10/30/2013

Disclosures

Key Rheumatoid Arthritis-Associated Pathogenic Pathways Revealed by Integrative Analysis of RA Omics Datasets Consultant: IGNYTA

Funding: Rheumatology Research Foundation By John W. Whitaker, Wei Wang and Gary S. Firestein

DNA methylation and regulation The RA methylation signature in FLS

DNA methylation – DNMT1 (maintaining methylation) OA – DNMT3a, 3b (de novo methylation)

RA

% of CpG methylation: 0% 100% Nakano et al. 2013 ARD

AA06 AANAT AARS ABCA6 ABCC12 ABCG1 ABHD8 ABL2 ABR ABRA ACACA ACAN ACAP3 ACCSL ACN9 ACOT7 ACOX2 ACP5 ACP6 ACPP ACSL1 ACSL3 ACSM5 ACVRL1 ADAM10 ADAM32 ADAM33 ADAMTS12 ADAMTS15 ADAMTS19 ADAMTS4 ADAT3 ADCK4 ADCK5 ADCY2 ADCY3 ADCY6 ADORA1 ADPGK ADPRHL1 ADTRP AFAP1 AFAP1L2 AFF3 AFG3L1P AGAP11 AGER AGTR1 AGXT AIF1L AIM2 AIRE AJUBA AK4 AKAP12 AKAP2 AKR1C2 AKR1E2 AKT2 ALAS1 ALDH1L1-AS1 ALDH3A1 ALDH3B1 ALDH8A1 ALDOB ALDOC ALOX12 ALPK3 ALS2CL ALX4 AMBRA1 AMPD2 AMPD3 ANGPT1 ANGPT2 ANGPTL5 ANGPTL6 ANK1 ANKMY2 ANKRD29 ANKRD37 ANKRD53 ANO3 ANO6 ANO7 ANP32C ANXA6 ANXA8L2 AP1G1 AP2A2 AP2M1 AP5B1 APBA2 APC APCDD1 APOBEC3B APOBEC3G APOC1 APOH APOL6 APOLD1 APOM AQP1 AQP10 AQP6 AQP9 ARAP1 ARHGAP24 ARHGAP42 ARHGEF19 ARHGEF25 ARHGEF3 ARHGEF37 ARHGEF7 ARL4C ARL6IP 5 ARL8B ARMC3 ARNTL2 ARPP21 ARRB1 ARSI ASAH2B ASB10 ASB2 ASCL2 ASIC4 ASPH ATF3 ATF7 ATL1 ATL3 ATP10A ATP1A1 ATP1A4 ATP2C1 ATP5A1 ATP5EP2 ATP5L2 ATP6V0CP3 ATP6V1C1 ATP6V1E2 ATXN7L1 ATXN7L2 AVPI1 AXIN2 B3GNT7 B3GNT8 B3GNTL1 BACH1 BAG3 Differential methylated in RA FLS BAIAP2L2 BANP BATF BATF2 BBS2 BCAS4 BCAT1 BCL7C BDKRB2 BEGAIN BEST1 BEST3 BFSP1 BHLHE22 BICC1 BID BIRC7 BLCAP BLVRA BMP4 BMP6 BMX BPI BRD2 BRD4 BRF1 BRP44L BTBD11 BTBD19 BTBD3 BTC BTF3P11 BTG2 BTG3 BTNL2 BUD31 BZRAP1 BZRAP1-C9orf142 C9orf170 C9orf66 C9orf71 CA3 CA4 CA9 CABLES1 CABP2 CACNA1E CACNA1F CACNA1S CACNB2 CACNG1 CACNG6 CADM3 CALCRL CALHM3 CALML6 CAP2 CAPG CAPS CAPZA3 CARD11 CARD14 CARD16 CARD17 CARD6 CASKIN2 CASP8 CASQ1 CATSPERB CAV2 CAV3 CBFB CCDC105 CCDC117 CCDC129 CCDC141 CCDC164 CCDC19 CCDC22 CCDC25 CCDC62 CCDC63 CCDC8 CCDC80 CCDC83 CCDC86 CCDC91 CCL14-CCL15 CCL15 CCL18 CCL2 CCL5 CCM2 CCR10 CCR2 CCR7 CCRL2 CD109 CD164L2 CD177 CD180 CD248 CD274 CD276 CD300LB CD34 CD38 