PLoS ONE (Jan 2013)

SNP association mapping across the extended major histocompatibility complex and risk of B-cell precursor acute lymphoblastic leukemia in children.

  • Kevin Y Urayama,
  • Anand P Chokkalingam,
  • Catherine Metayer,
  • Helen Hansen,
  • Suzanne May,
  • Patricia Ramsay,
  • Joseph L Wiemels,
  • John K Wiencke,
  • Elizabeth Trachtenberg,
  • Pamela Thompson,
  • Yasushi Ishida,
  • Paul Brennan,
  • Kent W Jolly,
  • Amanda M Termuhlen,
  • Malcolm Taylor,
  • Lisa F Barcellos,
  • Patricia A Buffler

DOI
https://doi.org/10.1371/journal.pone.0072557
Journal volume & issue
Vol. 8, no. 8
p. e72557

Abstract

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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.