MOLECULAR ANALYSIS OF HLA-DQB1 ALLELES IN CHILDHOOD COMMON ACUTE LYMPHOBLASTIC-LEUKEMIA

Epidemiological studies suggest that childhood common acute lymphoblas tic leukaemia (c-ALL) may be the rare outcome of early post-natal infe ction with a common infectious agent. One of the factors that may dete rmine whether a child succumbs to c-ALL is how it responds to the cand idate infection. Since immune responses to infection are under the par tial control of (human leucocyte antigen) HLA genes, an association be tween an HLA allele and c-ALL could provide support for an infectious aetiology. To define the limit of c-ALL susceptibility within the HLA region, we have compared HLA - DQB1 allele frequencies in a cohort of 62 children with c-ALL with 76 newborn controls, using group-specific polymerase chain reaction (PCR) amplification, and single-strand confo rmation polymorphism (SSCP) analysis. We find that a significant exces s of children with c-ALL type for DQB105 [relative risk (RR): 2.54, u ncorrected P=0.038], and a marginal excess with DeB10501 (RR: 2.18; P =0.095). Only 3 of the 62 children with c-ALL have the other susceptib ility allele, DPB10201 as well as DQB1*0501, whereas 15 had one or th e other allele. This suggests that HLA-associated susceptibility may b e determined independently by at least two loci, and is not due to lin kage disequilibrium. The combined relative risk of the two groups of c hildren with DPB10201 and/or DQB1*0501 is 2.76 (P=0.0076). Analysis o f amino acids encoded by exon 2 of DQB1 reveal additional complexity, with significant (P<0.05) or borderline-significant increases in Gly(2 6), His(30), Val(57), Glu(66)-Val(67) encoding motifs in c-ALL compare d with controls. Since these amino acids are not restricted to DeB105 01, our results suggest that, as with DPB1, the increased risk of c-AL L associated with DQB1 is determined by specific amino acid encoding m otifs rather than by an individual allele. These results also suggest that HLA-associated susceptibility to c-ALL may not be restricted to t he region bounded by DPB1 and DQB1.