Life-threatening NLRC4-associated hyperinflammation successfully treated with IL-18 inhibition.

doi:10.1016/J.JACI.2016.10.022

Journal Article•DOI•

Life-threatening NLRC4-associated hyperinflammation successfully treated with IL-18 inhibition.

Scott W. Canna¹, Charlotte Girard², Louise Malle¹, Adriana de Jesus¹, Neil Romberg³, Judith R. Kelsen³, Lea F. Surrey³, Pierre Russo³, Andrew Sleight, Eduardo Schiffrin, Cem Gabay², Raphaela Goldbach-Mansky¹, Edward M. Behrens³ - Show less +9 more•Institutions (3)

National Institutes of Health¹, Geneva College², Children's Hospital of Philadelphia³

01 May 2017-The Journal of Allergy and Clinical Immunology (J Allergy Clin Immunol)-Vol. 139, Iss: 5, pp 1698-1701

TL;DR: A critically ill infant with severe, refractory NLRC4-MAS who showed sustained response to treatment with experimental IL-18 inhibition is reported.

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Abstract: NLRC4-inflammasome hyperactivity causes infantile-onset Macrophage Activation Syndrome and enterocolitis with extraordinary serum IL-18 elevation (NLRC4-MAS). Herein, we report a critically ill infant with severe, refractory NLRC4-MAS who showed sustained response to treatment with experimental IL-18 inhibition.

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Journal Article•DOI•

Interleukin-18 Binding Protein: A Novel Modulator of the Th1 Cytokine Response

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Daniela Novick¹, Soohyun Kim¹, Giamila Fantuzzi², Leonid L. Reznikov², Charles A. Dinarello², Menachem Rubinstein¹ - Show less +2 more•Institutions (2)

Weizmann Institute of Science¹, Anschutz Medical Campus²

01 Jan 1999-Immunity

TL;DR: Interleukin-18 binding protein functions as an inhibitor of the early Th1 cytokine response, suggesting that viral products may attenuate IL-18 and interfere with the cytotoxic T cell response.

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788 citations

Journal Article•DOI•

An animal model of hemophagocytic lymphohistiocytosis (HLH): CD8+ T cells and interferon gamma are essential for the disorder.

[...]

Michael B. Jordan¹, David A. Hildeman, John W. Kappler, Philippa Marrack•Institutions (1)

Anschutz Medical Campus¹

01 Aug 2004-Blood

TL;DR: Insight is provided into the pathophysiology of HLH, new targets for specific therapeutic intervention in this fatal disorder are provided, and the excessive amount of IFNgamma seen in affected mice appears to be driven by increased antigen presentation to CD8+ T cells.