CD3EAP CD40 CD58 CD59 CD7 CD70 CD74 CD81 CD93 CD96 CDC42EP1 CDC42EP3 CDC42SE1 CDCP2 CDH11 CDH13 CDH26 CDH5 CDHR5 CDK16 CDK5 CDKL2 CDKN1C CDSN CDT1 CEBPA CELF3 CENPBD1 CEP135 CEP164 CEP85L CEP97 CETN1 CFD CHD3 CHI3L1 CHI3L2 CHIA CHID1 CHN2 CHRAC1 CHRM4 CHRM5 CHRNB1 CHRNB4 CHRNE CHST2 CHST6 CHST9 CILP CILP2 CITED4 CIZ1 CKB CKMT2 CLCF1 CLCNKA CLDN11 CLDN12 CLDN15 CLDN16 CLDN25 CLEC11A CLEC12A CLEC1A CLEC3A CLEC3B CLIC2 CLLU1 CLMP CLN5 CLPSL2 CLSTN3 CLU CLUL1 CMIP CNGA3 CNIH CNKSR1 CNP CNTFR CNTN2 CNTN6 CNTNAP4 COBL COL12A1 COL16A1 COL18A1 COL1A1 COL1A2 COL23A1 COL2A1 COL9A3 COLEC11 COLEC12 COLQ COMMD1 COMMD3 COMMD3-BMI1 COMP COMT CORIN CORO6 COX14 COX6B2 CPA1 CPM CPNE2 CPNE5 CREB5 CREM CRIM1 CRIP1 CRISPLD2 • 2,375 differentially methylated genes were compared to the CRY1 CRY2 CRYM CSF1 CSF2 CSGALNACT1 CSN3 CSNK1G2-AS1 CSNK2B CSPG4 CSRNP1 CSTB CTDSP1 CTF1 CTGF CTHRC1 CTRB1 CTSK CTTN CTXN3 CUEDC2 CUL7 CX3CL1 CXCL10 CXCL5 CXCL6 CXCR5 CXorf1 CXorf57 CXXC5 CYB561 CYB5R3 CYHR1 CYP17A1 CYP1A1 CYP21A1P CYP21A2 CYP26C1 CYP27B1 CYP2F1 CYP3A5 CYR61 CYS1 CYSLTR1 CYTIP DAB2IP DALRD3 DAOA DAPK3 DAPL1 DBH DCAF4 DCBLD1 DCC DCD DCDC2B DCHS1 DCN DCPS DCT DDAH1 DDAH2 DDR1 DDX19B DEAF1 DEF6 DEFB1 DEFB113 DEFB115 DEGS2 DERL1 DESI1 DFNB31 DGCR9 DGKA DHH DHRS12 DHRS3 DHRS4 DHRS7 DHRS7C DHRS9 DHX15 DHX16 DIO2 DIO2-AS1 DISP1 DKFZP434A062 DKFZp434J0226 DKFZP434K028 DKFZp434L192 DKFZp566F0947 DLEC1 DLG1 DLG2 DLGAP1 DLGAP2 DLK2 DLL1 DLL4 DLX3 DLX4 DLX6 DLX6-AS1 DMAP1 DMBT1 DMBX1 DMKN DMP1 DMRTA2 DNAH12 DNAH2 DNAI2 DNAJC7 DNASE1 DNMT3A DNTTIP1 DOCK3 DOCK9 DOK1 DOM3Z DONSON KEGG pathway database DOT1L DPCR1 DPEP1 DPF1 DPH1 DPYSL2 DPYSL5 DRD3 DRD4 DSCR4 DST DTHD1 DTNA DTWD2 DTYMK DUOX2 DUPD1 DUSP3 DUSP6 DUSP8 DVL1 EDARADD EDDM3A EDIL3 EDNRB EEF1D EEF2 EFCAB4B EFHD1 EFR3A EGF EGFLAM EGOT EHD4 EIF2AK4 EIF2D EIF4G1 EIF5A2 ELANE ELAVL4 ELF1 ELF3 ELK4 ELMO1 ELMO3 EMB EMBP1 EMX2 EMX2OS ENAH ENC1 ENDOU ENKUR ENO1-AS1 ENPP3 ENPP6 EPGN EPHX2 EPPK1 EPS15 EPS8L1 EPSTI1 ERI1 ERMAP ERN1 ERRFI1 ERVFRD-1 ESAM ESCO2 ESM1 ESR1 ESRP2 ETS1 EVI2A EVPL EVX2 EXOC3L1 EXOC3L4 FABP4 FABP5 FAIM3 FAM101A FAM106A FAM108C1 FAM109A FAM110A FAM111B FAM124A FAM124B FAM129B FAM131A FAM135B FAM13A-AS1 