Abstract
Epidemiological studies suggest that childhood common acute lymphoblastic leukaemia (c-ALL) may be the rare outcome of early post-natal infection with a common infectious agent. One of the factors that may determine whether a child succumbs to c-ALL is how it responds to the candidate infection. Since immune responses to infection are under the partial control of (human leucocyte antigen) HLA genes, an association between 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 conformation polymorphism (SSCP) analysis. We find that a significant excess of children with c-ALL type for DQB1*05 [relative risk (RR): 2.54, uncorrected P=0.038], and a marginal excess with DQB1*0501 (RR: 2.18; P=0.095). Only 3 of the 62 children with c-ALL have the other susceptibility allele, DPB1*0201 as well as DQB1*0501, whereas 15 had one or the other allele. This suggests that HLA-associated susceptibility may be determined independently by at least two loci, and is not due to linkage disequilibrium. The combined relative risk of the two groups of children with DPB1*0201 and/or DQB1*0501 is 2.76 (P=0.0076). Analysis of amino acids encoded by exon 2 of DQB1 reveal additional complexity, with significant (P<0.05) or borderline-significant increases in Gly26, His30, Val57, Glu66-Val67 encoding motifs in c-ALL compared with controls. Since these amino acids are not restricted to DQB1*0501, our results suggest that, as with DPB1, the increased risk of c-ALL associated with DQB1 is determined by specific amino acid encoding motifs rather than by an individual allele. These results also suggest that HLA-associated susceptibility to c-ALL may not be restricted to the region bounded by DPB1 and DQB1.
Highlights
We report that children who have DQBI*0501 are at increased risk of cALL, and that this does not appear to be in linkage disequilibrium with DPBJ*0201
Since there are nearly 50% more boys than girls in our common acute lymphoblastic leukaemia (c-acute lymphoblastic leukaemia (ALL)) cohort, we examined whether there might be a HLA-DQB1 in childhood c-ALL SP Dearden et al relative risk (RR) X2 P value
When we analysed the frequency of patients with both alleles, (Table V) we found that only 3 of the 62 children with c-ALL typed for DPBI*0201 and DQBI*0501, 29 had neither allele and 15 each had either DPBI*0201 or DQBI*0501
Summary
The patients in this study comprise the same cohort as that described previously (Taylor et al, 1995) and consists of 62 children (one child from the previous study is excluded) with c-ALL treated at a single centre (Royal Manchester Children's Hospital) in the north west of England, between 1990 and 1992. To reduce bias to an absolute minimum, only children in whom a diagnosis of c-ALL was confirmed by cytology and immunophenotyping according to the Medical Research Council's 11th ALL trial (UKALL XI) guidelines are included in the analysis. Including those with unclassified ALL are excluded. Blood samples were obtained from children, usually in remission, either in the clinic or at home with parental consent. Control blood samples were obtained from the placental side of the clamped umbilical cord of normal full-term babies delivered at St Mary's Hospital. Caesarean sections and pregnancies with complications were excluded
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