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599 citations

"Life-threatening NLRC4-associated h..." refers background in this paper

...MAS and HLH are life- threatening sepsis-like conditions notable for hyperferritinemia, acute cytopenias, and hepatitis....
[...]
...Notably, IFNγ is the cytokine most implicated in driving familial forms of HLH(4), although it’s role in MAS is more controversial....
[...]
...18 2.45 2.32 -1.30 1.79 -2.53 -0.53 0.11 HCG26 2.25 2.39 2.32 -1.40 3.02 -2.42 1.08 0.06 ERBB2 2.16 2.47 2.32 -1.30 0.46 -2.04 -0.92 0.13 C9orf117 2.49 2.15 2.32 -1.63 1.42 -2.33 -0.79 0.15 KCNC3 2.46 2.18 2.32 -1.58 0.90 -2.24 -1.02 0.12 IGFBP3 2.22 2.43 2.32 -0.78 -0.67 -0.74 -0.56 0.09 ADAMTSL5 2.62 2.03 2.33 -1.56 -0.06 -1.63 -0.75 0.25 NPIPB3 2.04 2.62 2.33 -0.47 1.73 -1.90 -0.81 0.25 GDF11 2.15 2.52 2.33 -2.18 0.92 -3.53 -1.46 0.16 CRHR1-IT1 2.16 2.52 2.34 -1.55 -0.03 -2.28 -1.40 0.16 KRTAP5-1 2.35 2.34 2.34 -1.54 0.67 -1.95 -0.30 0.01 ROBO3 2.13 2.56 2.34 -1.03 1.52 -2.00 -0.01 0.19 HES1 2.01 2.68 2.35 -2.69 -1.87 -2.55 -0.97 0.28 ZNF783 2.09 2.60 2.35 -1.30 1.94 -3.04 -1.09 0.22 ZNF204P 2.16 2.53 2.35 -1.07 1.03 -2.06 -0.79 0.16 ZDHHC8 2.03 2.67 2.35 -0.82 2.38 -2.83 -0.98 0.28 ZFP90 2.20 2.50 2.35 -1.36 1.46 -2.40 -0.45 0.12 NPIPB5 2.05 2.65 2.35 -0.45 1.77 -1.91 -0.83 0.25 TMED11P 2.19 2.53 2.36 -1.10 -0.03 -1.10 0.28 0.14 LOC642423 2.68 2.03 2.36 -1.80 -0.27 -1.68 -0.62 0.27 ZNF767P 2.52 2.21 2.36 -2.21 1.39 -2.82 -0.70 0.13 LOC613037 2.03 2.70 2.37 -0.41 1.83 -1.94 -0.83 0.28 BIVM 2.29 2.44 2.37 -1.22 1.92 -2.72 -1.38 0.06 SEC31B 2.07 2.66 2.37 -1.50 2.22 -2.92 0.51 0.25 DYNC1H1 2.03 2.70 2.37 -2.54 0.76 -4.02 -1.10 0.28 SLC2A4RG 2.38 2.36 2.37 -1.14 1.88 -1.85 0.16 0.01 DGKQ 2.67 2.08 2.37 -2.17 2.61 -1.50 2.31 0.25 CCDC7 2.01 2.75 2.38 -0.73 -0.06 -1.09 -0.54 0.31 LINC00987 2.01 2.74 2.38 -1.53 0.21 -2.45 -1.04 0.31 NRIP2 2.49 2.26 2.38 -1.06 0.77 -1.79 -1.16 0.10 CLIC5 2.06 2.70 2.38 -1.86 -0.25 -1.98 0.39 0.27 C5orf63 2.10 2.66 2.38 -0.91 1.23 -1.78 0.00 0.23 DNM1P41 2.02 2.74 2.38 -1.40 -0.32 -1.47 0.23 0.30 PVRIG 2.41 2.35 2.38 -0.97 1.37 -1.77 -0.62 0.03 PORCN 2.32 2.45 2.38 -1.40 4.79 -3.49 0.32 0.06 RNF43 2.39 2.38 2.38 -1.48 1.46 -2.48 -0.95 0.01 AES 2.13 2.64 2.38 -1.77 0.85 -2.38 0.39 0.21 SLFN14 2.71 2.06 2.39 -1.88 0.45 -2.08 -0.84 0.27 GPR25 2.74 2.03 2.39 -0.49 1.50 -1.34 -1.04 0.30 TIAM2 2.21 2.57 2.39 -2.07 -0.27 -2.36 -0.47 0.15 PRX 2.22 2.56 2.39 -1.65 0.45 -2.43 -0.93 0.15 MRPS6 2.25 2.54 2.39 -2.00 0.91 -2.48 0.38 0.12 C1orf106 2.38 2.40 2.39 -0.60 3.58 -2.41 -0.71 0.01 PLXNA1 2.07 2.72 2.39 -1.77 0.72 -3.04 -1.22 0.27 TTC21B-AS1 2.73 2.05 2.39 -0.40 1.58 -0.63 0.33 0.28 RRN3P2 2.08 2.71 2.39 -2.02 0.36 -3.23 -1.52 0.26 ZNF703 2.33 2.47 2.40 -0.67 1.15 -1.59 -0.93 0.06 SDCBP2-AS1 2.00 2.80 2.40 -1.64 0.66 -2.88 -0.97 0.33 ZNF568 2.12 2.68 2.40 -2.11 1.44 -4.09 -2.10 0.23 LYNX1 2.52 2.28 2.40 -1.94 1.19 -1.79 1.05 0.10 KIR3DL1 2.43 2.38 2.41 -0.88 -0.07 -1.01 -0.40 0.02 STXBP1 2.00 2.81 2.41 -2.27 -0.90 -2.52 -0.51 0.33 ZNF778 2.52 2.30 2.41 -1.56 1.11 -2.20 -0.75 0.09 ZNF530 2.03 2.79 2.41 -1.95 0.87 -3.28 -0.76 0.32 PHLDB2 2.29 2.54 2.41 -1.59 0.24 -2.23 -1.02 0.10 PCID2 2.03 2.80 2.42 -1.27 2.14 -2.71 0.67 0.32 M AN US CR IP T AC CE PT ED ACCEPTED MANUSCRIPTPIEZO1 2.01 2.82 2.42 -1.03 1.83 -2.84 -1.02 0.33 LIMD1-AS1 2.02 2.81 2.42 -1.13 2.36 -3.07 -0.36 0.33 SPRY2 2.09 2.76 2.42 -1.13 0.49 -1.78 -0.29 0.28 TMPRSS3 2.78 2.07 2.43 -0.93 2.18 -1.94 -1.15 0.29 HAR1A 2.62 2.23 2.43 -1.66 0.29 -1.39 0.42 0.16 LOC374443 2.55 2.31 2.43 -1.32 0.06 -1.38 -0.29 0.10 RIC8B 2.57 2.30 2.43 -2.32 1.61 -2.95 -0.51 0.11 C19orf12 2.04 2.82 2.43 -0.90 4.33 -4.43 -1.73 0.32 PLCXD2 2.40 2.47 2.43 -0.88 0.78 -1.59 -0.88 0.03 TMCO4 2.17 2.69 2.43 -1.06 6.11 -4.27 0.65 0.21 PPAP2C 2.44 2.43 2.44 -0.65 2.43 -1.08 1.38 0.00 DGKE 2.21 2.66 2.44 -1.51 0.82 -2.66 -1.37 0.18 URGCP 2.14 2.74 2.44 -2.25 1.50 -3.96 -1.19 0.25 HSH2D 2.25 2.63 2.44 -2.39 -1.02 -1.91 0.64 0.16 ABHD14A 2.53 2.35 2.44 -1.98 1.25 -2.14 0.47 0.08 FAM213B 2.15 2.72 2.44 -1.55 1.89 -2.94 -0.20 0.23 CACNA1C-AS1 2.24 2.63 2.44 -1.34 0.69 -2.24 -1.06 0.16 LINC00426 2.11 2.77 2.44 -1.95 1.98 -2.73 2.15 0.27 CFAP44 2.08 2.80 2.44 -1.67 0.56 -2.72 -0.89 0.29 GOLGA2P5 2.24 2.64 2.44 -1.40 1.38 -2.53 -0.72 0.16 LINC00649 2.78 2.12 2.45 -1.22 1.03 -1.97 -1.40 0.27 LOC100289561 2.49 2.41 2.45 -0.83 1.86 -1.83 -0.70 0.03 ZBTB42 2.03 2.87 2.45 -2.12 0.36 -3.00 -0.13 0.34 ANXA2R 2.63 2.26 2.45 -1.24 2.93 -1.92 0.45 0.15 GDPGP1 2.53 2.38 2.45 -1.06 1.84 -2.06 -0.82 0.06 SIRT4 2.17 2.74 2.46 -1.06 0.58 -1.68 -0.34 0.23 PLEKHG5 2.10 2.82 2.46 -1.45 -0.14 -1.88 -0.50 0.29 MBIP 2.05 2.87 2.46 -1.28 1.12 -2.31 0.03 0.33 NBPF7 2.50 2.43 2.47 -1.07 0.64 -1.89 -1.44 0.03 C11orf1 2.45 2.48 2.47 -2.03 1.15 -1.70 2.02 0.01 FAM118A 2.14 2.80 2.47 -1.65 -0.11 -0.54 3.88 0.27 PLLP 2.15 2.78 2.47 -0.70 0.40 -1.32 -0.71 0.25 FBF1 2.59 2.35 2.47 -1.56 2.53 -2.67 -0.70 0.10 PRKAB2 2.09 2.86 2.47 -1.09 1.57 -2.37 -0.19 0.31 KDM8 2.01 2.94 2.48 -1.08 2.09 -2.71 0.21 0.37 ATP6V0E2-AS1 2.31 2.65 2.48 -1.37 0.20 -1.53 0.17 0.14 ISG15 2.22 2.74 2.48 -0.41 -0.28 -0.17 0.44 0.21 TJP3 2.24 2.73 2.49 -1.34 -0.65 -1.45 -0.69 0.19 OTUD3 2.20 2.77 2.49 -1.38 1.47 -2.88 -1.34 0.23 EGFL8 2.29 2.68 2.49 -1.41 -0.01 -1.12 1.19 0.16 LOC100289580 2.02 2.96 2.49 -0.84 0.91 -2.09 -1.17 0.38 ANKMY1 2.15 2.83 2.49 -1.83 0.49 -2.79 -0.82 0.28 TTLL1 2.03 2.95 2.49 -2.34 2.67 -4.79 -0.09 0.37 PLXDC1 2.01 2.98 2.49 -1.06 0.20 -1.92 -1.14 0.39 FAAHP1 2.46 2.53 2.50 -1.27 -0.90 -0.52 1.00 0.03 MINOS1-NBL1 2.81 2.19 2.50 -1.63 -0.17 -1.14 0.39 0.25 IVD 2.01 2.99 2.50 -1.64 2.15 -3.79 -0.61 0.39 ENO3 2.55 2.46 2.50 -1.21 2.12 -1.91 0.20 0.04 ADAMTS10 2.19 2.83 2.51 -0.84 0.62 -1.82 -1.33 0.26 ZNF26 2.02 3.01 2.51 -0.98 1.46 -2.35 -0.27 0.39 MSANTD3 2.13 2.89 2.51 -2.17 0.21 -3.23 -1.27 0.30 SIGLEC17P 2.87 2.16 2.51 -2.27 -1.53 -2.19 -1.64 0.28 PERP 2.16 2.88 2.52 -1.18 2.82 -3.18 -0.48 0.28 RPGRIP1 2.56 2.49 2.52 -3.40 -1.54 -2.12 1.53 0.03 TMEM64 2.07 2.98 2.53 -1.19 0.74 -2.03 -0.13 0.36 CNNM3 2.05 3.00 2.53 -2.53 0.07 -3.85 -1.56 0.37 HDC 2.18 2.88 2.53 -1.90 -1.69 -1.48 -0.37 0.28 STMN3 2.17 2.90 2.53 -1.04 1.92 -2.26 0.24 0.29 ARIH2 2.10 2.97 2.54 -2.36 2.23 -4.29 0.09 0.34 M AN US CR IP T AC CE PT ED ACCEPTED MANUSCRIPTSERF1B 2.86 2.23 2.54 -1.50 1.54 -2.21 -1.07 0.25 ZNF33B 2.13 2.95 2.54 -1.69 0.61 -2.77 -0.90 0.32 ANKMY2 2.23 2.85 2.54 -2.00 1.97 -3.55 -0.48 0.24 CYP2S1 2.72 2.37 2.54 -2.59 -1.78 -2.38 -1.43 0.14 STARD9 2.18 2.91 2.55 -1.27 2.38 -3.32 -1.35 0.28 TNRC6C 2.01 3.09 2.55 -1.72 0.35 -3.15 -1.85 0.42 CFAP36 2.18 2.93 2.55 -1.72 -0.51 -1.73 0.24 0.29 LINC00674 2.23 2.88 2.55 -1.76 1.22 -3.20 -1.34 0.25 OVGP1 2.08 3.04 2.56 -1.35 0.36 -2.32 -1.05 0.38 GNAO1 2.70 2.41 2.56 -1.37 0.09 -1.36 -0.15 0.11 LOC541473 2.14 2.98 2.56 -0.85 0.44 -1.67 -1.04 0.33 CRYZ 2.48 2.63 2.56 -0.99 2.22 -2.01 -0.12 0.06 LRRC39 2.28 2.84 2.56 -1.10 1.00 -1.87 -0.26 0.22 PSMD6-AS2 2.26 2.86 2.56 -1.48 0.56 -2.01 0.05 0.24 SNED1 2.03 3.09 2.56 -1.97 -0.91 -2.38 -1.06 0.41 PDCD1 2.10 3.02 2.56 -0.83 1.43 -1.52 1.24 0.36 NDUFA6-AS1 2.15 2.97 2.56 -1.62 0.74 -2.61 -0.51 0.32 CYP4F35P 2.02 3.10 2.56 -1.24 -0.90 -1.26 -0.63 0.42 ZNF80 2.13 2.99 2.56 -1.50 -0.43 -1.62 0.00 0.33 KLHL42 2.54 2.58 2.56 -1.21 2.43 -2.59 -1.03 0.02 C1orf177 2.98 2.15 2.56 -1.37 1.07 -1.85 -1.00 0.33 OSBPL5 2.30 2.84 2.57 -2.03 1.93 -3.54 -0.72 0.21 RSAD1 2.04 3.11 2.57 -2.20 1.58 -3.89 0.26 0.42 PCSK7 2.22 2.93 2.57 -1.30 2.82 -3.02 0.18 0.28 DBH 2.86 2.30 2.58 -0.83 1.00 -1.35 -0.74 0.22 GPM6B 2.66 2.49 2.58 -1.12 0.75 -1.63 -0.70 0.06 CRTAM 2.62 2.54 2.58 -3.57 0.06 -3.49 0.07 0.03 BMP1 3.03 2.13 2.58 -2.13 3.03 -2.65 -0.37 0.35 YAE1D1 2.29 2.88 2.58 -0.91 0.54 -1.44 -0.33 0.23 LOC728743 2.29 2.88 2.58 -1.21 2.47 -2.46 0.55 0.23 PIK3R3 2.55 2.62 2.58 -1.97 1.63 -2.52 0.38 0.03 PTPRM 2.21 2.97 2.59 -0.52 1.73 -1.56 0.04 0.29 LOC100506076 2.05 3.13 2.59 -1.76 -0.96 -1.76 -0.13 0.41 ZNF14 2.33 2.85 2.59 -1.72 0.32 -2.26 -0.43 0.20 TNK1 2.15 3.03 2.59 -1.55 -0.42 -1.83 -0.39 0.34 LOC653160 2.51 2.67 2.59 -1.64 2.11 -2.78 -0.52 0.06 ANP32D 3.11 2.09 2.60 -0.38 4.08 -1.20 0.20 0.39 RAB37 2.18 3.02 2.60 -3.07 1.51 -4.24 1.26 0.33 PRKCQ-AS1 2.10 3.10 2.60 -1.33 0.77 -2.31 -0.40 0.38 PKD2 2.31 2.90 2.60 -1.11 1.90 -2.44 -0.62 0.23 APOBEC3H 2.44 2.76 2.60 -0.71 0.88 -0.77 1.08 0.12 STAG3L3 2.03 3.18 2.60 -0.52 1.55 -2.07 -1.04 0.44 JMJD7 2.63 2.58 2.60 -1.55 1.44 -2.14 -0.18 0.02 THEM4 2.13 3.09 2.61 -1.55 0.68 -2.57 -0.57 0.37 REEP6 2.02 3.19 2.61 -0.71 0.80 -1.61 -0.31 0.45 ZNF571 2.38 2.84 2.61 -1.34 0.32 -1.82 -0.48 0.18 ZNF441 2.03 3.19 2.61 -1.24 -0.19 -1.72 -0.53 0.44 MRFAP1L1 2.21 3.02 2.61 -1.79 1.35 -3.05 -0.35 0.31 DEGS2 2.62 2.61 2.62 -1.46 0.47 -1.99 -0.94 0.01 RUNX2 2.27 2.96 2.62 -2.40 -1.53 -2.40 -1.08 0.26 SEPT8 2.06 3.17 2.62 -1.98 1.68 -4.00 -0.91 0.42 C1orf216 3.01 2.23 2.62 -2.96 5.38 -3.26 1.49 0.30 FAM153A 2.10 3.14 2.62 -1.44 -1.08 -1.55 -1.09 0.40 KANK3 2.63 2.61 2.62 -1.72 0.16 -2.27 -1.30 0.01 FBLN7 2.12 3.12 2.62 -0.96 1.08 -1.95 -0.19 0.38 ZNF549 2.04 3.21 2.62 -2.43 0.87 -4.38 -1.63 0.45 AHNAK 2.24 3.01 2.62 -1.33 -0.09 -1.87 -0.92 0.30 WDR54 2.21 3.06 2.63 -1.67 1.08 -2.51 0.44 0.32 ACER1 2.36 2.91 2.64 -1.28 0.40 -1.72 -0.19 0.21 M AN US CR IP T AC CE PT ED ACCEPTED MANUSCRIPTOPTN 2.64 2.63 2.64 -1.78 -0.43 -1.68 -0.20 0.00 SDR42E1 2.70 2.57 2.64 -1.53 0.98 -1.79 0.13 0.05 ANKRD36B 2.65 2.63 2.64 -0.88 0.92 -1.78 -1.46 0.01 SMYD2 2.03 3.25 2.64 -1.21 1.71 -2.88 -0.32 0.46 KLHL25 2.50 2.78 2.64 -2.26 0.79 -3.21 -1.30 0.10 SLC25A38 2.13 3.16 2.64 -2.03 1.78 -3.59 0.30 0.39 CYP4F29P 2.09 3.20 2.65 -0.99 -0.81 -1.00 -0.64 0.42 ZNF248 2.23 3.06 2.65 -1.51 0.73 -2.36 -0.39 0.31 SV2A 2.17 3.13 2.65 -2.07 0.22 -2.87 -0.42 0.36 CRTC3-AS1 2.27 3.03 2.65 -0.97 0.25 -1.51 -0.66 0.29 PPP1R12B 2.41 2.89 2.65 -1.77 -0.77 -1.82 -0.56 0.18 NMT2 2.11 3.19 2.65 -1.71 0.42 -2.85 -1.14 0.41 SIT1 2.44 2.87 2.65 -1.05 2.34 -1.84 1.10 0.16 PEX11A 2.51 2.79 2.65 -2.15 2.01 -3.59 -1.26 0.11 SARM1 2.69 2.61 2.65 -1.79 1.05 -2.45 -0.79 0.03 CKB 2.63 2.68 2.66 -1.77 -0.96 -1.65 -0.60 0.02 HOXC4 2.50 2.81 2.66 -1.38 0.38 -1.50 0.40 0.12 PGAP3 2.32 3.02 2.67 -2.30 2.27 -3.80 0.17 0.26 ABI2 2.23 3.11 2.67 -1.96 0.42 -3.17 -1.63 0.33 ZNF181 2.28 3.08 2.68 -0.88 1.33 -1.97 -0.65 0.30 CEP85L 2.05 3.31 2.68 -1.21 0.12 -1.90 -0.56 0.47 ACAD11 2.08 3.28 2.68 -2.47 1.45 -4.40 -0.53 0.45 NNAT 2.12 3.25 2.68 -0.78 0.72 -1.87 -1.30 0.42 CXCL9 2.29 3.08 2.69 -1.04 1.57 -0.64 4.41 0.30 NSUN6 2.19 3.18 2.69 -1.46 0.58 -2.53 -1.14 0.37 C11orf84 2.10 3.28 2.69 -0.77 3.49 -3.07 0.55 0.44 COLQ 2.70 2.69 2.69 -1.71 -0.94 -1.72 -0.96 0.00 TREX2 3.35 2.04 2.69 -1.26 2.60 -1.71 -0.47 0.49 ZBTB46 2.86 2.53 2.69 -2.67 0.75 -2.91 -0.47 0.12 CHD3 2.47 2.93 2.70 -2.22 1.59 -3.55 -1.11 0.17 WNT1 3.14 2.26 2.70 -1.63 0.44 -1.57 -0.28 0.32 PCNT 2.31 3.09 2.70 -2.27 2.13 -4.44 -1.93 0.29 CENPQ 2.43 2.98 2.70 -0.54 1.87 -1.47 0.04 0.20 CDKN2A 2.13 3.29 2.71 1.37 6.98 -2.17 1.11 0.43 KIF22 2.45 2.97 2.71 -2.46 2.94 -3.85 0.77 0.19 ESR2 3.12 2.30 2.71 -1.55 0.40 -1.27 0.29 0.30 TRIM68 2.01 3.42 2.71 -2.30 1.64 -4.78 -1.31 0.52 TP73-AS1 2.13 3.30 2.72 -1.28 2.41 -3.51 -1.14 0.43 EXOG 2.29 3.16 2.72 -1.34 0.80 -2.31 -0.81 0.32 CRY2 2.07 3.37 2.72 -3.58 0.29 -5.20 -0.46 0.48 C5orf56 2.23 3.22 2.72 -1.20 1.69 -1.91 1.71 0.36 LINC00925 2.64 2.81 2.72 -1.81 -0.53 -1.57 0.28 0.06 ADGRL1 2.40 3.05 2.73 -1.45 0.62 -2.38 -1.28 0.24 SPDYE5 2.16 3.30 2.73 -1.04 -0.22 -1.49 -0.90 0.42 PEA15 2.26 3.19 2.73 -2.73 0.42 -3.65 -0.19 0.34 DENND2D 2.23 3.24 2.73 -1.73 0.70 -2.53 0.09 0.37 SFI1 2.52 2.94 2.73 -1.72 1.27 -2.74 -0.88 0.16 ORMDL3 2.42 3.05 2.73 -1.60 3.00 -3.41 -0.44 0.23 APOBEC3D 2.12 3.35 2.73 -0.59 2.52 -2.67 -1.06 0.45 SLC22A17 2.07 3.40 2.73 -1.56 -0.87 -1.77 -0.72 0.49 CAPRIN2 2.25 3.21 2.73 -2.15 0.16 -2.95 -0.65 0.35 WHAMMP2 2.45 3.02 2.73 -1.91 1.13 -3.28 -1.80 0.21 LOC100132741 2.06 3.41 2.74 -0.76 0.58 -1.55 -0.40 0.50 OTUD7B 2.66 2.81 2.74 -2.41 0.79 -3.22 -1.17 0.06 TTYH2 2.92 2.56 2.74 -3.33 1.20 -3.38 0.21 0.13 RHOF 2.41 3.07 2.74 -1.37 2.26 -2.89 -0.73 0.24 INPP5F 2.05 3.43 2.74 -1.33 0.78 -2.44 -0.22 0.50 ACOT7 2.27 3.22 2.75 1.69 9.11 -2.23 2.01 0.34 TRIM59 2.06 3.43 2.75 -1.09 1.72 -3.14 -1.69 0.50 M AN US CR IP T AC CE PT ED ACCEPTED MANUSCRIPTCD7 2.51 2.98 2.75 -0.71 1.20 -1.51 -0.58 0.17 PFN2 2.73 2.77 2.75 -2.07 -0.43 -2.16 -0.63 0.01 S100B 2.56 2.94 2.75 -1.06 -0.45 -0.95 0.02 0.14 EPHB1 2.57 2.94 2.75 -2.40 -1.72 -2.20 -0.97 0.14 TMEM14A 2.40 3.11 2.75 -1.80 2.15 -3.20 -0.19 0.26 GIMAP7 2.50 3.00 2.75 -1.21 0.83 -1.72 -0.05 0.18 CACNA1C-AS2 3.13 2.38 2.76 -0.65 2.27 -0.99 0.45 0.27 WDR60 2.07 3.45 2.76 -1.09 1.71 -3.06 -1.46 0.50 CACNB3 2.75 2.78 2.76 -1.39 1.26 -1.80 0.18 0.01 ZNF600 2.06 3.47 2.77 -2.11 -0.75 -2.67 -0.87 0.51 EVC2 2.95 2.58 2.77 -0.77 3.96 -1.54 1.06 0.13 WHAMM 2.02 3.51 2.77 -1.63 1.97 -4.15 -1.60 0.54 RNF213 2.10 3.44 2.77 -0.67 0.68 -1.41 -0.19 0.48 TMEM181 2.77 2.77 2.77 -1.35 1.65 -2.22 -0.78 0.00 SP4 2.03 3.52 2.77 -1.46 0.44 -2.72 -1.22 0.54 GPR19 2.53 3.02 2.78 -2.20 3.68 -3.83 0.65 0.18 LOC100507424 2.37 3.18 2.78 -1.54 0.98 -2.38 -0.20 0.29 DFNB31 3.21 2.35 2.78 -2.02 -0.35 -2.07 -1.11 0.31 ETAA1 2.02 3.54 2.78 -1.21 0.29 -2.04 -0.41 0.55 ST3GAL5 2.08 3.49 2.78 -1.50 1.99 -3.36 0.08 0.51 AFG3L1P 2.11 3.46 2.79 -1.64 3.19 -4.43 -0.59 0.48 COQ10A 2.37 3.21 2.79 -2.67 1.17 -3.66 0.36 0.30 GIPC1 2.67 2.90 2.79 -1.26 1.68 -2.12 -0.39 0.08 ZNF83 2.04 3.54 2.79 -1.53 -0.30 -2.09 -0.49 0.54 ADHFE1 2.83 2.75 2.79 -2.63 1.74 -2.83 1.00 0.03 SPON2 3.36 2.23 2.80 -0.69 1.57 -1.21 -0.69 0.40 PTCH1 2.57 3.03 2.80 -1.21 0.71 -2.14 -1.54 0.16 IL10RA 2.22 3.41 2.81 -3.65 1.45 -5.53 