FAM167B FAM170B FAM176A FAM180B FAM184A FAM187B FAM19A3 FAM20B FAM213A FAM217B FAM228B FAM26E FAM27A FAM45B FAM59A FAM71B FAM71E2 FAM75E1 FAM8A1 FAM9A FARP1 FAS FBLIM1 FBN3 FBXL22 FBXO3 FBXO44 FBXW7 FCHSD1 FCRL6 FERD3L FERMT3 FGD4 FGD5 FGF1 FGF11 FGF19 FGF20 FGF5 FGFBP2 FGFR2 FGL2 FGR FHL2 FITM1 FKBP10 FKBP5 FLI1 FLI1-AS1 FLJ27354 FLJ31485 FLJ33360 FLJ35776 FLJ37505 FLJ39051 FLJ42289 FLJ42709 FLJ42969 • 20 KEGG pathways were identified as significantly enriched FLJ45079 FLNC FMN1 FMNL1 FMOD FNDC9 FOLR4 FOSL1 FOXC1 FOXD2 FOXF2 FOXG1 FOXJ1 FOXL1 FOXO1 FOXP1 FPR2 FPR3 FRAS1 FRK FRMD1 FRMD4B FRMD6 FRMD8 FSCN1 FSCN2 FTH1 FTLP10 FURIN FXYD1 FXYD3 FXYD7 FYB FYN FZD6 G6PC GAB2 GABBR1 GAL GAL3ST4 GALK1 GALNT12 GALNT6 GALNTL2 GAS2 GAS7 GATAD2B GATM GBAP1 GBX1 GC GCFC1 GCLC GCNT1 GDNF GDPD3 GEM GFAP GFI1 GGH GGT1 GIMAP4 GIPC1 GJB2 GJC2 GJD3 GLA GLDN GLIPR1 GLIS1 GLIS3 GLP2R GLT25D2 GMPR GNE GNG10 GNG12-AS1 GNG2 GNPDA1 GOLGA4 GOLGA8C GON4L GPATCH8 GPBAR1 GPC2 GPD2 GPER GPR1 GPR108 GPR133 GPR179 GPR183 GPR55 GPR62 GPR75 GPR75-ASB3 GPR84 GPR88 GPRC5A GPSM1 GPT GPT2 GPX3 GRAMD1A GRAMD1B GRAMD2 GRAMD3 GRB10 GRB7 GREB1 GREM1 GRHL3 GRIA1 GRIK1-AS1 GRIK4 GRM2 GRM8 GRXCR1 GSDMC GSDMD GSG1 GSPT1 GSTCD GTSF1 GUCY1B2 GUK1 GZF1 H6PD HAPLN1 HAUS1 HCAR1 HCG22 HCG4B HCRT HCRTR1 HDAC11 HDAC9 HDGF HEATR8 HEATR8-TTC4 HEMGN HERC5 HES5 HEYL HGS HHAT HHATL HHIP HHIP-AS1 HHIPL1 HIAT1 HIBADH HIF1A-AS2 HIGD1C HILS1 HIPK3 HIST1H1A HIST1H1T HIST1H3A HIST1H4A HIST1H4D HIST3H2BB HK2 HKDC1 HLA-DMA HLADifferentially-DMB HLA-DPA1 HLA-DPB1 HLA-DQA1 HLA-DRB1 HLA-DRB6 HLA-F-AS1 HLA-J HLX HMHA1 HMOX1 HMOX2 HMX2 HNF1A HNRNPH2 HNRNPKP3 HOMER3 HOTAIR HOXA1 HOXA 2 HOXC4 HOXD10 HPD HPSE • The KEGG RA pathway is most enriched! HRAS HRASLS5 HSD17B14 HSD3B7 HSF2BP HSPA2 HSPG2 HTR1D HTRA1 HTRA4 IBTK ICAM2 ICAM4 ICAM5 ID3 IDO2 IFI16 IFITM1 IFLTD1 IFNGR2 IFRD1 IGF1 IGF2R IGSF6 IL11RA IL12B IL12RB1 IL17RD IL17REL IL18 IL18BP IL1B IL1RAPL1 IL1RL1 IL1RN IL22RA1 IL23R IL27RA IL31RA IL32 IL6 IMMP2L IMPA2 INHA INPP5A INSR INTS12 IP6K3 IPO5 IPO9 IQCA1 IQCH-AS1 IQCJ IQCJ-SCHIP1 IRF8 IRS1 IRX3 ISG20 ISYNA1 ITGA10 ITGA4 ITGA7 ITGAE ITGB4 ITGBL1 ITIH2 ITIH6 ITPKB ITPKC IVL IZUMO1 JAZF1 JDP2 JMJD1C JPH2 