Abstract
Acute myeloid leukemia (AML) is a hematological malignancy with an undefined heritable risk. Here we perform a meta-analysis of three genome-wide association studies, with replication in a fourth study, incorporating a total of 4018 AML cases and 10488 controls. We identify a genome-wide significant risk locus for AML at 11q13.2 (rs4930561; P = 2.15 × 10−8; KMT5B). We also identify a genome-wide significant risk locus for the cytogenetically normal AML sub-group (N = 1287) at 6p21.32 (rs3916765; P = 1.51 × 10−10; HLA). Our results inform on AML etiology and identify putative functional genes operating in histone methylation (KMT5B) and immune function (HLA).
Highlights
Acute myeloid leukemia (AML) is a hematological malignancy with an undefined heritable risk
We combined the association test statistic for 6694056 autosomal single nucleotide polymorphisms (SNPs) common to all three genome-wide association studies (GWAS) after exclusion of those with an INFO score of
We identified strong statistical evidence for an association with cytogenetically normal AML for rs3916765, which maps to the HLA locus on 6p21.32, intergenic to HLA-DQB1 and HLA-DQA2 within the major histocompatibility (MHC) class II region (Fig. 3b)
Summary
Acute myeloid leukemia (AML) is a hematological malignancy with an undefined heritable risk. Rare germline variants in transcription factors and other genes regulating hematopoietic cell differentiation and proliferation are highly penetrant for AML3, with some causative for debilitating human syndromes that include AML as a component, while others cause familial AML with high penetrance Such variants demonstrate a role for genetics in AML susceptibility, they are rare and do not make a major contribution to population disease burden[4]. We report the identification of risk loci for AML, including panAML irrespective of disease sub-type and for cytogenetically normal AML These data inform on disease etiology and demonstrate the existence of common, low-penetrance susceptibility alleles for AML with heterogeneity in risk across sub-types
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