0.02 0.42 CHST10 2.46 3.17 2.82 -1.94 1.20 -2.67 0.40 0.25 CCDC146 2.25 3.39 2.82 -2.52 -0.50 -2.49 1.44 0.40 ARHGEF10L 2.76 2.88 2.82 -2.88 1.10 -3.77 -1.20 0.04 NAA40 2.17 3.47 2.82 -1.38 4.27 -4.84 -1.44 0.46 SLC46A1 2.31 3.34 2.83 -2.69 0.61 -3.78 -0.49 0.36 LOC100506124 3.03 2.62 2.83 -1.30 0.57 -1.45 -0.20 0.14 TRIM52 2.17 3.50 2.83 -0.90 1.24 -2.15 -0.67 0.47 ADGRD1 2.91 2.76 2.83 -0.92 2.78 -2.01 -0.53 0.05 DDHD1 2.11 3.56 2.83 -0.84 1.63 -2.37 -0.57 0.51 SMG1P3 2.14 3.53 2.84 -0.91 0.00 -1.54 -1.12 0.49 FSBP 2.47 3.21 2.84 -0.18 1.75 -1.15 -0.40 0.26 GGT7 2.68 3.00 2.84 -2.43 0.19 -2.92 -0.77 0.11 TAS2R5 3.09 2.60 2.85 -2.08 1.58 -2.80 -1.14 0.17 LTBP4 2.61 3.08 2.85 -0.97 0.78 -1.53 -0.44 0.17 AGAP9 2.20 3.50 2.85 -1.98 1.14 -3.82 -1.92 0.46 LOC103091866 2.72 2.98 2.85 -1.66 2.36 -2.88 -0.69 0.09 PDXDC2P 2.00 3.70 2.85 -1.07 1.00 -2.48 -0.73 0.60 SYNM 2.24 3.47 2.86 -0.43 1.04 -1.16 -0.04 0.43 PRRT3-AS1 3.13 2.58 2.86 -1.01 1.20 -1.54 -0.73 0.19 CACNB1 3.32 2.40 2.86 -1.89 1.28 -1.97 -0.17 0.32 C1orf61 3.72 2.01 2.86 -0.75 4.92 0.56 3.98 0.60 KIR2DL1 3.20 2.54 2.87 -0.95 1.14 -1.52 -0.92 0.23 ARL10 2.33 3.40 2.87 -0.92 0.84 -1.93 -1.19 0.37 H1FNT 2.83 2.91 2.87 -1.60 0.68 -1.72 0.41 0.03 ITPKB 2.17 3.57 2.87 -2.50 0.20 -3.87 -1.47 0.49 CAMK2N1 2.75 2.99 2.87 -1.68 -0.51 -1.74 -0.51 0.09 LIM2 3.53 2.22 2.87 -1.55 -0.31 -1.65 -1.17 0.45 CTLA4 2.44 3.30 2.87 -1.90 -0.14 -2.11 0.20 0.30 ST6GALNAC6 3.32 2.43 2.87 -2.92 1.31 -3.37 -1.40 0.31 RALGDS 2.66 3.09 2.88 -2.98 3.65 -4.47 0.78 0.15 XPNPEP2 3.06 2.70 2.88 -0.65 4.84 -1.38 1.89 0.13 M AN US CR IP T AC CE PT ED ACCEPTED MANUSCRIPTSMG1P1 2.09 3.68 2.89 -0.90 -0.01 -1.55 -1.11 0.55 MTERF4 2.50 3.28 2.89 -1.36 2.15 -2.57 -0.02 0.27 POU6F1 2.02 3.77 2.90 -1.72 -0.51 -2.38 -0.91 0.60 GRPEL2 2.33 3.47 2.90 -1.15 1.14 -2.32 -0.96 0.39 GSDMB 2.92 2.89 2.90 -1.46 3.81 -2.55 0.57 0.01 OSBPL7 2.48 3.32 2.90 -2.66 3.24 -4.38 0.87 0.29 ZNF10 2.23 3.58 2.90 -1.58 0.38 -2.39 -0.39 0.46 ATP6V0E2 2.34 3.47 2.91 -1.20 1.88 -2.22 0.94 0.39 ANO9 2.12 3.70 2.91 -1.40 0.45 -1.97 0.95 0.54 CROCC 2.61 3.21 2.91 -1.42 0.89 -2.32 -1.13 0.21 AGAP5 2.03 3.80 2.92 -2.03 1.28 -4.37 -2.00 0.60 RARRES3 2.24 3.59 2.92 -0.93 2.21 -1.50 3.61 0.47 ARL14EP 2.04 3.79 2.92 -1.32 0.39 -2.26 -0.28 0.60 ZNF792 2.20 3.63 2.92 -1.74 0.97 -3.13 -0.88 0.49 ECHDC2 2.46 3.37 2.92 -1.38 1.71 -2.39 0.20 0.31 NLRP1 2.22 3.61 2.92 -2.82 -0.31 -3.77 -0.91 0.48 ACKR3 2.22 3.63 2.92 -2.17 -0.68 -2.59 -0.50 0.48 ADA 2.67 3.18 2.92 -0.71 4.01 -1.90 1.67 0.17 LYSMD2 2.28 3.58 2.93 -1.46 0.10 -1.68 0.92 0.44 TPM2 3.00 2.86 2.93 -1.35 -0.26 -1.37 -0.39 0.05 ACYP1 2.42 3.45 2.93 -2.06 1.19 -2.73 1.27 0.35 TNRC6C-AS1 2.05 3.81 2.93 -1.34 1.22 -2.84 -0.21 0.60 FYN 2.20 3.66 2.93 -3.49 1.86 -5.61 0.56 0.50 SEPT11 2.16 3.72 2.94 -2.79 0.47 -4.55 -1.71 0.53 WHAMMP3 2.04 3.84 2.94 -1.66 0.47 -3.12 -1.49 0.61 RNF125 2.38 3.51 2.94 -1.79 1.25 -3.31 -1.60 0.38 NBPF11 2.00 3.88 2.94 -3.00 0.00 -3.38 -0.70 0.64 FCGBP 2.93 2.95 2.94 -2.11 -0.66 -2.41 -1.51 0.01 ENPP5 3.41 2.49 2.95 -1.22 1.60 -1.64 -0.51 0.31 OBSCN 2.39 3.52 2.95 -1.05 0.27 -1.72 -0.99 0.38 FITM2 2.03 3.88 2.96 -0.42 1.87 -2.30 -1.34 0.63 C10orf35 2.05 3.86 2.96 -2.32 -1.18 -2.49 0.12 0.61 GIMAP5 2.63 3.30 2.96 -1.68 0.84 -1.86 1.30 0.23 NR4A1 3.39 2.55 2.97 -2.14 -0.65 -1.97 -0.74 0.28 LINC00852 2.07 3.87 2.97 -0.74 0.54 -1.61 -0.64 0.61 PRPF39 2.06 3.90 2.98 -1.15 1.32 -2.72 -0.49 0.62 ID2 2.08 3.88 2.98 -0.97 1.97 -2.71 0.14 0.60 RNF157-AS1 2.62 3.34 2.98 -1.27 0.46 -1.73 -0.31 0.24 MGC57346 2.48 3.48 2.98 -2.16 -0.06 -2.90 -1.23 0.34 LOC93622 2.43 3.56 2.99 -2.13 1.28 -3.57 -1.14 0.38 CDK20 2.66 3.33 3.00 -1.79 1.39 -2.77 -0.61 0.22 CA11 2.46 3.54 3.00 -1.74 1.17 -2.66 0.06 0.36 FOXP3 2.48 3.52 3.00 -2.45 -0.18 -2.44 1.45 0.35 GLS2 2.62 3.40 3.01 -2.20 0.37 -2.69 -0.06 0.26 ZNF256 2.16 3.87 3.01 -1.56 0.79 -2.84 -0.68 0.57 OLFM2 2.33 3.71 3.02 -1.18 0.14 -1.66 -0.27 0.46 ZNF506 2.03 4.02 3.02 -1.17 -0.05 -1.94 -0.97 0.66 ARHGAP10 3.18 2.89 3.03 -2.33 1.87 -2.87 -0.26 0.10 CRY1 2.01 4.07 3.04 -1.47 0.81 -3.11 -1.25 0.68 CCDC14 2.09 3.99 3.04 -1.20 0.97 -2.43 -0.16 0.62 LANCL1 2.08 4.01 3.05 -1.51 0.78 -2.74 -0.09 0.63 SELM 3.44 2.66 3.05 -2.06 -1.00 -1.45 0.30 0.25 LOC101929829 3.31 2.80 3.06 -0.56 0.15 -0.62 -0.16 0.17 SLC7A6 2.02 4.10 3.06 -1.43 1.26 -3.26 -0.76 0.68 NOL4L 2.60 3.53 3.06 -3.33 -0.11 -4.28 -1.59 0.30 ZNF419 2.11 4.02 3.06 -1.75 0.33 -2.89 -0.65 0.62 DIP2A 2.05 4.08 3.06 -1.76 0.06 -2.95 -1.30 0.66 SYNE2 3.69 2.44 3.06 -2.74 1.97 -2.52 0.32 0.41 ASF1A 2.06 4.07 3.06 -1.32 0.59 -2.45 -0.44 0.65 M AN US CR IP T AC CE PT ED ACCEPTED MANUSCRIPTCCDC92 2.21 3.92 3.07 -2.72 0.94 -4.39 -0.45 0.56 PAFAH2 2.90 3.23 3.07 -2.66 3.20 -4.41 -1.44 0.11 BTN3A2 2.27 3.86 3.07 -1.75 4.60 -4.51 1.84 0.52 SBDSP1 2.27 3.87 3.07 -1.61 0.28 -2.56 -1.05 0.52 GPR75 2.76 3.38 3.07 -1.15 0.79 -1.92 -1.12 0.20 C9orf41 2.04 4.12 3.08 -0.55 1.53 -2.17 -0.96 0.67 TNIK 2.59 3.58 3.08 -2.74 0.82 -4.11 -1.85 0.32 MME 3.29 2.87 3.08 -2.19 -1.74 -1.20 1.03 0.14 HOXB3 2.80 3.36 3.08 -0.15 6.27 -2.98 -1.26 0.18 HOXB2 3.23 2.94 3.09 -0.65 3.24 -2.11 -1.57 0.09 RAB11FIP3 2.67 3.51 3.09 -2.03 3.56 -4.17 -1.14 0.27 NUP210 2.24 3.95 3.10 -1.70 2.37 -3.99 -1.07 0.55 CHCHD6 2.50 3.70 3.10 -1.83 0.41 -2.50 -0.27 0.39 GIPR 2.72 3.48 3.10 -1.50 0.90 -2.30 -0.86 0.24 ANKRD36 3.09 3.11 3.10 -0.98 0.61 -1.62 -1.36 0.01 LRRC37A4P 2.01 4.20 3.11 -0.64 0.90 -1.83 -0.79 0.70 DNAI2 3.21 3.00 3.11 -0.84 2.35 -1.22 0.90 0.07 AGAP4 2.10 4.11 3.11 -2.45 0.43 -4.25 -1.72 0.64 CXCL10 2.26 3.96 3.11 -0.21 0.07 -0.32 0.01 0.55 PLEKHG4 2.05 4.18 3.12 -1.69 1.56 -3.75 -0.44 0.68 PDGFB 2.17 4.07 3.12 -1.65 -0.96 -1.84 -0.63 0.61 TMEM116 2.62 3.63 3.13 -2.19 -0.15 -2.17 1.19 0.32 ZNF32-AS1 3.10 3.16 3.13 -1.72 0.76 -1.52 1.46 0.02 ENTPD2 2.22 4.04 3.13 -1.29 -0.72 -1.22 0.41 0.58 ZC3H8 2.08 4.19 3.13 -0.73 2.01 -2.57 -0.38 0.67 OCIAD2 2.54 3.73 3.14 -0.94 1.30 -1.67 0.33 0.38 CTGLF12P 2.20 4.10 3.15 -2.04 0.84 -3.79 -1.78 0.60 ZNF540 2.01 4.30 3.15 -1.99 -0.65 -2.70 -0.64 0.73 LINC01278 2.47 3.84 3.15 -3.20 0.25 -4.03 0.32 0.44 LGR6 3.27 3.04 3.16 -1.20 -0.90 -1.06 -0.52 0.07 ADCY9 3.36 2.96 3.16 -1.74 0.96 -2.28 -1.09 0.13 ZNF337 2.29 4.03 3.16 -1.80 1.69 -3.34 0.22 0.55 CD83 2.07 4.26 3.16 -1.36 0.96 -2.77 -0.28 0.69 PLVAP 3.70 2.63 3.17 -1.32 -0.86 -1.03 -0.27 0.34 SAMD10 2.57 3.76 3.17 -1.16 2.36 -2.20 1.12 0.38 CCDC136 2.93 3.41 3.17 -2.40 1.10 -3.06 -0.25 0.15 SEPT1 2.56 3.78 3.17 -1.09 1.88 -2.18 0.07 0.38 IL21R 2.86 3.48 3.17 -1.88 0.70 -2.68 -1.22 0.20 C3orf18 2.59 3.76 3.17 -3.31 0.43 -4.27 -0.44 0.37 NFATC2IP 2.06 4.30 3.18 -1.39 2.36 -4.07 -1.24 0.70 KCTD7 3.02 3.34 3.18 -2.45 1.33 -3.20 -0.57 0.10 UBE2Q2 2.42 3.94 3.18 -1.60 1.00 -2.60 -0.18 0.48 RTN4R 2.61 3.78 3.19 -1.22 0.30 -1.80 -0.79 0.36 ANKH 2.35 4.04 3.20 -2.63 -0.45 -3.55 -1.41 0.53 BHLHE40 2.05 4.34 3.20 -2.34 -0.87 -3.17 -1.26 0.72 HIST1H2AH 3.43 2.97 3.20 -0.48 0.06 -0.52 -0.16 0.14 CD244 4.37 2.03 3.20 -3.31 1.48 -2.61 -0.41 0.73 ZNF827 2.72 3.69 3.21 -1.30 2.15 -2.88 -1.74 0.30 ZNF225 2.22 4.23 3.22 -1.43 1.61 -3.13 -0.58 0.62 COMMD3-BMI1 2.11 4.34 3.23 -0.82 -0.36 -0.87 0.36 0.69 CROT 2.41 4.06 3.23 -1.96 1.87 -3.69 -0.65 0.51 CD96 2.72 3.75 3.24 -2.56 1.17 -3.70 -0.86 0.32 DTHD1 3.45 3.03 3.24 -1.66 0.48 -1.89 -0.61 0.13 ZRANB2-AS1 2.54 3.95 3.24 -1.00 0.73 -1.68 -0.40 0.44 ANAPC1P1 3.89 2.61 3.25 -2.05 6.68 -3.74 -1.60 0.39 DUSP14 2.37 4.13 3.25 -2.70 0.10 -3.36 0.98 0.54 PURA 2.04 4.47 3.25 -1.91 0.48 -3.64 -1.68 0.75 SIDT1 2.04 4.47 3.25 -1.82 1.75 -4.51 -1.94 0.74 RFTN1 2.05 4.46 3.26 -2.58 0.14 -4.19 -0.85 0.74 M AN US CR IP T AC CE PT ED ACCEPTED MANUSCRIPTAZIN2 2.69 3.83 3.26 -2.19 -0.34 -2.72 -1.11 0.35 NPAT 2.08 4.44 3.26 -1.97 -0.26 -2.94 -0.86 0.72 SH2D2A 3.19 3.34 3.26 -2.38 0.47 -2.54 0.14 0.05 SLC5A3 2.22 4.30 3.26 -1.13 0.25 -1.89 -0.68 0.64 FAM83G 2.20 4.33 3.26 -2.00 1.26 -3.88 -1.06 0.65 PTGDR2 2.35 4.19 3.27 -2.27 -2.02 -1.91 -0.16 0.56 ZNF77 2.52 4.02 3.27 -1.56 1.69 -2.74 0.13 0.46 FLT3LG 2.28 4.27 3.27 -1.79 0.14 -2.37 0.69 0.61 ZNF32-AS2 3.22 3.33 3.28 -1.23 2.30 -2.12 -0.52 0.03 LPIN1 2.20 4.38 3.29 -1.49 2.56 -4.10 -1.49 0.66 LAMP3 2.13 4.45 3.29 -0.41 -0.24 -0.49 -0.20 0.71 SLFN13 2.65 3.93 3.29 -1.31 2.62 -2.99 -0.95 0.39 ADRB2 2.44 4.14 3.29 -1.14 2.06 -2.75 -0.87 0.52 HERC2P9 2.00 4.59 3.30 -1.52 1.81 -3.85 -0.34 0.79 DLG5 3.36 3.24 3.30 -1.56 0.19 -1.86 -0.88 0.04 CCDC66 2.54 4.06 3.30 -1.34 0.74 -2.14 -0.47 0.46 GZMB 4.38 2.24 3.31 -1.43 0.97 -1.24 -0.12 0.65 PNMA3 3.56 3.11 3.34 -0.99 1.93 -1.58 -0.42 0.13 NPIPA1 2.26 4.42 3.34 -2.31 2.18 -4.40 0.64 0.65 PFN1P2 2.51 4.16 3.34 -1.23 0.07 -1.93 -1.41 0.49 ARVCF 3.74 2.94 3.34 -1.44 1.82 -2.17 -1.30 0.24 VPS13A 2.17 4.51 3.34 -0.91 0.71 -1.91 -0.56 0.70 ZNF30 2.49 4.20 3.34 -1.82 0.71 -2.84 -0.69 0.51 ACOT4 2.47 4.22 3.35 -1.60 0.34 -1.76 1.98 0.52 GSTA4 2.58 4.13 3.35 -0.86 2.79 -2.37 0.09 0.46 HABP4 2.96 3.76 3.36 -2.23 -0.42 -2.44 -0.47 0.24 ITFG2 2.12 4.60 3.36 -1.35 2.47 -3.97 -1.09 0.74 KIAA1671 4.17 2.57 3.37 -2.02 2.03 -2.47 -1.15 0.47 CHST12 2.43 4.32 3.37 -0.34 5.57 -3.80 -1.54 0.56 IFFO2 2.29 4.46 3.38 -2.62 0.28 -4.10 -1.45 0.64 PRH1 2.93 3.83 3.38 -1.43 -0.33 -1.54 -0.25 0.27 HIVEP3 2.54 4.22 3.38 -1.61 3.37 -4.00 -1.32 0.50 BTG3 2.33 4.44 3.38 -1.31 2.44 -3.14 0.22 0.62 CHIC1 2.02 4.75 3.39 -1.59 0.22 -2.71 -0.26 0.81 AGAP6 2.07 4.71 3.39 -1.73 2.13 -4.52 -1.55 0.78 IL21R-AS1 2.72 4.07 3.40 -2.06 1.09 -3.25 -1.29 0.40 ID3 2.76 4.05 3.41 -1.12 0.42 -1.62 -0.44 0.38 TRANK1 2.48 4.34 3.41 -1.83 -0.37 -2.20 -0.16 0.54 OLFM1 3.58 3.25 3.41 -1.44 -0.38 -1.45 -0.55 0.10 SNPH 3.00 3.83 3.41 -1.74 0.70 -2.36 -0.67 0.24 ZNF853 3.45 3.38 3.41 -2.16 2.56 -3.08 -0.70 0.02 IKZF2 2.49 4.34 3.41 -1.17 0.03 -1.64 -0.53 0.54 ZNF790-AS1 3.32 3.52 3.42 -1.20 2.39 -1.88 0.31 0.06 BFSP1 4.45 2.39 3.42 -0.80 5.86 -1.64 -0.15 0.60 PDZD4 3.78 3.05 3.42 -1.97 1.22 -2.35 -0.77 0.21 PPP3CC 2.44 4.41 3.42 -1.61 3.75 -4.03 0.40 0.57 SLAMF6 2.39 4.46 3.43 -2.65 1.59 -4.14 1.25 0.61 MPHOSPH9 2.14 4.72 3.43 -0.71 1.78 -2.42 -0.68 0.75 DCANP1 3.76 3.11 3.43 -3.21 -0.34 -3.47 -1.82 0.19 TNFRSF25 3.00 3.88 3.44 -1.24 0.98 -1.88 -0.55 0.25 GPR55 2.80 4.09 3.44 -1.76 4.76 -3.99 0.35 0.37 KIR3DL2 3.17 3.74 3.45 -1.68 -0.39 -1.84 -0.66 0.16 CYP4F22 3.84 3.07 3.45 -1.28 3.63 -2.12 -0.28 0.22 CREBZF 2.01 4.91 3.46 -0.93 0.81 -2.24 -0.69 0.84 APBA2 3.22 3.70 3.46 -1.38 1.33 -2.13 -0.85 0.14 TTC12 2.10 4.83 3.47 -1.38 0.12 -2.17 0.02 0.79 HOXB-AS1 4.52 2.43 3.47 -0.80 2.77 -1.36 -0.71 0.60 LRFN3 2.40 4.55 3.48 -1.12 0.44 -1.89 -0.69 0.62 DGCR8 2.77 4.19 3.48 -2.18 5.56 -5.15 -0.61 0.41 M AN US CR IP T AC CE PT ED ACCEPTED MANUSCRIPTPATL2 2.07 4.88 3.48 -0.53 2.23 -2.31 0.78 0.81 LINC00920 2.67 4.29 3.48 -1.93 -0.42 -2.34 -0.73 0.46 PHC1 2.39 4.58 3.48 -1.89 1.15 -3.36 -0.76 0.63 LIMA1 2.87 4.10 3.49 -2.20 1.32 -3.27 -0.78 0.35 IGIP 2.37 4.61 3.49 -1.91 -0.56 -2.44 -0.82 0.64 LINC01550 2.19 4.81 3.50 -1.41 0.25 -2.16 0.30 0.75 DHRS3 2.82 4.19 3.50 -2.36 -0.38 -2.90 -1.17 0.39 SSBP3 2.13 4.88 3.51 -1.65 0.76 -3.29 -1.39 0.78 BTN3A3 2.13 4.89 3.51 -1.91 4.30 -5.37 2.46 0.78 C8G 4.26 2.77 3.52 -0.68 4.53 -1.18 0.78 0.42 IL11RA 2.74 4.30 3.52 -1.58 1.19 -2.26 0.74 0.44 RAB11FIP5 3.60 3.44 3.52 -1.58 1.84 -1.90 0.51 0.04 ADAT2 2.32 4.76 3.54 -1.21 2.88 -3.45 -0.26 0.69 ASB2 2.57 4.52 3.54 -2.17 -0.80 -1.97 1.82 0.55 MORN3 2.19 4.90 3.55 -1.63 -0.73 -2.01 -0.57 0.76 CTSF 2.57 4.56 3.56 -1.94 1.39 -2.99 0.88 0.56 GZMM 4.08 3.05 3.56 -1.17 2.80 -1.81 -0.48 0.29 PKD1P1 2.31 4.82 3.57 -1.30 1.77 -3.02 -0.72 0.70 TSEN54 4.56 2.58 3.57 -3.16 3.96 -3.22 -0.15 0.55 PLCH2 3.06 4.08 3.57 -1.95 -0.56 -2.19 -0.84 0.28 CLEC2D 3.13 4.01 3.57 -1.43 2.29 -2.44 -0.19 0.25 CDRT4 2.48 4.66 3.57 -0.86 0.74 -1.52 0.00 0.61 TRAF1 3.66 3.49 3.57 -3.23 1.53 -3.28 1.06 0.05 TMEM204 3.23 3.92 3.58 -1.13 0.83 -1.76 -1.04 0.19 TBC1D31 2.33 4.83 3.58 -1.35 1.16 -2.70 -0.66 0.70 RAB40B 2.54 4.63 3.58 -1.98 1.03 -3.37 -1.25 0.58 PVRIG2P 3.00 4.19 3.60 -1.23 1.39 -2.12 -0.78 0.33 PTGER4 2.58 4.62 3.60 -1.80 0.60 -2.87 -1.25 0.57 RGS1 2.08 5.14 3.61 -0.74 0.74 -1.40 1.57 0.85 MYCL 2.43 4.80 3.62 -2.05 0.19 -3.01 -0.65 0.66 MAP4K1 2.16 5.08 3.62 -1.51 1.98 -3.52 0.62 0.81 APBB1 2.03 5.21 3.62 -1.30 -0.05 -2.10 -0.38 0.88 CCDC88C 2.56 4.68 3.62 -1.61 2.21 -3.42 -1.11 0.58 ENO2 2.66 4.58 3.62 -2.45 -1.30 -2.50 -0.21 0.53 ATP10A 2.56 4.69 3.62 -1.63 2.93 -3.71 -0.64 0.59 TTC22 4.03 3.22 3.63 -1.37 2.32 -2.09 -0.97 0.22 GUSBP1 2.66 4.60 3.63 -1.20 1.84 -2.66 -1.35 0.53 MAN1C1 2.27 4.99 3.63 -0.99 0.60 -2.00 -0.99 0.75 OSBPL3 2.11 5.16 3.64 -1.02 2.40 -3.26 0.27 0.84 RRN3P1 2.60 4.68 3.64 -2.18 1.16 -3.53 -0.79 0.57 NKTR 2.03 5.31 3.67 -1.58 0.74 -3.33 -1.24 0.89 EID3 2.75 4.60 3.67 -1.83 2.00 -3.10 0.25 0.51 CXCL8 2.61 4.73 3.67 -1.84 -1.65 -1.73 -0.86 0.58 ADAM1A 2.27 5.08 3.68 -0.93 1.66 -2.51 -0.64 0.76 PMAIP1 2.07 5.30 3.68 -1.49 -0.66 -1.96 -0.61 0.88 DPH6 2.27 5.10 3.68 -1.43 0.37 -2.28 0.06 0.77 PACSIN1 2.94 4.44 3.69 -3.59 -1.75 -3.92 -1.80 0.41 BTN3A1 2.44 4.94 3.69 -2.07 4.08 -4.48 2.87 0.68 CASS4 2.12 5.26 3.69 -3.44 -2.53 -3.72 -1.43 0.85 GALNT12 2.02 5.37 3.69 -1.65 0.02 -2.84 -0.91 0.91 LRRC75A 3.82 3.57 3.69 -2.70 -0.14 -2.53 0.24 0.07 PPP1R13B 2.48 4.92 3.70 -3.02 0.30 -4.37 -0.82 0.66 SUGP2 2.06 5.33 3.70 -0.98 3.27 -4.11 -0.37 0.88 INPP4B 2.21 5.20 3.70 -1.23 0.11 -2.05 -0.80 0.81 LOC100190986 2.32 5.09 3.71 -0.75 0.31 -1.48 -1.17 0.75 SOX13 3.75 3.67 3.71 -2.11 -0.56 -2.01 -0.25 0.02 AGAP7P 2.37 5.06 3.71 -2.05 0.92 -3.72 -1.63 0.73 HERC2P2 2.00 5.44 3.72 -1.36 0.67 -2.81 -0.21 0.92 GUSBP4 2.12 5.35 3.73 -1.04 0.76 -2.44 -1.55 0.86 M AN US CR IP T AC CE PT ED ACCEPTED MANUSCRIPTLOC100130744 2.41 5.06 3.74 -2.10 1.31 -3.78 -0.81 0.71 LOC100507387 3.00 4.48 