JTB JUP KAL1 KANK2 KAZN KBTBD5 KCNA2 KCNA3 KCNAB1 KCNE1 KCNE3 KCNH2 KCNIP1 KCNIP3 KCNJ14 KCNJ16 KCNJ2 KCNQ1DN KCNQ1OT1 KCNS1 KCNS3 KCNT1 KCNU1 KCTD17 KCTD7 KDM2B KDM3B KHK KIAA0087 KIAA0240 KIAA0922 KIAA1644 KIAA1671 KIF7 KIFC2 KIR3DL1 KIRREL3 KIRREL3-AS2 KIRREL3-AS3 KLB KLC2 KLF8 KLHDC7A KLHL2 KLK11 KLRC2 KNCN KRT17 KRT19 KRT2 KRT23 KRT26 KRT31 KRT32 KRT34 KRT4 KRT5 KRT6A KRT6B KRT75 KRT78 KRT8 KRT83 KRT85 KRTAP1-1 KRTAP12-4 KRTAP1-5 KRTAP16-1 KRTAP17-1 KRTAP2-1 KRTAP24-1 KRTAP26-1 KRTAP3-1 KRTAP4-7 KRTAP4-9 KRTAP9-8 KTN1-AS1 KY LACTB2 LAG3 LAIR1 LAMA2 LAMA4 LAMB3 LARP1 LARP4 LASP1 LAYN LBH LBX2 LCAT LCMT1 LCN2 LCP2 LDB3 LDLR LEFTY2 LEPREL4 LFNG LGALS12 LGALS17A LGALS3BP LGI1 LGI4 LGR6 LHFPL2 LHPP LIMCH1 LIMD1 LIME1 LIMK1 LIMS2 LIN28B LIN9 LINC00114 LINC00163 LINC00189 LINC00239 LINC00242 LINC00244 LINC00293 LINC00310 LINC00410 LINC00460 LINC00467 LINC00473 LINC00478 LINC00482 LINC00514 LINC00523 LINC00605 LINC00606 LINGO4 LIPA LIPE LMBRD1 LMF1 LMNA LMO1 LMO2 LMO3 LMO7 LMX1A LNPEP LNX1 LNX1-AS2 LOC100127888 -AS1 LOXL3 LOXL4 LPCAT2 LPL LPP LPXN LRP11 LRP1B LRP5L LRRC15 LRRC27 LRRC32 LRRC33 LRRC56 LRRC8C LRRIQ4 LRRN2 LRRN4 LSM3 LTBP4 LTC4S LTF LY6D LY6G6D LY6G6E LY86-AS1 LY9 LYNX1 LYRM2 LYZL4 MACC1-AS1 MAF MAFA MAFG MAGED1 MAGI2 MAL MAL2 MALL MAP1LC3B2 MAP3K1 MAP3K8 MAP9 MAPK10 8-Mar MARCKSL1 MARK2 MARVELD1 MAST2 MATN2 MATR3 MBD4 MBL2 MBNL1 MBP MC3R MCC MCCD1 MCF2 MCM3AP MCM3AP-AS1 MCMDC2 MDC1 ME3 MEFV MEOX1 METAP1 METRN MFAP2 MFSD6L MGARP MGAT1 MGAT3 MGAT4B MGAT4C MGAT5B MGC12916 MGC12982 MGC2889 MGP MGST1 MGST2 MIA MIA2 MIA-RAB4B MICALCL MID1 MIR103A2 MIR103B2 MIR1180 MIR1182 MIR1200 MIR1203 MIR1204 MIR1228 MIR1231 MIR1248 MIR125B1 MIR125B2 MIR1260B MIR1276 MIR1282 MIR128-2 MIR1286 MIR1306 MIR130B MIR137 MIR141 MIR143HG MIR146A MIR146B MIR153-2 MIR155 MIR155HG MIR185 MIR190A MIR191 MIR1915 MIR192 MIR193A MIR194-2 MIR195 MIR1976 MIR199B MIR200C MIR2052 MIR205HG MIR206 MIR208A MIR21 MIR210 MIR210HG MIR2117 MIR214 MIR216B MIR219-1 MIR2276 MIR2682 MIR26A1 MIR296 MIR298 MIR29C MIR301B MIR3120 MIR3154 MIR3176 MIR320B1 MIR329-1 MIR329-2 MIR3605 MIR3615 MIR3618 MIR365A MIR3676 MIR3677 MIR3684 MIR425 MIR4254 MIR4269 MIR4270 MIR4437 MIR4456 