Journal
NATURE GENETICS
Volume 41, Issue 9, Pages 1001-U67Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.432
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Funding
- NATIONAL CANCER INSTITUTE [R01CA036401, U01CA157937, U10CA029139, P30CA021765, R01CA051001, U10CA098543, R37CA036401, R29CA051001, U10CA098413, R01CA078224] Funding Source: NIH RePORTER
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [U01HL065899] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [U01GM061374, U01GM061393] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF MENTAL HEALTH [R01MH060879, U01MH046318, Z01MH002810, R01MH059565, R01MH059567, R01MH060068, R01MH059545, R01MH060870, R01MH081800, R01MH059571, R01MH059533, R01MH059548, R01MH059556, R01MH059535, R01MH059534, R01MH059566, R01MH059587, U01MH079469, R01MH067257, U01MH046276, R01MH059588, R01MH059553, R01MH059586, R01MH061675, U01MH079470] Funding Source: NIH RePORTER
- Intramural NIH HHS [Z01 MH002810] Funding Source: Medline
- NCI NIH HHS [P30 CA021765, R37 CA036401-24, CA 078224, CA 21765, P30 CA021765-259006, CA 36401, U10 CA029139-22, U10 CA098413, R01 CA051001, R01 CA078224-10, U10 CA098543, U01 CA157937, U10 CA098543-07, R01 CA036401, U10 CA098413-07, R37 CA036401, R01 CA078224, CA 51001, R01 CA051001-15] Funding Source: Medline
- NHLBI NIH HHS [U01 HL65899, U01 HL065899, U01 HL065899-07] Funding Source: Medline
- NIGMS NIH HHS [U01 GM061393, U01 GM61393, U01 GM061374-07, U01GM61374, U01 GM061393-100007, U01 GM061374] Funding Source: Medline
- NIMH NIH HHS [R01 MH059553, R01 MH059586, R01 MH059567, R01 MH059548, R01 MH067257, R01 MH059566, U01 MH079469, R01 MH059545, R01 MH060870, R01 MH081800, R01 MH059535, R01 MH059534, R01 MH059588, U01 MH046318, R01 MH059571, R01 MH059565, U01 MH079470, R01 MH059587, R01 MH059533, U01 MH046276, R01 MH060879, R01 MH059556, R01 MH061675, R01 MH060068] Funding Source: Medline
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Using the Affymetrix 500K Mapping array and publicly available genotypes, we identified 18 SNPs whose allele frequency differed significantly(P < 1 x 10(-5)) between pediatric acute lymphoblastic leukemia (ALL) cases (n = 317) and non-ALL controls (n = 17,958). Two SNPs in ARID5B not only differed between ALL and non-ALL groups (rs10821936, P = 1.4 x 10(-15), odds ratio (OR) = 1.91; rs10994982, P = 5.7 x 10(-9), OR = 1.62) but also distinguished B-hyperdiploid ALL from other subtypes (rs10821936, P = 1.62 x 10(-5), OR = 2.17; rs10994982, P = 0.003, OR 1.72). These ARID5B SNPs also distinguished B-hyperdiploid ALL from other subtypes in an independent validation cohort (n 124 children with ALL; P 0.003 and P = 0.0008, OR 2.45 and 2.86, respectively) and were associated with methotrexate accumulation and gene expression pattern in leukemic lymphoblasts. We conclude that germline variants affect susceptibility to, and characteristics of, specific ALL subtypes.
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