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Bipolar disorder (BD) is a heritable mental illness with complex etiology. While the largest published genome-wide association study identified 64 BD risk loci, the causal SNPs and genes within these loci remain unknown. We applied a suite of statistical and functional fine-mapping methods to these loci, and prioritized 22 likely causal SNPs for BD. We mapped these SNPs to genes, and investigated their likely functional consequences by integrating variant annotations, brain cell-type epigenomic annotations, brain quantitative trait loci, and results from rare variant exome sequencing in BD. Convergent lines of evidence supported the roles of SCN2A, TRANK1, DCLK3, INSYN2B, SYNE1, THSD7A, CACNA1B, TUBBP5, PLCB3, PRDX5, KCNK4, AP001453.3, TRPT1, FKBP2, DNAJC4, RASGRP1, FURIN, FES, YWHAE, DPH1, GSDMB, MED24, THRA, EEF1A2, and KCNQ2 in BD. These represent promising candidates for functional experiments to understand biological mechanisms and therapeutic potential. Additionally, we demonstrated that fine-mapping effect sizes can improve performance and transferability of BD polygenic risk scores across ancestrally diverse populations, and present a high-throughput fine-mapping pipeline (https://github.com/mkoromina/SAFFARI).
While interleukin (IL)-1β is a potent pro-inflammatory cytokine involved in host defense, high levels can cause life-threatening sterile inflammation including systemic inflammatory response syndrome. Hence, the control of IL-1β secretion is of outstanding biomedical importance. In response to a first inflammatory stimulus such as lipopolysaccharide, pro-IL-1β is synthesized as a cytoplasmic inactive pro-form. Extracellular ATP originating from injured cells is a prototypical second signal for inflammasome-dependent maturation and release of IL-1β. The human anti-protease alpha-1 antitrypsin (AAT) and IL-1β regulate each other via mechanisms that are only partially understood. Here, we demonstrate that physiological concentrations of AAT efficiently inhibit ATP-induced release of IL-1β from primary human blood mononuclear cells, monocytic U937 cells, and rat lung tissue, whereas ATP-independent IL-1β release is not impaired. Both, native and oxidized AAT are active, suggesting that the inhibition of IL-1β release is independent of the anti-elastase activity of AAT. Signaling of AAT in monocytic cells involves the lipid scavenger receptor CD36, calcium-independent phospholipase A2β, and the release of a small soluble mediator. This mediator leads to the activation of nicotinic acetylcholine receptors, which efficiently inhibit ATP-induced P2X7 receptor activation and inflammasome assembly. We suggest that AAT controls ATP-induced IL-1β release from human mononuclear blood cells by a novel triple-membrane-passing signaling pathway. This pathway may have clinical implications for the prevention of sterile pulmonary and systemic inflammation.
Assessment of individual therapeutic responses provides valuable information concerning treatment benefits in individual patients. We evaluated individual therapeutic responses as determined by the Disease Activity Score-28 joints critical difference for improvement (DAS28-dcrit) in rheumatoid arthritis (RA) patients treated with intravenous tocilizumab or comparator anti-tumor necrosis factor (TNF) agents. The previously published DAS28-dcrit value [DAS28 decrease (improvement) ≥ 1.8] was retrospectively applied to data from two studies of tocilizumab in RA, the 52-week ACT-iON observational study and the 24-week ADACTA randomized study. Data were compared within (not between) studies. DAS28 was calculated with erythrocyte sedimentation rate as the inflammatory marker. Stability of DAS28-dcrit responses and European League Against Rheumatism (EULAR) good responses was determined by evaluating repeated responses at subsequent timepoints. A logistic regression model was used to calculate p values for differences in response rates between active agents. Patient-reported outcomes (PROs; pain, global health, function, and fatigue) in DAS28-dcrit responder versus non-responder groups were compared with an ANCOVA model. DAS28-dcrit individual response rates were 78.2% in tocilizumab-treated patients and 58.2% in anti-TNF-treated patients at week 52 in the ACT-ion study (p = 0.0001) and 90.1% versus 59.1% at week 24 in the ADACTA study (p < 0.0001). DAS28-dcrit responses showed greater stability over time (up to 52 weeks) than EULAR good responses. For both active treatments, DAS28-dcrit responses were associated with statistically significant improvements in mean PRO values compared with non-responders. The DAS28-dcrit response criterion provides robust assessments of individual responses to RA therapy and may be useful for discriminating between active agents in clinical studies and guiding treat-to-target decisions in daily practice.