MIR4470 MIR4489 MIR4513 MIR4646 MIR4648 MIR4655 MIR4669 MIR4686 MIR4692 MIR4708 MIR4710 MIR4740 MIR4761 MIR4784 MIR4787 MIR497 MIR5191 MIR523 MIR525 MIR548AV MIR548C MIR548F2 MIR549 MIR5699 MIR572 MIR591 MIR600HG MIR620 MIR623 MIR641 MIR648 MIR885 MIR938 MIR940 MIR941-1 MIR941-2 MIR941-3 MIR941-4 MIR99A MIRLET7BHG MIRLET7C MIRLET7I MITF MKX MLLT4 MMP13 MMP19 MMP27 MMP3 MMRN1 MMRN2 MOV10 MPP4 MPPE1 MRPL23-AS1 MRPL34 MRPL42P5 MRPL55 MRPS28 MRPS30 MS 4A3 MSGN1 MSI2 MSMP MSRB3 MST1P9 MSX2 MT1G MT1HMethylated MT1L MTA1 MTHFD1 MTHFSD MTIF3 MTMR11 MTO1 MTSS1L MUC12 MUC2 MUC6 MUM1 MUSTN1 MX2 MXRA5 MXRA8 MYBPC1 MYBPH MYEF2 MYEOV 2 MYF5 MYF6 MYH1 MYH10 MYH15 MYH7 MYL10 MYL5 MYL9 MYLK2 MYO15A MYO18A MYO1C MYO1G MYOC MYOG MYOM1 MYOZ2 MYOZ3 MYPN NADK NALCN NAPG NAV1 NAV2 NBL1 NCAM2 NCCRP1 NCEH1 NCKAP5 NCOA6 NCOA7 NCS1 NDRG1 NDUFAF3 NDUFS2 NEDD1 NEDD4 NEDD4L NEK6 NEURL3 NEUROD6 NEXN NFATC1 NFATC3 NFIA NFIC NFYB NGF NGFR NID1 NINJ2 NISCH NKIRAS2 NME2 NMNAT2 NNAT NNMT NOC2L NOD2 NODAL NOS3 NOTCH3 NOTCH4 NOTO NOX4 NPAS2 NPBWR2 NPEPL1 NPHS2 NPR3 NPTXR NPW NPY1R NR1I3 NR2E3 NRAP NRARP NRBP2 NRG1 NRXN2 NT5C2 NT5DC2 NTRK1 NUDT4 NUDT4P1 NUMB NXF1 NXPH2 OAS3 OBP2B OBSCN OCIAD2 OCSTAMP ODF3B OLFML3 OPN1SW OPRM1 OPTC OR10A5 OR10G4 OR10H2 OR10J1 OR10X1 OR2C3 OR2F2 OR4A16 OR4D2 OR51E2 OR5D13 OR6P1 OR6T1 OR6Y1 OR7E91P ORC2 OSR1 OSR2 OST4 OTOL1 OTX2 OTX2-AS1 OVCH2 OXCT1 OXT P2RX6 P2RX7 P2RY11 P2RY2 P2RY6 PACRG-AS1 PAK6 PALLD PAM PAMR1 PAN2 PANX3 PAOX PAPPA PAPPA2 PAPSS2 PAQR7 PARG PARVB PARVG PATL1 PCBD1 PCDHAC2 PCDHB13 PCDHB2 PCDHGC3 PCED1B-AS1 PCGF5 PCK1 PCOLCE-AS1 PCTP PCYT2 PDCD1LG2 PDE1A PDE4A PDE4D PDE4DIP PDE6B PDIA3P PDIA6 PDLIM4 PDYN PDZK1IP1 PEAR1 PEBP4 PFKM PGA3 PGA5 PGCP1 PGLYRP3 PHACTR2 PHF11 PHKA2-AS1 PHLDA2 PHLDB1 PHLDB2 PHPT1 PHYHD1 PIEZO2 PIGV PIK3C2B PIK3CG PIK3R1 PIN1P1 PIPSL PISD PITPNM3 PIWIL2 PKD2 PLA1A PLA2G2A PLA2G3 PLCB2 PLCH2 PLCZ1 PLD6 PLEC PLEKHA4 PLEKHG1 PLEKHG5 PLEKHG6 PLEKHG7 PLEKHN1 PLEKHS1 PLK1S1 PLXNA4 PLXNB1 PLXNB2 PMAIP1 PMEPA1 PNMA2 PNMT PNPLA2 POC5 PODNL1 PODXL2 POMC POMGNT1 POTED POU2AF1 POU2F1 POU5F1 POU6F1 PPAN PPAN-P2RY11 PPP1CC PPP1R13L PPP1R17 PPP1R18 PPP1R32 PPP2R2B PPP2R5C PPT2 PPT2-EGFL8 PQLC3 PRC1 PRDM10 PRDM11 PRDM6 