Genetic control of nonresponsiveness to hepatitis B virus vaccine by an extended HLA haplotype

We previously reported evidence for a statistical association between the serologically determined HLA‐Bw54, DR4 and DRw53 alleles and the non‐immune responsiveness to hepatitis B virus surface antigen (HBsAg) in the Japanese population. To identify the locus and allele within the HLA region associated with the nonresponsiveness to HBsAg, serological HLA typing, DNA typing of HLA‐DQ and DP alleles using amplified HLA genes and sequence‐specific oligonucleotide probes, and restriction fragment length polymorphism (RFLP) analysis of the fourth component of complement (C4) genes were performed in healthy unrelated Japanese vaccinees who were immunized subcutaneously three times with plasma‐derived HBsAg vaccine. In nonresponders to HBsAg, the frequencies of HLA‐Bw54 cross‐reactive epitope group (CREG); (Bw54, Bw55, Bw56 and other Bw22), C4 RFLP (6.5 kb + 12.0 kb), DR4, DRw53 and DQw4 (DQA1^*0301‐DQB1^*0401) were increased and the frequencies of HLA‐DR1, DRw6 and DQw1 were decreased as compared with those in healthy unrelated controls. Further analysis revealed that the coexistence of HLA‐Bw54CREG and DR4‐DRw53‐DQw4 (DQA1^*0301‐DQB1^*0401) was associated with the nonresponder group, whereas, donors positive for exclusively either Bw54 CREG or DR4‐DRw53‐DQw4 (DQA1^*0301‐DQB1^*0401) were not associated with the nonresponder group. Because there is a strong linkage disequilibrium between HLA‐Bw54CREG, C4 RFLP (6.5 kb + 12.0 kb) and HLA‐DR4‐DRw53‐DQw4 (DQA1^*0301‐DQB1^*0401) in the Japanese population, the extended HLA‐Bw54CREG‐C4 RFLP (6.5 kb + 12.0 kb)‐DR4‐DRw53‐DQw4 (DQA1^*0301‐DQB1^*0401) haplotype may well control nonimmune responsiveness to HBsAg. This extended HLA haplotype controls nonresponsiveness as a dominant genetic trait because all ten heterozygotes and two of three probable homozygotes of this extended HLA haplotype were nonresponders.