Abstract
The extended major histocompatibility complex (xMHC) is the most gene-dense region of the genome and harbors a disproportionately large number of genes involved in immune function. The postulated role of infection in the causation of childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL) suggests that the xMHC may make an important contribution to the risk of this disease. We conducted association mapping across an approximately 4 megabase region of the xMHC using a validated panel of single nucleotide polymorphisms (SNPs) in childhood BCP-ALL cases (n=567) enrolled in the Northern California Childhood Leukemia Study (NCCLS) compared with population controls (n=892). Logistic regression analyses of 1,145 SNPs, adjusted for age, sex, and Hispanic ethnicity indicated potential associations between several SNPs and childhood BCP-ALL. After accounting for multiple comparisons, one of these included a statistically significant increased risk associated with rs9296068 (OR=1.40, 95% CI=1.19-1.66, corrected p=0.036), located in proximity to HLA-DOA. Sliding window haplotype analysis identified an additional locus located in the extended class I region in proximity to TRIM27 tagged by a haplotype comprising rs1237485, rs3118361, and rs2032502 (corrected global p=0.046). Our findings suggest that susceptibility to childhood BCP-ALL is influenced by genetic variation within the xMHC and indicate at least two important regions for future evaluation.
Highlights
Acute lymphoblastic leukemia (ALL) is a clonal disorder involving the dysregulated proliferation of genetically altered lymphoid progenitor cells that lack the ability for differentiation and maturation
Analysis of 1,145 single nucleotide polymorphisms (SNPs) in childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL), assuming a log-additive genetic model of inheritance, showed a quantilequantile (Q-Q) plot of the expected versus observed –log10 pvalue distribution that suggested little evidence of inflation in results caused by systematic error (Figure S1)
Twenty SNPs were associated with a nominal p-value of less than 0.01, many of which were in linkage disequilibrium (LD) (Figure 1 and Figure S2)
Summary
Acute lymphoblastic leukemia (ALL) is a clonal disorder involving the dysregulated proliferation of genetically altered lymphoid progenitor cells that lack the ability for differentiation and maturation. BCP-ALL, which demonstrates a unique ageincidence peak between 2 and 5 years of age, is widely suspected to be caused by environmental exposures, though these have yet to be definitively identified [1] Foremost among these are thought to be factors such as the effect of timing of exposure to infectious agents leading to inappropriate immune responses, in conjunction with variants in genes of the immunological pathway and early lymphoid development [2]. Genetic association studies of the xMHC have focused on the classical human leukocyte antigen (HLA) genes of the class I (HLA-A, B, and C) and class II (HLA-DP, DQ, and DR) regions These encode cell surface glycoproteins that selectively bind and present, in allele selective fashion, processed antigenic peptides to T lymphocytes that initiate T-cell responses. While HLA genes are among the most polymorphic in humans, they account for only a small proportion of over 250 expressed xMHC loci, which include genes encoding cytokines, complement factors, and various others involved in critical cellular processes
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