PRDX1 PRG4 PRKAA2 PRKACA PRKAG3 PRKCG PRKCZ PRKD1 PRKD2 PRM1 PRO1768 PROC PROCR PROKR1 PROL1 PROSAPIP1 PRPF6 PRR15L PRR4 PRR5-ARHGAP8 PRRT1 PRSS54 PRSS8 PRX PSD3 PSMA4 PSMB9 PSMD5 PSORS1C1 PSTPIP1 PTGDR PTH2 PTK6 PTPN7 PTPRK PTRF PTTG1IP PXDNL PYCARD PYCR1 PYGB QSOX1 QSOX2 R3HDM2 RAB17 RAB19 RAB4A RAB7L1 RAET1E RANBP1 RANGAP1 RAPGEF4 RAPGEF4-AS1 RAPGEFL1 RARRES1 RARRES3 RASAL1 RASAL2 RASAL2-AS1 RASSF2 RASSF5 RASSF9 RBFOX3 RBM41 RBP5 RCAN3AS RCC2 RD3 RDH5 REC8 REG3G RFFL RFT1 RFX8 RGMA RGS22 RHBDF2 RHBDL3 RHOBTB1 RHOD RHOJ RHOU RIN2 RIPK1 RNASE2 RNASE7 RNF103-CHMP3 RNF112 RNF114 RNF144B RNF182 RNF187 RNF208 RNF222 RNF39 RNH1 RNPS1 RNU86 ROBO4 RORA RORC RP1L1 RPH3AL RPL21P44 RPL26L1 RPLP0P2 RPS6KL1 RPSAP58 RRAD RRAGB RRP1B RTBDN RTKN RTP4 RUFY3 RUNX1 RUNX1T1 RUNX2 S100A14 S100A4 S100A5 S100A9 S100Z SAA1 SAA2 SAA2-SAA4 SALL4 SAMD10 SAMD13 SAMD9 SBK2 SBSN SBSPON SCAMP4 SCARF1 SCD SCML4 SCN3B SCNN1A SCNN1B SCPEP1 SCRG1 SCRN1 SCT SCUBE1 SDCBP2 SDHAF1 SDK1 SDK2 SEC14L1 SEC14L3 SEC14L4 SEC31B SELENBP1 SELPLG SEMA3A SEMA3B SEMA3F SEMA3G SEMA5B SENP8 SEPP1 12-Sep 4-Sep 8-Sep 9-Sep SERF2 SERPINA1 SERPINA12 SERPINA5 SERPINA6 SESTD1 SETX SFRP5 SFTA1P SGCA SGCG SGIP1 SGK1 SGK2 SGMS2 SH2D2A SH2D3C SH2D4A SH2D4B SH3BGRL3 SH3BP2 SH3RF1 SH3RF2 SHANK2 SHISA2 SHISA6 SIGLEC1 SIGLEC15 SIRPG SIT1 SIX2 SKIL SLA SLAIN1 SLAMF8 SLC10A4 SLC10A6 SLC14A1 SLC16A14 SLC16A3 SLC16A5 SLC17A5 SLC19A1 SLC1A2 SLC20A2 SLC22A1 SLC22A11 SLC22A17 SLC22A18 SLC22A18AS SLC22A20 SLC22A4 SLC23A1 SLC24A5 SLC25A38 SLC25A45 SLC25A47G SLC26A4 SLC29enesA1 SLC2A2 SLC30A1 SLC34A1 SLC35G2 SLC36A2 SLC38A2 SLC38A8 SLC39A7 SLC39A8 SLC41A3 SLC43A3 SLC44A3 SLC44A4 SLC45A1 SLC45A4 SLC47A2 SLC4A1 SLC4A2 SLC4A7 SLC4A8 SLC52A3 SLC5A1 SLC6A19 SLC7A2 SLC9A3R1 SLC9A3R2 SLC9B2 SLCO4A1 SLMAP SLPI SMAD3 SMCR5 SMG6 SMG9 SMOC1 SMOC2 SMPD2 SMPD4 SMU1 SNAI2 SND1-IT 1 SNHG4 SNHG6 SNHG8 SNORA24 SNORA33 SNORA4 SNORA48 SNORA61 SNORA63 SNORA74B SNORA81 SNORD100 SNORD105 SNORD66 SNORD93 SNORD99 SNRK SNUPN SNX2 SOCS3 SOCS5 SOD1 SOHLH1 SORBS2 SORT1 SOSTDC1 SOX15 SP6 SP7 SP9 SPACA4 SPACA5 SPAG6 SPARCL1 SPATA12 SPATA2L SPATS2 SPDEF SPDYA SPDYE4 SPEM1 SPERT SPG20OS SPHK1 SPOCK3 SPON2 SPPL2C SPPL3 SPRED2 SPRR1B SPRR2D