3.74 -1.95 -1.34 -1.95 -0.85 0.39 GATA2 2.08 5.39 3.74 -1.62 -1.50 -1.59 -0.97 0.89 ZNF302 2.18 5.30 3.74 -1.19 0.38 -2.14 -0.53 0.83 PCBP4 3.83 3.67 3.75 -2.25 3.56 -2.91 0.80 0.04 USP36 2.13 5.38 3.76 -1.30 1.41 -3.17 -0.87 0.87 SLA2 2.17 5.36 3.76 -2.90 1.37 -5.55 -1.26 0.85 MMP23B 4.87 2.67 3.77 -1.97 1.68 -2.10 -0.73 0.59 IKZF3 2.43 5.12 3.78 -1.78 1.91 -3.75 -1.27 0.71 PLEKHA1 2.62 4.94 3.78 -1.69 1.10 -2.99 -1.32 0.61 ZMYND11 2.06 5.54 3.80 -1.39 0.43 -2.66 -0.59 0.92 BZRAP1-AS1 2.19 5.42 3.81 -2.07 0.24 -3.30 -0.21 0.85 CBR3 3.28 4.33 3.81 -1.12 1.60 -1.55 0.98 0.28 FUT11 2.65 4.97 3.81 -0.93 2.20 -2.50 -1.21 0.61 CHI3L2 2.15 5.48 3.81 -0.68 0.43 -1.23 0.60 0.87 IL23A 2.28 5.34 3.81 -1.65 0.17 -2.44 0.32 0.80 LAG3 4.83 2.81 3.82 -1.52 4.23 -1.29 1.87 0.53 ZBTB25 2.22 5.42 3.82 -1.35 0.23 -2.34 -1.00 0.84 ATP1A3 3.96 3.69 3.83 -2.82 2.81 -3.47 -0.11 0.07 TTC39B 2.37 5.29 3.83 -0.74 1.14 -1.85 -0.71 0.76 RTN1 2.38 5.29 3.83 -2.43 -1.32 -2.90 -1.50 0.76 GUSBP9 2.03 5.65 3.84 -0.80 0.85 -2.25 -1.57 0.94 TRABD2A 2.13 5.56 3.84 -1.81 -0.17 -2.88 -1.05 0.89 LOC100294362 2.33 5.36 3.84 -0.94 0.98 -2.13 -1.05 0.79 NOV 4.54 3.17 3.85 -2.75 -1.94 -1.26 2.48 0.36 ITPRIPL1 3.94 3.79 3.86 -1.23 4.47 -2.51 -0.69 0.04 PDE4DIP 2.08 5.65 3.87 -2.44 -0.61 -3.62 -1.23 0.93 LINC01260 4.42 3.32 3.87 -2.38 0.66 -1.57 2.36 0.28 PKD1 2.50 5.26 3.88 -0.87 1.74 -2.28 -0.86 0.71 ITM2A 2.85 4.91 3.88 -0.77 1.55 -1.69 -0.38 0.53 TGIF2-C20orf24 2.46 5.30 3.88 -0.78 -0.73 -0.44 1.18 0.73 SMPD3 2.27 5.51 3.89 -2.59 -1.55 -2.92 -0.68 0.83 BZRAP1 4.55 3.25 3.90 -1.57 0.93 -1.79 -0.70 0.33 RPS6KA5 2.05 5.75 3.90 -2.50 -1.31 -3.23 -1.36 0.95 MDN1 2.10 5.71 3.91 -1.45 0.71 -3.05 -1.38 0.92 LOC100288162 2.19 5.63 3.91 -0.74 1.27 -2.19 -1.07 0.88 PRF1 3.85 4.00 3.93 -1.96 1.29 -2.68 -1.42 0.04 RAP2A 2.66 5.20 3.93 -0.92 1.10 -1.84 -0.54 0.65 LOC100506123 2.23 5.65 3.94 -2.03 0.76 -3.62 -0.46 0.87 ICOS 2.97 4.95 3.96 -1.25 0.61 -1.73 0.14 0.50 USP18 2.26 5.66 3.96 -0.38 -0.27 -0.40 -0.08 0.86 LY9 3.09 4.87 3.98 -2.64 1.61 -3.79 -0.40 0.45 CCL4L1 5.68 2.30 3.99 -1.64 0.77 -1.15 0.15 0.85 CDC25B 2.22 5.76 3.99 -1.81 1.48 -3.64 0.47 0.89 STK39 2.29 5.71 4.00 -1.62 1.97 -3.56 0.45 0.86 IL32 4.52 3.48 4.00 -1.61 1.99 -1.16 2.49 0.26 SKAP1 3.29 4.72 4.00 -2.62 2.06 -3.76 -0.42 0.36 SLC4A7 2.68 5.33 4.00 -1.18 0.82 -2.02 -0.53 0.66 NDRG2 2.02 6.00 4.01 -4.81 -2.33 -6.16 -0.69 0.99 ZAP70 3.83 4.20 4.02 -2.62 3.15 -3.49 0.23 0.09 COL6A2 4.20 3.85 4.02 -1.85 -0.55 -2.06 -1.50 0.09 CACNA2D2 5.28 2.78 4.03 -2.12 0.98 -2.28 -1.26 0.62 WNT10B 4.32 3.75 4.04 -2.65 2.46 -2.76 1.17 0.14 CCL4 5.41 2.68 4.04 -1.18 0.23 -0.86 0.23 0.67 SLC25A42 2.43 5.66 4.05 -0.78 4.63 -3.90 -0.85 0.80 GOLGA7B 4.20 3.90 4.05 -2.15 2.70 -2.65 0.27 0.08 TSHZ1 2.11 6.00 4.05 -1.86 1.02 -3.91 -1.19 0.96 GRAP2 2.86 5.27 4.06 -2.17 1.76 -3.65 -0.96 0.59 AGFG2 3.24 4.89 4.07 -1.79 1.10 -2.53 -0.41 0.41 M AN US CR IP T AC CE PT ED ACCEPTED MANUSCRIPTDLG3 4.12 4.02 4.07 -2.78 3.89 -3.46 0.94 0.02 CCR3 3.34 4.80 4.07 -2.46 -2.34 -1.99 0.01 0.36 LAT 3.79 4.37 4.08 -2.38 2.18 -3.01 0.38 0.14 MAF 2.41 5.78 4.09 -1.97 -0.72 -2.45 -0.55 0.82 NIPA1 2.38 5.83 4.11 -1.34 1.27 -2.70 -0.11 0.84 GPR183 2.19 6.02 4.11 -2.47 -0.96 -2.98 0.83 0.93 ZBTB4 2.50 5.72 4.11 -3.52 0.15 -5.20 -1.55 0.78 HEATR9 4.95 3.27 4.11 -1.05 8.06 -1.93 1.29 0.41 IFT80 2.11 6.12 4.12 -0.69 0.92 -1.86 -0.38 0.98 KLRD1 5.21 3.06 4.13 -1.54 2.60 -1.99 -0.89 0.52 SLFN12L 4.18 4.09 4.14 -0.97 0.34 -1.22 -0.70 0.02 EVL 2.94 5.33 4.14 -2.17 2.67 -3.76 0.16 0.58 HOPX 6.02 2.26 4.14 -1.94 1.45 -1.67 -0.48 0.91 ABCB1 4.00 4.30 4.15 -2.90 2.92 -4.30 -2.53 0.07 NIPAL3 2.01 6.30 4.15 -1.45 1.42 -3.85 -1.50 1.03 MSTO2P 2.65 5.73 4.19 -1.00 1.57 -4.47 0.08 0.73 LOC100240735 2.31 6.12 4.21 -0.05 6.14 -3.80 1.20 0.90 ABCD2 3.10 5.33 4.22 -1.23 0.84 -1.83 -0.20 0.53 LOC100101148 2.31 6.15 4.23 -0.53 0.58 -1.21 -0.39 0.91 TBC1D4 2.74 5.72 4.23 -1.67 0.62 -2.54 -0.35 0.71 FMNL3 2.74 5.72 4.23 -1.63 0.90 -2.68 -0.75 0.70 PPT2-EGFL8 3.16 5.31 4.24 -1.13 3.64 -2.88 -0.93 0.51 CYB561 2.89 5.60 4.25 -1.95 0.24 -2.51 0.20 0.64 ARL4C 2.91 5.59 4.25 -2.60 2.36 -4.51 -1.33 0.63 GSE1 2.24 6.26 4.25 -1.86 0.85 -3.59 -1.19 0.95 CTSW 4.09 4.43 4.26 -2.62 1.24 -2.98 0.06 0.08 IFNG 6.21 2.33 4.27 -1.10 2.41 -1.01 0.00 0.91 HIST1H2BF 2.49 6.07 4.28 -0.56 -0.05 -0.83 -0.48 0.84 PCNXL2 2.86 5.70 4.28 -2.10 0.06 -2.82 -0.69 0.66 TMX2-CTNND1 3.19 5.38 4.29 -0.65 0.62 -0.65 1.89 0.51 XCL2 6.55 2.02 4.29 -2.57 0.36 -2.00 -0.88 1.06 GLB1L2 5.39 3.19 4.29 -0.30 7.48 -1.01 1.33 0.51 TKTL1 5.77 2.81 4.29 -1.34 2.67 -1.57 -0.46 0.69 PTPN4 3.42 5.16 4.29 -2.06 0.91 -2.78 -0.68 0.41 LOC388692 3.54 5.08 4.31 -1.46 3.03 -2.79 -1.04 0.36 PRKACB 3.21 5.42 4.31 -1.12 1.62 -1.98 -0.31 0.51 TGFBR3 5.87 2.76 4.32 -1.34 1.39 -1.51 -0.84 0.72 DTX3 2.86 5.78 4.32 -2.20 1.16 -3.08 1.33 0.67 NCALD 4.46 4.22 4.34 -3.09 1.33 -3.50 -0.66 0.06 SNURF 3.64 5.05 4.34 -0.84 0.55 -1.20 -0.52 0.33 TIGD3 3.94 4.76 4.35 -3.22 -2.47 -2.77 -0.11 0.19 MATK 6.54 2.18 4.36 -2.05 4.46 -2.10 -0.77 1.00 MSX2P1 2.98 5.74 4.36 -0.91 3.84 -2.61 0.69 0.63 LCK 3.67 5.05 4.36 -2.11 2.34 -2.96 0.32 0.32 GATA3 2.77 5.97 4.37 -2.39 0.46 -3.56 -1.36 0.73 KIF21A 4.85 3.89 4.37 -1.54 0.90 -1.78 -0.64 0.22 ITPR3 2.55 6.31 4.43 -1.54 4.23 -4.53 -0.65 0.85 GFI1 3.80 5.05 4.43 -0.17 8.53 -2.66 -0.19 0.28 TRG-AS1 3.13 5.72 4.43 -1.70 1.17 -2.55 -0.24 0.58 HPCAL4 2.68 6.19 4.43 -2.08 -0.86 -2.38 -0.23 0.79 KLF12 2.03 6.84 4.44 -1.40 -0.26 -2.24 -0.62 1.08 KLRC4-KLRK1 4.97 3.93 4.45 -1.94 4.61 -2.95 -1.06 0.23 SLC41A1 2.36 6.53 4.45 -2.11 2.22 -4.65 -1.16 0.94 GPR18 2.86 6.06 4.46 -1.12 1.38 -1.98 0.49 0.72 REREP3 3.72 5.20 4.46 -1.42 -0.77 -1.44 -0.53 0.33 CXCR3 3.41 5.53 4.47 -1.56 0.29 -1.92 -0.07 0.47 CX3CR1 4.43 4.52 4.48 -2.04 2.10 -2.62 -0.40 0.02 PDGFD 6.85 2.11 4.48 -1.75 2.66 -1.80 -1.04 1.06 LDOC1L 3.05 5.90 4.48 -2.59 1.64 -3.92 -0.38 0.64 M AN US CR IP T AC CE PT ED ACCEPTED MANUSCRIPTZNF831 3.38 5.59 4.48 -2.02 1.42 -2.99 -0.77 0.49 DUSP8 6.07 2.91 4.49 -1.88 3.63 -2.03 -0.23 0.70 AMIGO1 2.29 6.69 4.49 -1.59 0.19 -2.73 -1.42 0.98 STAT4 4.12 4.87 4.50 -3.16 1.73 -3.67 0.40 0.17 GCNT4 2.06 6.94 4.50 -1.27 -0.36 -1.89 -0.54 1.08 UBASH3A 3.21 5.82 4.51 -1.85 2.27 -3.05 0.20 0.58 RAD51-AS1 2.08 6.95 4.51 -0.53 1.02 -1.84 -1.02 1.08 LLGL2 6.02 3.01 4.52 -2.31 6.20 -3.07 -1.19 0.67 NFATC2 3.57 5.47 4.52 -2.24 1.27 -3.11 -0.88 0.42 KLRB1 6.71 2.34 4.53 -2.22 -1.15 -1.74 -0.86 0.97 KMT2A 2.79 6.28 4.54 -2.09 1.13 -3.52 -1.59 0.77 CARD11 2.12 6.96 4.54 -1.58 1.88 -4.17 -1.31 1.06 CD247 3.70 5.39 4.54 -2.30 1.33 -3.14 -0.90 0.37 SIRPG 2.29 6.79 4.54 -1.55 0.10 -2.26 1.00 0.99 TTC16 5.57 3.52 4.54 -2.17 0.37 -1.79 0.56 0.45 RRAS2 2.08 7.05 4.56 -0.83 1.38 -2.46 0.03 1.09 SEMA4C 3.73 5.39 4.56 -2.28 1.10 -3.14 -1.49 0.36 CD3E 2.70 6.44 4.57 -2.30 0.25 -3.13 0.54 0.82 PLEKHF1 6.27 2.86 4.57 -1.80 