The prevalence of HPA-1a alloimmunization and the potential risk of FNAIT depend on both the DRB3*01:01 allele and associated DR-DQ haplotypes

Abstract

Alloimmunization against human platelet antigen (HPA)-1a during pregnancy can cause foetal/neonatal alloimmune thrombocytopenia (FNAIT) and severe bleeding in the foetus or newborn and likely depends on several factors. HPA-1a alloimmunization is associated with <i>DRB3*01:01</i>, which is associated with several DR-DQ haplotypes. However, it is not known to what extent these haplotypes contribute to the prevalence of HPA-1a alloimmunization. HPA-1a–alloimmunized women, identified in a prospective study, and random donors were typed for selected <i>DRB3, DRB4, DRB1, DQA1</i> and <i>DQB1</i> alleles to determine allele and DR-DQ haplotype frequencies. <i>DRB3*01:01</i> was carried by 94% HPA-1a–immunized women compared to 27% in the general population. In the first population, the DR3-DQ2 haplotype was overrepresented (<i>P</i> < .003). The prevalence of HPA-1a alloimmunization was estimated to be about twice as frequent with DR3-DQ2 compared to DR13-DQ6, together accounting for about 90% of <i>DRB3*01:01</i>–positive individuals. Further, we examined <i>DQB1*02</i> and <i>DRB4*01:01</i> alleles for their reported association with HPA-1a alloimmunization, in the context of DR-DQ haplotypes. Since ~ 80% of <i>DQB1*02</i> alleles are linked to the DR3-DQ2 haplotype, the association might be coincidental. However, the <i>DQB1*02:02</i>–associated DR7-DQ2 haplotype was also overrepresented in alloimmunized women, suggesting a role for this allele or haplotype in HPA-1a alloimmunization. As <i>DRB4*01:01</i> is predominantly associated with the DR7-DQ2 haplotype in HPA-1a–alloimmunized individuals, the reported association with FNAIT may be coincidental. Typing for DR-DQ haplotypes revealed important genetic associations with HPA-1a alloimmunization not evident from typing individual alleles, and the presence of different DRB3-associated DR-DQ haplotypes showed different prevalence of HPA-1a alloimmunization.