Acute myeloid leukemia (AML) is a complex hematologic malignancy with multiple disease subgroups defined by somatic mutations and heterogeneous outcomes. Although genome-wide association studies (GWAS Show more
Acute myeloid leukemia (AML) is a complex hematologic malignancy with multiple disease subgroups defined by somatic mutations and heterogeneous outcomes. Although genome-wide association studies (GWAS) have identified a small number of common genetic variants influencing AML risk, the heritable component of this disease outside of familial susceptibility remains largely undefined. Here, we perform a meta-analysis of 4 published GWAS plus 2 new GWAS, totaling 4710 AML cases and 12 938 controls. We identify a new genome-wide significant risk locus for pan-AML at 2p23.3 (rs4665765; P = 1.35 × 10-8; EFR3B, POMC, DNMT3A, and DNAJC27), which also significantly associates with patient survival (P = 6.09 × 10-3). Our analysis also identifies 3 new genome-wide significant risk loci for disease subgroups, including AML with deletions of chromosome 5 and/or 7 at 1q23.3 (rs12078864; P = 7.0 × 10-10; DUSP23) and cytogenetically complex AML at 2q33.3 (rs12988876; P = 3.28 × 10-8; PARD3B) and 2p21 (rs79918355; P = 1.60 × 10-9; EPCAM). We also investigated loci previously associated with the risk of clonal hematopoiesis (CH) or CH of indeterminate potential and identified several variants associated with the risk of AML. Our results further inform on AML etiology and demonstrate the existence of disease subgroup specific risk loci. Show less
Lipids, which constitute half of the brain's solid matter, are essential for forming specialized membranes of neural cells, providing energy sources, and facilitating cell-to-cell communication. Altho Show more
Lipids, which constitute half of the brain's solid matter, are essential for forming specialized membranes of neural cells, providing energy sources, and facilitating cell-to-cell communication. Although the blood-brain barrier restricts lipid movement between peripheral circulation and the brain, multiple mechanisms supply the building blocks necessary to synthesize the diverse lipid species present in the central nervous system (CNS). In this issue of the JCI, Song et al. characterize specialized microvascular niches that metabolize circulating triglyceride-rich lipoproteins (TRLs) to deliver fatty acids into the brain. They located GPIHBP1, an essential chaperone for lipoprotein lipase (LPL) in the fenestrated endothelial cells of the choroid plexus (ChP) and circumventricular organs (CVOs), demonstrating lipolytic processing of peripheral TRLs and brain uptake of fatty acids. This advance implicates the GPIHBP1/LPL lipid metabolic hub in supporting the roles of the ChP and CVO in cerebrospinal fluid composition, immunity, satiety, thirst, and metabolic homeostasis. Show less