6.20 -2.30 -0.42 0.75 SYTL2 4.13 5.04 4.58 -2.01 0.02 -2.36 -1.19 0.20 PID1 3.50 5.67 4.59 -2.42 -1.22 -2.52 -0.75 0.47 C1orf21 6.23 2.94 4.59 -1.44 2.99 -1.59 -0.22 0.72 CD2 4.46 4.73 4.60 -2.81 1.78 -2.93 1.55 0.06 TESPA1 2.49 6.71 4.60 -2.27 0.27 -3.41 -0.25 0.92 LAX1 2.79 6.42 4.61 -1.09 3.56 -3.32 -1.39 0.79 SPN 2.66 6.59 4.62 -1.82 1.36 -3.42 -1.68 0.85 XCL1 6.74 2.52 4.63 -1.98 0.16 -1.67 -0.64 0.91 LOC728989 2.02 7.27 4.65 -0.84 -0.42 -0.59 3.52 1.13 LINC00861 4.15 5.19 4.67 -2.20 1.04 -2.69 -0.43 0.22 FAM179A 6.65 2.70 4.67 -1.97 7.78 -2.19 0.39 0.84 CD226 3.91 5.48 4.69 -1.39 1.79 -2.20 -0.90 0.33 MLLT10P1 2.61 6.79 4.70 -1.11 -0.25 -1.45 -0.32 0.89 CXCR6 6.01 3.39 4.70 -2.02 1.08 -1.91 -0.16 0.56 CEP78 3.69 5.75 4.72 -1.52 2.96 -2.67 -0.24 0.44 TRAT1 2.53 6.92 4.73 -0.90 0.95 -1.84 -0.27 0.93 MSC 3.83 5.66 4.74 -0.95 3.77 -1.83 1.80 0.39 CD200R1 2.44 7.07 4.75 -1.34 -0.30 -1.77 -0.03 0.97 GVINP1 2.57 6.95 4.76 -1.09 1.03 -2.22 -0.87 0.92 FAM102A 2.02 7.54 4.78 -1.05 0.26 -2.07 -0.34 1.16 SMKR1 6.43 3.14 4.79 -1.83 3.47 -2.02 -0.33 0.69 KPNA5 2.26 7.35 4.80 -1.27 0.49 -2.42 -0.82 1.06 GNLY 7.14 2.46 4.80 -1.80 2.87 -1.34 0.45 0.97 PRR5L 3.07 6.57 4.82 -1.45 2.05 -2.59 0.47 0.73 RUNX3 3.27 6.40 4.83 -2.81 2.61 -4.56 -1.09 0.65 PPP1R16B 2.01 7.74 4.87 -1.06 2.21 -3.76 -0.09 1.18 PASK 3.17 6.57 4.87 -1.15 1.99 -2.21 -0.02 0.70 USP28 2.74 7.02 4.88 -1.44 4.03 -4.07 -0.96 0.88 ZFYVE28 4.61 5.16 4.88 -2.28 1.95 -2.82 -0.20 0.11 GPR68 5.59 4.18 4.89 -2.94 0.87 -3.17 -1.27 0.29 OSGEPL1 2.19 7.61 4.90 -2.57 0.79 -4.79 -0.74 1.11 ABLIM1 2.13 7.70 4.91 -1.26 0.34 -2.46 -1.04 1.13 CENPK 2.83 7.00 4.92 -0.09 2.17 -1.12 0.11 0.85 NMUR1 7.00 2.91 4.96 -1.68 3.54 -2.18 -1.46 0.82 GPR15 2.68 7.27 4.98 -1.86 -1.43 -1.93 -0.72 0.92 SH3YL1 2.06 7.92 4.99 -0.93 0.40 -1.89 0.11 1.17 CD5 3.02 7.06 5.04 -2.19 1.17 -3.30 -0.01 0.80 CD28 3.16 6.92 5.04 -1.99 0.22 -2.62 -0.33 0.74 NELL2 2.35 7.73 5.04 -2.25 -1.20 -2.67 -0.29 1.07 SMAD7 4.08 6.02 5.05 -2.05 1.71 -2.91 -1.09 0.39 M AN US CR IP T AC CE PT ED ACCEPTED MANUSCRIPTCCL5 6.70 3.42 5.06 -1.96 2.89 -1.67 1.10 0.65 TOX 2.34 7.80 5.07 -1.22 0.65 -2.31 -0.20 1.08 BCL11B 2.71 7.45 5.08 -1.63 0.56 -2.70 -1.29 0.93 B3GAT1 7.65 2.53 5.09 -1.07 5.51 -1.39 -0.37 1.01 DYRK2 2.31 7.88 5.09 -1.36 0.41 -2.50 -1.02 1.09 ADGRG5 3.93 6.27 5.10 -2.29 4.02 -3.98 -1.52 0.46 CCR5 6.37 3.85 5.11 -2.33 1.36 -2.30 -0.24 0.49 CAMK4 2.30 7.96 5.13 -1.05 0.59 -2.10 -0.66 1.10 GAS5-AS1 3.61 6.71 5.16 -1.59 0.56 -2.08 -0.19 0.60 TM4SF19 5.98 4.35 5.16 -1.50 0.72 -1.50 0.00 0.32 ATP8B2 2.09 8.27 5.18 -0.97 1.93 -3.31 -1.03 1.19 FCRL3 3.00 7.37 5.18 -1.63 0.70 -2.36 0.47 0.84 LBH 2.28 8.10 5.19 -1.26 0.96 -2.73 -0.84 1.12 MCOLN2 5.32 5.10 5.21 -1.43 4.25 -2.01 0.98 0.04 NLRC3 3.40 7.03 5.22 -2.04 2.33 -3.51 -1.43 0.70 ENHO 4.46 6.00 5.23 -2.29 -0.90 -2.08 0.97 0.29 SH2D1B 6.38 4.16 5.27 -1.43 -0.39 -1.43 -0.84 0.42 EPHX2 2.01 8.58 5.29 -1.77 -0.44 -2.76 -0.30 1.24 PLCG1 2.39 8.25 5.32 -2.02 1.06 -3.81 -0.63 1.10 HERC5 2.21 8.45 5.33 -0.37 -0.27 -0.39 0.10 1.17 JAKMIP1 6.87 3.81 5.34 -0.87 6.86 -1.36 0.99 0.57 CD6 4.55 6.14 5.34 -2.24 2.08 -2.91 -0.08 0.30 PRKCH 3.22 7.53 5.37 -2.85 2.78 -4.78 -0.77 0.80 MYBL1 6.83 3.93 5.38 -1.65 -0.54 -1.58 -0.83 0.54 S1PR1 2.27 8.56 5.41 -1.52 1.12 -3.31 -1.07 1.16 PTGDR 7.64 3.24 5.44 -2.04 1.60 -2.23 -1.43 0.81 CD40LG 2.60 8.45 5.52 -1.62 0.21 -2.49 -0.39 1.06 CCDC64 3.31 7.75 5.53 -2.44 1.48 -3.64 -0.26 0.80 CD3G 3.48 7.61 5.55 -1.15 2.55 -2.43 -1.07 0.74 CD8B 7.17 4.02 5.60 -1.45 3.17 -1.25 1.61 0.56 KLRC2 8.64 2.96 5.80 -1.23 2.34 -1.30 -0.54 0.98 TC2N 3.40 8.20 5.80 -1.73 0.49 -2.40 -0.56 0.83 SH2D1A 4.78 6.87 5.82 -1.65 1.37 -2.11 -0.11 0.36 PRKCQ 2.56 9.21 5.88 -2.66 1.24 -4.58 0.27 1.13 SLFN5 2.08 9.88 5.98 -1.17 0.11 -2.23 -1.04 1.30 C12orf75 2.75 9.28 6.01 -0.18 5.94 -3.42 -1.20 1.09 GPR174 3.77 8.39 6.08 -1.03 0.75 -1.53 -0.44 0.76 CLDND2 9.91 2.32 6.11 -1.68 7.95 -1.50 0.17 1.24 CLUHP3 3.48 8.76 6.12 -1.90 1.22 -2.94 -1.24 0.86 LYPD2 9.31 2.95 6.13 -2.31 -1.15 -0.58 3.06 1.04 ADGRG1 8.04 4.25 6.15 -1.72 4.46 -2.12 -0.60 0.62 FCER1A 8.97 3.33 6.15 -1.62 -1.44 -1.35 -0.67 0.92 TIGIT 5.65 6.80 6.22 -2.62 -0.58 -2.52 0.63 0.18 BCL9L 2.87 9.62 6.25 -2.27 0.90 -3.68 -1.27 1.08 OAS3 2.08 10.44 6.26 -0.37 -0.24 -0.43 0.06 1.34 NOG 4.65 7.96 6.30 -0.70 0.89 -1.09 -0.77 0.53 RASGRP1 2.50 10.28 6.39 -1.64 0.80 -3.00 -0.57 1.22 CD8A 7.16 5.63 6.40 -1.64 6.96 -2.27 1.28 0.24 TRIB2 2.01 10.92 6.47 -0.91 1.31 -2.85 -0.35 1.38 SBK1 4.50 8.46 6.48 -1.84 3.39 -3.01 -0.62 0.61 SAMD3 6.00 6.99 6.49 -2.46 4.94 -3.39 -0.09 0.15 KLRG1 8.54 4.49 6.52 -1.91 1.19 -2.03 -0.99 0.62 TCF7 2.09 10.96 6.53 -1.46 -0.01 -2.57 -0.47 1.36 ITK 2.08 11.01 6.55 -1.49 0.72 -3.24 -0.32 1.36 GZMH 9.77 3.43 6.60 -0.95 6.44 -0.61 2.27 0.96 KLRC3 11.13 2.13 6.63 -1.61 1.91 -1.30 -0.57 1.36 TARP 8.86 4.45 6.65 -1.74 1.23 -1.45 0.85 0.66 TBX21 7.44 5.98 6.71 -2.32 5.92 -3.08 -0.49 0.22 S1PR5 8.98 4.57 6.78 -2.16 3.74 -2.54 -1.24 0.65 M AN US CR IP T AC CE PT ED ACCEPTED MANUSCRIPTRORA 5.94 7.80 6.87 -1.42 1.15 -1.72 -0.28 0.27 THEMIS 3.64 10.17 6.91 -1.40 2.10 -2.48 -0.25 0.95 KLRK1 10.48 3.67 7.08 -2.51 3.08 -2.24 0.06 0.96 RSAD2 2.59 11.61 7.10 -0.32 -0.21 -0.36 -0.01 1.27 PPP2R2B 9.39 5.19 7.29 -1.80 3.24 -1.92 0.06 0.58 KLRC4 11.23 3.60 7.41 -1.26 2.59 -1.36 -0.66 1.03 GZMK 11.27 3.75 7.51 -2.46 0.46 -1.58 1.62 1.00 FGFBP2 12.38 3.10 7.74 -1.42 4.20 -1.23 0.20 1.20 DOC2GP 3.05 12.63 7.84 -1.39 -0.19 -1.79 0.39 1.22 KIF19 12.85 3.41 8.13 -0.43 25.31 -1.48 1.22 1.16 CCR4 2.66 13.82 8.24 -1.98 -0.60 -2.62 -0.19 1.35 PYHIN1 7.34 9.24 8.29 -2.15 2.34 -2.53 0.18 0.23 IFIT1 5.29 11.41 8.35 -0.40 -0.27 -0.38 0.12 0.73 GOLGA8A 2.61 14.18 8.40 -1.58 1.02 -3.01 -0.74 1.38 GOLGA8B 2.40 14.45 8.42 -1.38 1.15 -2.98 -0.24 1.43 PRSS23 12.13 4.75 8.44 -1.71 3.09 -1.83 -0.68 0.88 FASLG 8.16 8.84 8.50 -2.03 2.82 -2.49 -0.75 0.08 EOMES 7.91 9.13 8.52 -2.42 2.42 -2.77 0.05 0.14 IL2RB 6.84 11.19 9.02 -2.56 0.46 -2.93 -1.43 0.48 FCRL6 11.67 6.97 9.32 -1.34 7.25 -1.82 0.12 0.50 TRIM74 11.65 7.05 9.35 -2.28 0.67 -2.28 -0.61 0.49 CD160 14.15 5.13 9.64 -1.90 2.64 -1.84 -0.12 0.93 ZNF683 16.57 3.80 10.19 -1.63 4.44 -1.26 0.89 1.25 M AN US CR IP T AC CE PT ED ACCEPTED MANUSCRIPTA 0 200 400 Pl at el et s x1 0^ 9/ L 36 37 38 39 40 41 M ax Te m p ( o C ) 6 8 10 12 14 Hg b g /dL B 0 5 10 15 20 25 Do se (m g/ kg /d ay ) Steroid* Cyclosporine anakinra canakinumab infliximab vedolizumab tadekinig Time (days)...
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...An animal model of hemophagocytic lymphohistiocytosis (HLH): CD8+ T cells and interferon gamma are essential for the disorder....
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...Notably, IFNγ is the cytokine most implicated in driving familial forms of HLH(4),...
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Journal Article•DOI•