SPRR3 SPRR4 SRCRB4D SRGAP2 SRGN SRPRB SRRM3 SRSF3 SS18L2 SSC5D SSH1 SSR4P1 ST13P4 ST14 ST3GAL1 ST3GAL4 ST3GAL6-AS1 ST5 ST6GALNAC2 ST7-OT3 STAB2 STAG3 STAP2 STARD13 STAT5A STEAP1 STEAP1B STEAP2 STEAP4 STK10 STK19 STK24 STK3 STON1-GTF2A1L STON2 STRA6 STX11 STX1B SULT2B1 SUN1 SUN2 SUSD2 SV2A SYBU SYN3 SYNC SYNDIG1 SYNE1 SYNGR1 SYNPO SYNPO2 SYT11 SYT5 T TAB3 TACC2 TACR2 TAF5 TAGAP TAGLN TANC1 TANK TAP1 TAS1R3 TAS2R1 TAS2R20 TBC1D21 TBC1D9B TBPL2 TBR1 TBX10 TBX15 TBX2 TBX6 TCAP TCEA2 TCERG1L TCF21 TCF23 TCIRG1 TCTEX1D4 TEF TEPP TES TEX12 TEX15 TEX26 TEX26-AS1 TEX33 TEX34 TFDP2 TFF3 TGFB1I1 TGFBI TGFBR1 TGFBR3 TGIF1 TGIF2 TGIF2-C20ORF24 TGM3 TH THAP4 THBS4 THEM5 THRB THSD7A THUMPD2 THY1 TIMP3 TINAGL1 TLE2 TLE3 TLE6 TLR1 TLR4 TLR5 TLX1 TLX1NB TM4SF1 TM4SF18 TMCO6 TMEFF1 TMEM100 TMEM119 TMEM121 TMEM145 TMEM174 TMEM182 TMEM185B TMEM19 TMEM196 TMEM204 TMEM212 TMEM225 TMEM232 TMEM235 TMEM237 TMEM30C TMEM37 TMEM45A TMEM50A TMEM88 TMEM8C TMEM92 TMEM95 TMEM98 TMIE TMOD4 TMPRSS11E TNF TNFAIP2 TNFRSF18 TNFRSF6B TNFSF10 TNFSF8 TNIP2 TNNC1 TNNC2 TNNI2 TNNI3 TNNT3 TNPO1 TNS3 TNXA TNXB TOM1L1 TOX2 TP53AIP1 TP53INP1 TP63 TPI1 TPRG1 TPRN TRABD TRAF3IP2 TRAF6 TRAK1 TRAPPC3 TRAPPC8 TREH TREM1 TREM2 TRIB1 TRIB2 TRIL TRIM10 TRIM15 TRIM2 TRIM22 TRIM29 TRIM34 TRIM40 TRIM41 TRIM59 TRIM6 TRIM66 TRIM69 TRIM6-TRIM34 TRIO TRIP10 TRIP4 TRIP6 TRPC3 TRPM1 TSC22D1-AS1 TSC22D2 TSGA10 TSKU TSPAN10 TSPAN32 TSPAN7 TSPYL4 TSSK3 TTC22 TTLL10 TTLL6 TUBA3FP TUBA4B TUBB TUBB2B TWIST1 TXNDC15 TXNRD2 TYSND1 UACA UBXN11 UCN UCN3 UGT2A3 UGT2B7 UHRF1 UNC13D UNC45A UNKL UPK1B UPRT USP44 USP46 USP54 UXS1 VANGL1 VARS2 VAV3 VAX2 VCX2 VEPH1 VEZF1 VGLL4 VIM VPREB1 VPS18 VPS52 VSIG4 VSTM5 VTRNA1-2 VWA1 VWA2 VWA3B VWF WAC WBP11P1 WBP1L WDR59 WDR6 WDR66 WDR86-AS1 WDR90 WFDC11 WFDC3 WFDC6 WFIKKN1 WIBG WIPF1 WNT1 WNT10A WNT10B WNT3 WSB2 WWC2 WWP2 XKR5 XKR9 XRCC6 YBEY YPEL4 ZBED3- AS1 ZBTB16 ZBTB32 ZBTB7C ZC3H12D ZCCHC5 ZDHHC12 ZDHHC17 ZFAT ZFHX4-AS1 ZHX3 ZMAT4 ZMYND10 ZNF212 ZNF215 ZNF22 ZNF238 ZNF239 ZNF267 ZNF280C ZNF280D ZNF295 ZNF385B ZNF436 ZNF438 ZNF638 ZNF658 ZNF83 ZNF844 24 (27%) genes in the pathway; blue=hypo, yellow=hyper ZNF92 ZP1 ZP2 ZP3 ZSWIM6 Whitaker et al. 2013 Genome Medicine

