The association of anti-r-HuEpo-associated pure red cell aplasia with HLA-DRB1*09-DQB1*0309.
BACKGROUND
Anti-r-HuEpo associated PRCA developed in patients received subcutaneous injection of r-HuEpo for treatment of renal anemia in chronic kidney disease. This adverse immunological effect of r-HuEpo causes sudden loss of r-HuEpo efficacy, low circulating reticulocyte count and bone marrow biopsy shows an absence of erythroid precursor cells with normal cell population of non-erythroid lineage. There are postulation cause of anti-r-HuEpo associated PRCA including genetic factor, immunogenicity factor, storage and handlings factor and formulation of r-HuEpo product. Previous observation of our report showed an aggregation of HLA-DRB1*09 in four anti-r-HuEpo associated PRCA cases. This allele is rare in Caucasian (<1%) but more common in Thai population (8.4-12.5%). This study was aimed to investigate the possible association between HLA-DRB1*09 or other specific HLA and anti-r-HuEpo associated PRCA.


METHODS
Twenty two cases of proven anti-r-HuEpo associated PRCA were recruited and studied retrospectively based on the incidence report of serious adverse drug reaction. The EDTA bloods were drawn for HLA typing using sequence specific primer polymerase chain reaction (SSP-PCR). The HLA data of 1,800 potential cadaveric kidney transplantation recipients in the waiting list as chronic kidney disease control and 1,500 potential bone marrow stem cell donors in national stem cell registry as healthy population control were retrieved from the database of Thai Red Cross for comparison.


RESULTS
The distribution of gene frequency of HLA-A, -B, -DR and -DQ alleles in anti-r-HuEpo associated PRCA cases showed high gene frequency of HLA-A*02, HLA-A*11 and HLA-A*24 for HLA-A loci, HLA-B*18, HLA-B*46, HLA-B*60 and HLA-B*62 for HLA-B loci, and HLA-DRB1*09, HLA-DRB1*12 and HLA-DRB1*15 for HLA-DR loci. There was a significant difference of HLA-DRB1*09 gene frequency (P < 0.001) which associated with HLA-DQB1*0309 between anti-r-HuEpo associated PRCA cases, and potential cadaveric kidney transplantation in the waiting list or potential national stem cell registry donor. The odd ratio of HLA-DRB1*09 allele for anti-r-HuEpo associated PRCA was 2.89 (95% CI: 1.88-4.46; p-value: <0.001).


CONCLUSIONS
Our data demonstrated the association of HLA-DRB1*09-DQB1*0309 and anti-r-HuEpo associated PRCA cases. This association may be used in identifying the risk of the patients.
Praditpornsilpa
Kearkiat
K
Division of Nephrology, Department of Medicine, Faculty of Medicine, Chulalongkorn University Hospital, Bangkok, Thailand. fmedkpd@md.chula.ac.th
Kupatawintu
Pawinee
P
Mongkonsritagoon
Wichean
W
Supasyndh
Ouppatham
O
Jootar
Saengsuree
S
Intarakumthornchai
Tanin
T
Pongskul
Cholatip
C
Prasithsirikul
Wisit
W
Achavanuntakul
Bunlersak
B
Ruangkarnchanasetr
Prajej
P
Laohavinij
Sudsawat
S
Eiam-Ong
Somchai
S
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000740:Anemia / Q000188:drug therapy / Q000209:etiology; D000888:Antibodies, Anti-Idiotypic / Q000097:blood / Q000276:immunology*; D016022:Case-Control Studies; D002908:Chronic Disease; D004921:Erythropoietin / Q000008:administration & dosage / Q000276:immunology* / Q000627:therapeutic use; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; 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; D007279:Injections, Subcutaneous; D007674:Kidney Diseases / Q000150:complications; D008297:Male; D008875:Middle Aged; D011994:Recombinant Proteins; D012010:Red-Cell Aplasia, Pure / Q000235:genetics* / Q000276:immunology*; D012189:Retrospective Studies; D012307:Risk Factors; D055815:Young Adult
D000888:Antibodies, Anti-Idiotypic; 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