A multicentre, randomised, double-blind, placebo-controlled trial with the interleukin-1 receptor antagonist anakinra in patients with systemic-onset juvenile idiopathic arthritis (ANAJIS trial)

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Pierre Quartier¹, Florence Allantaz, Rolando Cimaz, Pascal Pillet, Claude Messiaen, Christophe Bardin, Xavier Bossuyt, Anne Boutten, Jacques Bienvenu, Agnès Duquesne, O. Richer, Damien Chaussabel, Agnes Mogenet, Jacques Banchereau, Jean-Marc Tréluyer, Paul Landais, Virginia Pascual - Show less +13 more•Institutions (1)

Necker-Enfants Malades Hospital¹

01 May 2011-Annals of the Rheumatic Diseases

TL;DR: Anakinra treatment is effective in SJIA, at least in the short term, and is associated with normalisation of blood gene expression profiles in clinical responders and induces a de novo IFN signature.

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Abstract: Objectives To assess the effi cacy of the interleukin 1 receptor antagonist anakinra in systemic-onset juvenile idiopathic arthritis (SJIA). Methods A multicentre, randomised, double-blind, placebo-controlled trial was conducted. The primary objective was to compare the effi cacy of a 1-month treatment with anakinra (2 mg/kg subcutaneous daily, maximum 100 mg) with a placebo between two groups each with 12 patients with SJIA. Response was defi ned by a 30% improvement of the paediatric American College of Rheumatology criteria for JIA, resolution of systemic symptoms and a decrease of at least 50% of both C-reactive protein and erythrocyte sedimentation rate compared with baseline. After month 1 (M1), patients taking placebo were switched to anakinra. Secondary objectives included tolerance and effi cacy assessment for 12 months, and analyses of treatment effect on blood gene expression profi ling. Results At M1, 8/12 responders were receiving anakinra and 1 responder receiving placebo (p=0.003). Ten patients from the placebo group switched to anakinra; nine were responders at M2. Between M1 and M12, six patients stopped treatment owing to an adverse event (n=2), lack of effi cacy (n=2) or a disease fl are (n=2). Blood gene expression profi ling at enrolment and at 6 months’ follow-up showed one set of dysregulated genes that reverted to normal values in the clinical responders and a different set, including interferon (IFN)-inducible genes, that was induced by anakinra. Conclusions Anakinra treatment is effective in SJIA, at least in the short term. It is associated with normalisation of blood gene expression profi les in clinical responders and induces a de novo IFN signature. Trial Registration Number: NCT00339157.

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538 citations

Journal Article•DOI•

An activating NLRC4 inflammasome mutation causes autoinflammation with recurrent macrophage activation syndrome

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01 Oct 2014-Nature Genetics

TL;DR: A new monoallelic inflammasome defect is described that expands the monogenic autoinflammatory disease spectrum to include MAS and suggests new targets for therapy.

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Abstract: Inflammasomes are innate immune sensors that respond to pathogen- and damage-associated signals with caspase-1 activation, interleukin (IL)-1β and IL-18 secretion, and macrophage pyroptosis. The discovery that dominant gain-of-function mutations in NLRP3 cause the cryopyrin-associated periodic syndromes (CAPS) and trigger spontaneous inflammasome activation and IL-1β oversecretion led to successful treatment with IL-1-blocking agents. Herein we report a de novo missense mutation (c.1009A > T, encoding p.Thr337Ser) affecting the nucleotide-binding domain of the inflammasome component NLRC4 that causes early-onset recurrent fever flares and macrophage activation syndrome (MAS). Functional analyses demonstrated spontaneous inflammasome formation and production of the inflammasome-dependent cytokines IL-1β and IL-18, with the latter exceeding the levels seen in CAPS. The NLRC4 mutation caused constitutive caspase-1 cleavage in cells transduced with mutant NLRC4 and increased production of IL-18 in both patient-derived and mutant NLRC4-transduced macrophages. Thus, we describe a new monoallelic inflammasome defect that expands the monogenic autoinflammatory disease spectrum to include MAS and suggests new targets for therapy.

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513 citations

"Life-threatening NLRC4-associated h..." refers background or result in this paper

...clinically improved ((2) & Fig 2A), demonstrating that IL-18 alone is not sufficient to drive...
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...with our original reports (Fig 2A)(2, 3)....
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...compared with similar profiles in a previously described NLRC4-MAS patient(2), and...
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...NLRC4-MAS patients have extraordinary and chronic elevation of serum IL-18(2, 3); and...
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...patient (V341A), another NLRC4-MAS patient (T337S)(2), and seven NOMID patients....
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Journal Article•DOI•

Mutation of NLRC4 causes a syndrome of enterocolitis and autoinflammation

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Neil Romberg¹, Khatoun Al Moussawi¹, Carol Nelson-Williams¹, Amy L. Stiegler¹, Erin Loring¹, Murim Choi¹, John D. Overton¹, Eric Meffre¹, Mustafa K. Khokha¹, Anita Huttner¹, Brian L. West¹, Nikolai A. Podoltsev¹, Titus J. Boggon¹, Barbara I. Kazmierczak¹, Richard P. Lifton¹ - Show less +11 more•Institutions (1)

Yale University¹

01 Oct 2014-Nature Genetics

TL;DR: The cause of a life-threatening but treatable autoinflammatory disease that underscores the divergent roles of the NLRC4 inflammasome is identified and described, and a previously unreported syndrome featuring neonatal-onset enterocolitis, periodic fever, and fatal or near-fatal episodes of autoinflammation is described.

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Abstract: Upon detection of pathogen-associated molecular patterns, innate immune receptors initiate inflammatory responses. These receptors include cytoplasmic NOD-like receptors (NLRs) whose stimulation recruits and proteolytically activates caspase-1 within the inflammasome, a multiprotein complex. Caspase-1 mediates the production of interleukin-1 family cytokines (IL1FCs), leading to fever and inflammatory cell death (pyroptosis). Mutations that constitutively activate these pathways underlie several autoinflammatory diseases with diverse clinical features. We describe a family with a previously unreported syndrome featuring neonatal-onset enterocolitis, periodic fever, and fatal or near-fatal episodes of autoinflammation. We show that the disease is caused by a de novo gain-of-function mutation in NLRC4 encoding a p.Val341Ala substitution in the HD1 domain of the protein that cosegregates with disease. Mutant NLRC4 causes constitutive IL1FC production and macrophage cell death. Infected macrophages from affected individuals are polarized toward pyroptosis and exhibit abnormal staining for inflammasome components. These findings identify and describe the cause of a life-threatening but treatable autoinflammatory disease that underscores the divergent roles of the NLRC4 inflammasome.

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395 citations

"Life-threatening NLRC4-associated h..." refers background in this paper

...including an infant who succumbed soon after birth(3)....
[...]
...NLRC4-MAS patients have extraordinary and chronic elevation of serum IL-18(2, 3); and...
[...]
...total IL-18 elevation, and the chronic course associated with this mutation(3), further...
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...with our original reports (Fig 2A)(2, 3)....
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Life-threatening NLRC4-associated hyperinflammation successfully treated with IL-18 inhibition.

Citations

Cites background from "Life-threatening NLRC4-associated h..."

Cites background from "Life-threatening NLRC4-associated h..."

References

"Life-threatening NLRC4-associated h..." refers background in this paper

"Life-threatening NLRC4-associated h..." refers background or result in this paper

"Life-threatening NLRC4-associated h..." refers background in this paper

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