Journal Article

SNP Association Mapping across the Extended Major Histocompatibility Complex and Risk of B-Cell Precursor Acute Lymphoblastic Leukemia in Children

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

2013

Overview

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.

• Publisher: Public Library of Science (PLoS),Public Library of Science
• Subject: Acute lymphoblastic leukemia / Acute lymphocytic leukemia / Adolescent / Bioinformatics / Cancer / Cancer research / Causation / Child / Child, Preschool / Childhood leukemia / Children / Epidemiology / Female / Gene mapping / Genetic aspects / Genetic diversity / Genome-Wide Association Study / Genomes / Genomics / Genotype / Haplotypes / Health aspects / Health risks / Histocompatibility antigen HLA / Hospitals / Humans / Immune response / Infant / Infant, Newborn / Laboratories / Leukemia / Leukemia, B-Cell / Leukemia, B-Cell - genetics / Lymphatic leukemia / Lymphocytes B / Major Histocompatibility Complex / Major Histocompatibility Complex - genetics / Male / Mapping / Medicine / Minority & ethnic groups / Pediatrics / Polymorphism, Single Nucleotide / Population studies / Precursor Cell Lymphoblastic Leukemia-Lymphoma / Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics / Precursors / Public health / Q / R / Regression analysis / Research Article / Risk / Science / Single nucleotide polymorphisms / Single-nucleotide polymorphism / Statistical analysis / Studies