title: SNP association mapping across the extended major histocompatibility complex and risk of B-cell precursor acute lymphoblastic leukemia in children.
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.
authors.affiliation: School of Public Health, University of California, Berkeley, Berkeley, California, USA. kurayama@luke.or.jp
authors.forename: Kevin Y
authors.initials: KY
authors.lastname: Urayama
authors.forename: Anand P
authors.initials: AP
authors.lastname: Chokkalingam
authors.forename: Catherine
authors.initials: C
authors.lastname: Metayer
authors.forename: Helen
authors.initials: H
authors.lastname: Hansen
authors.forename: Suzanne
authors.initials: S
authors.lastname: May
authors.forename: Patricia
authors.initials: P
authors.lastname: Ramsay
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Wiemels
authors.forename: John K
authors.initials: JK
authors.lastname: Wiencke
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Trachtenberg
authors.forename: Pamela
authors.initials: P
authors.lastname: Thompson
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Ishida
authors.forename: Paul
authors.initials: P
authors.lastname: Brennan
authors.forename: Kent W
authors.initials: KW
authors.lastname: Jolly
authors.forename: Amanda M
authors.initials: AM
authors.lastname: Termuhlen
authors.forename: Malcolm
authors.initials: M
authors.lastname: Taylor
authors.forename: Lisa F
authors.initials: LF
authors.lastname: Barcellos
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Buffler
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D005260:Female; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D015448:Leukemia, B-Cell / Q000235:genetics*; D008285:Major Histocompatibility Complex / Q000235:genetics*; D008297:Male; D020641:Polymorphism, Single Nucleotide; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*