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Differentially Differentially Prioritizing genes through omics integration methylated genes expressed genes

Sequence variants (SNPs) NIH GWAS Gene database

Publically overlap - 357 multi-evidence genes available microarray Methylation - six triple evidence genes Differentially (P=0.0001): HLA-DQA1, methylated ELMO1 … genes GWAS genes

KEGG Pathway analysis of multi-evidence genes KEGG pathway analysis: “RA pathway”

Fold enrichment

*q-values are P-values after multiple test correction; significance threshold = q<0.05; 271 pathway tested. 3.88-fold enriched with 7/89 genes (pink)

KEGG pathway analysis: Jak-STAT signaling Conclusions • Integrative analysis of multiple genome-wide datasets demonstrates non-random identification of RA related genes • The identified genes are enriched in immune and signaling pathways e.g. – Cytokine-cytokine int. – Jak-STAT signaling • Deregulation of these pathways reflects the pathogenesis of disease • Pathways identified through integrative analysis could be novel targets for treatment of RA – e.g. ELMO1 (see Boyle abstract #2735)

2.84-fold enriched with 8/139 genes (pink)

2 10/30/2013

KEGG pathway analysis: Cytokine- int.

2.98-fold enriched with 15/248 genes (pink)

KEGG pathway analysis: Cell adhesion

4.59-fold enriched with 12/129 genes (pink)

3