Differences in Meiotic Recombination Rates in Childhood Acute Lymphoblastic Leukemia at an MHC Class II Hotspot Close to Disease Associated Haplotypes

<div><p>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 <i>HLA-DPB1</i> 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 (<i>DNA3</i>), adjacent to <i>HLA-DOA</i> and centromeric of <i>HLA-DPB1</i>. To determine the relationship between this observation and <i>HLA-DPB1</i> associations, we constructed high density SNP haplotypes of the 316 kb region from <i>HLA-DMB</i> to <i>COL11A2</i> 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 <i>DNA3</i>) differed significantly between BCP-ALL and controls (P = 0.002) and in Block 4 (including <i>HLA-DPB1</i>) 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 <i>DNA3</i>, with BCP-ALL showing increased and T-ALL decreased levels compared to controls. <i>In silico</i> analysis using LDsplit sotware indicated that recombination rates at <i>DNA3</i> 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.</p>