title: Impact of HLA alleles and cytokine polymorphisms on inhibitors development in children with severe haemophilia A.
abstract: Human Leucocyte Antigen (HLA) alleles, cytokine polymorphisms and the type of factor VIII (FVIII) gene mutation are among predisposing factors for inhibitors (inh) development in children with severe haemophilia A (HA). The aim was to investigate the correlations among (i) FVIII gene intron-22 inversion, (ii) HLA alleles and haplotypes and (iii) certain cytokine polymorphisms, with the risk for FVIII inhibitors development in 52 Greek severe HA children, exclusively treated with recombinant concentrates. We performed Long-Range PCR for detection of intron-22 inversion and PCR-SSP, PCR-SSO for genotyping of HLA-A, B, C, DRB1, DQB1 alleles and also for cytokine polymorphisms of TNF-α, TGF-β1, IL-10, IL-6 and IFN-γ. Chi-squared test and Fischer's exact test were used for statistical analysis. A total of 28 children had developed inhibitors (Group I), 71.4% high responding, while 24 had not (Group II). No statistically increased intron-22 inversion prevalence was found in Group I compared with Group II (P = 0.5). Comparison of HLA allele frequencies between the two groups showed statistically significant differences in the following genotypes (i) promoting inhibitors development: DRB1*01(P = 0.014), DRB1*01:01(P = 0.011) and DQB1*05:01 (P = 0.005) and (ii) possibly protecting from inhibitors development: DRB1*11 (P = 0.011), DRB1*11:01 (P = 0.031), DQB1*03 (P = 0.004) and DQB1*03:01 (P = 0.014). Analysis of cytokines revealed a higher incidence of inhibitor detection only in homozygotes of the haplotypes ACC and ATA for IL-10 polymorphisms (P = 0.05). There is evidence that HLA alleles and cytokine polymorphisms play an important role in FVIII inh development. On the contrary, no statistically significant results were obtained for intron-22 inversion and its impact on FVIII inhibitors formation.
authors.affiliation: Haemophilia Centre/Haemostasis Unit, Aghia Sophia Children's Hospital, Athens, Greece. haemofilia@paidon-agiasofia.gr
authors.forename: H
authors.initials: H
authors.lastname: Pergantou
authors.forename: I
authors.initials: I
authors.lastname: Varela
authors.forename: O
authors.initials: O
authors.lastname: Moraloglou
authors.forename: M
authors.initials: M
authors.lastname: Economou
authors.forename: K
authors.initials: K
authors.lastname: Spanou
authors.forename: Z
authors.initials: Z
authors.lastname: Kapsimali
authors.forename: N
authors.initials: N
authors.lastname: Constantinidou
authors.forename: H
authors.initials: H
authors.lastname: Platokouki
mesh_terms: D000293:Adolescent; D000483:Alleles; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D016207:Cytokines / Q000235:genetics* / Q000276:immunology; D005169:Factor VIII / Q000037:antagonists & inhibitors / Q000276:immunology*; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006680:HLA Antigens / Q000235:genetics* / Q000276:immunology; D006467:Hemophilia A / Q000235:genetics* / Q000276:immunology; D006801:Humans; D007223:Infant; D007518:Isoantibodies / Q000096:biosynthesis / Q000276:immunology*; D008297:Male; D011110:Polymorphism, Genetic
chemical_list: D016207:Cytokines; D006680:HLA Antigens; D007518:Isoantibodies; C078147:F8 protein, human; D005169:Factor VIII
keywords: FVIII inhibitors; HLA alleles; cytokines polymorphisms; severe Haemophilia A