB1*9 occurs at a significantly higher frequency in Ab-positive PRCA cases than in controls; however, within this sample set, carrying the *9 allele was neither necessary nor sufficient to cause Ab-positive PRCA.
Fijal
Bonnie
B
Johnson & Johnson Pharmaceutical Research and Development, Raritan, NJ, USA.
Ricci
Deborah
D
Vercammen
Els
E
Palmer
Peter A
PA
Fotiou
Fotis
F
Fife
Daniel
D
Lindholm
Anders
A
Broderick
Erin
E
Francke
Stephan
S
Wu
Xiaodong
X
Colaianne
James
J
Cohen
Nadine
N
D000328:Adult; D000368:Aged; D000483:Alleles; D001323:Autoantibodies / Q000032:analysis*; D016022:Case-Control Studies; D004921:Erythropoietin / Q000276:immunology* / Q000627:therapeutic use; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006680:HLA Antigens / Q000235:genetics*; D015236:HLA-C Antigens / Q000235:genetics / Q000276:immunology; D006683:HLA-DQ Antigens / Q000235:genetics / Q000276:immunology; D059866:HLA-DQ beta-Chains; D006684:HLA-DR Antigens / Q000235:genetics / Q000276:immunology; D059811:HLA-DRB1 Chains; D006801:Humans; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D011994:Recombinant Proteins; D012010:Red-Cell Aplasia, Pure / Q000235:genetics* / Q000276:immunology*; D012189:Retrospective Studies
D001323:Autoantibodies; D006680:HLA Antigens; D015236:HLA-C Antigens; D006683:HLA-DQ Antigens; D059866:HLA-DQ beta-Chains; C069051:HLA-DQB1 antigen; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; D011994:Recombinant Proteins; D004921:Erythropoietin