Abstract
Childhood Acute Lymphoblastic Leukemia (ALL) is a malignant lymphoid disease of which B-cell precursor- (BCP) and T-cell- (T) ALL are subtypes. The role of alleles encoded by major histocompatibility loci (MHC) have been examined in a number of previous studies and results indicating weak, multi-allele associations between the HLA-DPB1 locus and BCP-ALL suggested a role for immunosusceptibility and possibly infection. Two independent SNP association studies of ALL identified loci approximately 37 kb from one another and flanking a strong meiotic recombination hotspot (DNA3), adjacent to HLA-DOA and centromeric of HLA-DPB1. To determine the relationship between this observation and HLA-DPB1 associations, we constructed high density SNP haplotypes of the 316 kb region from HLA-DMB to COL11A2 in childhood ALL and controls using a UK GWAS data subset and the software PHASE. Of four haplotype blocks identified, predicted haplotypes in Block 1 (centromeric of DNA3) differed significantly between BCP-ALL and controls (P = 0.002) and in Block 4 (including HLA-DPB1) between T-ALL and controls (P = 0.049). Of specific common (>5%) haplotypes in Block 1, two were less frequent in BCP-ALL, and in Block 4 a single haplotype was more frequent in T-ALL, compared to controls. Unexpectedly, we also observed apparent differences in ancestral meiotic recombination rates at DNA3, with BCP-ALL showing increased and T-ALL decreased levels compared to controls. In silico analysis using LDsplit sotware indicated that recombination rates at DNA3 are influenced by flanking loci, including SNPs identified in childhood ALL association studies. The observed differences in rates of meiotic recombination at this hotspot, and potentially others, may be a characteristic of childhood leukemia and contribute to disease susceptibility, alternatively they may reflect interactions between ALL-associated haplotypes in this region.
Highlights
Acute lymphoblastic leukemia (ALL) is the most common malignant disease in children under 16 years of age in socioeconomically developed countries including the UK [1]
In view of our results suggesting weak associations between certain human leukocyte antigen (HLA)-DPB1 alleles and childhood B-cell precursor- (BCP)-ALL [14,16,22], recent evidence [18] that an major histocompatibility loci (MHC) single nucleotide polymorphisms (SNPs) most strongly associated with childhood ALL is approximately 97 kb telomeric of HLA-DPB1, and a significant association of ALL cases in the Northern California Childhood Leukemia Study (NCCLS) with rs9296068, located approximately 60 kb telomeric from HLADPB1, we considered that these SNPs might be in linkage disequilibrium (LD) with BCPALL-associated HLA-DPB1 alleles
We confirmed the weak association between rs3135034 and B-cell precursor ALL (BCP-ALL), but found no evidence of association of this SNP with T-ALL (P = 0.6), or an association of rs9296068 with either ALL subtype (P.0.3)(Figure 1; Table S1)
Summary
Acute lymphoblastic leukemia (ALL) is the most common malignant disease in children under 16 years of age in socioeconomically developed countries including the UK [1]. Genome wide association studies (GWAS) of sporadic ALL have, identified single nucleotide polymorphisms (SNPs) in linkage disequilibrium (LD) with 4 genes (IKZF1, ARID5B, CEBPE, CDKN2A) [2,3,4] having roles in B-Cell development [5,6,7,8]. Clues provided by evidence that susceptibility to mouse retroviral ALL is linked to the MHC [11], and that certain human leukocyte antigen (HLA) alleles are associated with susceptibility to specific infections (reviewed in [12]), have encouraged the search for HLA allele associations with childhood ALL as a proxy for infection [13,14,15,16,17]. Interactions were identified between the DP1 supertype and proxies for delayed immune exposure in early life, providing further support for HLA-DP function in susceptibility to childhood BCP-ALL [14]
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